Nephron Anatomy and Physiology

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Physiology
Topic –Nephron
• The kidneys act as endocrine organs, releasing renin, erythropoietin, and 1,25-dihydroxy-vitamin D3
into the circulation. (MCQ)
• Blood from renal arteries is delivered to the glomeruli
• At one fifth of cardiac output, this is the highest tissue-specific blood flow (MCQ)
• The amount of a substance excreted by the kidney is determined by the amount filtered by the
glomerulus less the amount absorbed plus the amount secreted
• Renal Anatomy
o The kidneys are located in the retroperitoneum.
o The human kidney is multilobed and grossly divided into a cortex and a medulla.
o The basic functional unit of the kidney is the nephron
§ The nephron is composed of a long, thin tubule that is closed at one end
§ (Bowman’s capsule).
§ Bowman’s capsule surrounds a high-pressure capillary network, the glomerulus.
§ Together, Bowman’s capsule and the glomerulus serve as a filtration unit, which
forms the glomerular filtrate that enters the tubule.
o The tubular fluid generated by glomerular filtration is modified by reabsorption and secretion
across the epithelial cells that form the tubule wall.
§ Net movement of water or solutes from the tubular lumen into the interstitium is
referred to as tubular reabsorption.
§ Net transport of substances from the interstitium to the lumen is called secretion.
• Each nephron has its own blood supply , which is composedof two arterioles and two capillary
systems in series
o The first capillary system is a high-pressure capillary glomerulus
§ It favors filtration
§ It is the source of the tubular fluid.
o peritubular capillary system
§ After passing through the afferent arteriole, the glomerulus, and the efferent arteriole,
the blood enters the peritubular capillary system
§ It is a low-pressure system that favors reabsorption.
• There are two types of nephrons
o cortical (about 85%) . (MCQ)
o juxtamedullary (15%).
o Cortical nephrons
§ have short loops of Henle with peritubular capillaries
§ Peritubular capillaries differ depending on their association with different nephrons.
o Juxtamedullary nephrons
§ have long loops of Henle and vasa
§ The vasa recta are long narrow capillary tubules that have a great resistance to
blood flow. (MCQ)
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o A portion of the arterial plasma leaves the glomerulus (ie, the product of filtration) to form the
protein-free tubular fluid.
o The remaining arterial plasma enters the peritubular capillary system or vasa recta.
• The renal tubule consists of the
o proximal convoluted tubule
o the loop ofHenle
o the distal convoluted tubule
o collecting duct that carries the final urine to the renal pelvis and ureter.
• Renal Blood Flow and Glomerular Filtration
o Approximately 25% of cardiac output supplies the kidneys, which account for about 1% of
body mass. (MCQ)
o The high blood flow is necessary to generate the large hydrostatic pressure responsible for
the formation of glomerular ultrafiltrate.
o Most of the renal blood flow goes to the cortex, where the glomeruli are located. (MCQ)
o Autoregulation of Renal blood flow
§ Renal blood flow remains constant over a wide range of arterial pressures.
§ autoregulation is accomplished by increases in afferent arteriolar resistance.
• Renal handling of p-aminohippuric acid (PAH)
o an example of active secretion by a transport-maximum (Tm)-limited mechanism.
(MCQ)
o PAH is foreign to the body and is excreted by filtration plus secretion.
o The active secretory mechanism is located on the basolateral membrane of the proximal
convoluted tubule.
o The PAH carrier is saturable and is inhibited by the drug probenecid.
o The transport of PAH increases linearly with the concentration of PAH
o (PPAH) until the delivery of PAH to the peritubular capillaries increases to the point whereTm
is attained
o Secretion of PAH then becomes constant (TmPAH) and equals about 80 mg/min/1.73 m2
in a young male adult. (MCQ)
o Because PAH is actively secreted in the proximal tubular segment, the TmPAH is a
measure of the functional mass of proximal tubules. (MCQ)
• Renal plasma flow
o Renal plasma flow can be measured by the Fick method. (MCQ)
o Most of the arterial plasma entering the kidneys perfuses the proximal tubular segment.
o Arterial plasma flow entering the kidneys splits into two parallel paths
o One path perfuses the proximal tubular segment used for urine production (ie, secretory
tissue),
o Other path keeps the tissue alive, perfuses inert tissue.
o These facts are used to develop the Fick method for measuring total renal plasma flow using
PAH as the marker
o Under steady-state conditions
§ PAH entering kidneys/min = PAH leaving kidneys/min

o PAH clearance can be used to measure renal plasma flow. (MCQ)

o If it is assumed that the kidneys can remove all of the PAH from arterial
o plasma, then the venous plasma concentration of PAH would be 0, and the Fick equation would be
equal to the clearance of PAH:
o Why CP AH is is about 90% of total RPF but not 100% of total RPF
o Because a fraction of arterial plasma does not perfuse nephrons but rather perfuses
inert tissue, the venous plasma concentration of PAH is not 0.
o PvPAH concentration is about 10% of PaPAH when PPAH levels are low .
o Thus, if CPAH is measured when PPAH levels are low, it is about 90% of total RPF
o CPAH measures effective renal plasma flow (ERPF)
o Total renal plasma flow is designated as RPF .
o Glomerular filtration rate
o The rate at which tubular fluid is produced is termed the glomerular filtration rate (GFR)
o Normally GFR = 120–125 mL/min (MCQ)
o The driving force for glomerular filtration is the net ultrafiltration pressure, which always
favors fluid movement out of the capillaries.
o The glomerulus is a high-pressure capillary system, and the peritubular capillary system
(as well as the vasa recta) is a low-pressure system.
o Thus, the GFR can be related to Starling’s forces:
hydrostatic pressures (Pgc)
colloid osmotic pressure (gc)
o Variables that influence GFR include

o Hydrostatic pressures in the glomerulus and Bowman’s capsule
o Oncotic pressures in the glomerular plasma and filtrate
o Permeability of glomerular barriers
o Surface area available for filtration
o Negative electrical charge on filtered solutes (which hinders filtration)
o Renal blood flow
o In the glomerulus, hydrostatic pressures (Pgc) provide the driving force for filtration
o Starling’s forces are also responsible for reabsorption across the peritubular capillary endothelium.
o Because tubular filtrate is virtually protein free, proteins are concentrated in the glomerulus, and
colloid osmotic pressure (gc) increases as blood flows through the glomerulus
o As gc rises and meets the hydrostatic pressure, filtration equilibrium (ie, where net filtration
pressure is 0) is attained.
o An increase in blood flow through the glomerulus increases the GFR because it increases the distance
over which filtration occurs before equilibrium is reached.
o Clearance
o Clearance is defined as the volume of arterial plasma required to produce the amount of
substance X excreted in the urine per minute
o where
o Cx = clearance of X (mL/min)
o Ux = urine concentration of X (mg/mL)
o Px = arterial plasma concentration of X (mg/mL) V = urine flow (mL/min)
o Clearance is usually measured in the steady state
o If a substance is present in arterial plasma but is not excreted (Ux = 0), then the clearance of
that substance is 0. (MCQ)
o If a substance is secreted into the tubular fluid (eg, a foreign substance), then it cannot be
excreted at a rate faster than it is presented to the kidneys via the renal arteries (ie,clearance
cannot exceed renal plasma flow).
o If a substance X is freely filterable and is not secreted or reabsorbed by the tubules, then
the clearance of X can be used to measure the GFR.
o Thus, the GFR for substance X is identical to its clearance:
o The GFR of a particular substance can be measured by the clearance method as long as the
substance satisfies the following criteria. (MCQ)
o The substance should be freely filtered (ie, not bound to plasma protein)
o It should not be reabsorbed or secreted.
o It should not be stored or metabolized by the kidneys
o It should be nontoxic.
o It should not alter the GFR.
o It should be easily measurable in plasma and urine.
o A substance that meets the criteria for measurement of the GFR is inulin, a fructose extracted from
dahlia roots.
Creatinine clearance (Ccr)
In general, Ccr overestimates the GFR by 15–20% because the GFR decreases with age but Pcr
remains constant due to decreased muscle mass.
Consider the following example of a GFR calculation:
A 72-kg patient has a urine volume of 2.88 L/24 h. The Ucr is 0.9 mg/mL, and the Pcr is0.8 mg/100
mL.
Urine flow = V = 2880 mL/24h = 2.0 mL/min
1440 min/24h
Pcr = 0.8 mg = 0.008 mg/mL
100 mL
GFR = Ucr XV = (0.9 mg/mL X 2 mL/min) = 234 mL/min
Pcr 0.008 mg/mL
• Filtration fraction (FF) (MCQ)

o fraction of renal plasma volume (RPF) that is filtered at the glomerulus
o FF = GFR RPF
o RPF =BF (1− Hct), (MCQ)
o Normally 20% of the RBF is filtered, and the remainder flows into the peritubular capillary.
(MCQ)
o An increase in FF causes an increased protein concentration in peritubular capillary blood.
o Increased postglomerular resistance increases FF and vice versa.
o Renal blood flow (RBF) can be calculated from the RPF ifthe hemat-
o ocrit (Hct, %) is known:

o The GFR increases when glomerular capillary pressure is increased and decreases when
glomerular capillary pressure is decreased.
o Alterations in preglomerular and postglomerular renal vascular resistance influence RBF ,
GFR, and FF
• Transport Mechanisms of Nephron Segments

o Proximal Tubule
§ Loose tight junctions make the proximal tubule water permeable.
§ The bulk of filtered small solutes is absorbed.
• 60% of filtered Na+,Cl, K+, Ca2+, and H2O is absorbed(MCQ)
• 90% of filtered HCO3 is absorbed. (MCQ)
§ All filtered glucose and amino acid (100%) is absorbed. (MCQ)
§ Phosphate transport is regulated by parathyroid hormone. (MCQ)
§ Osmolarity does not change due to passive reabsorption of water.
Consequences of independent isolated constrictions or dilations of the afferent and efferent arterioles.
• Loop of Henle
o The volume of fluid reaching the loop of Henle is about one third of the originally filtered
volume.
o The descending limb is water permeable, increasing the osmolarity of the tubular fluid.
o The ascending limb is impermeable to water, decreasing the tubular fluid osmolarity.
§ This segment is known as the diluting segment because hypotonic fluid leaves.
o Mg2+ reabsorption occurs in the loop of Henle. (MCQ)

o The Na+-K+-Cl2 cotransporter is located here and is affected by loop di-uretics (eg,
furosemide). (MCQ)
o Flow through the loop of Henle is relatively slow, allowing the kidney tomaintain a high
medullary osmolarity. (MCQ)
• BARTTER SYNDROME
o Characterized by Na+,K+,and Cl wasting. (MCQ)
o The primary defect is in Cl−reabsorption in the ascending limb of the loop of Henle,
(MCQ)
o It leads to decreased tonicity of the interstitium and an inability to concentrate urine.
o Renin and aldosterone levels are increased(MCQ)
o blood pressure remains low. (MCQ)
o Symptoms include polyuria (excessive urination), nocturia (nighttime urination),
developmental delay , and dehydration.
o The syndrome results in hypokalemic metabolic alkalosis(MCQ)
o Treatment is aimed at converting K+ balance by oral potassium supplementation. (MCQ)
• Distal Nephron
o The distal convoluted tubule and the collecting duct reabsorb variable amounts of water
depending on circulating levels of antidiuretic hormone (ADH) and aldosterone.
o ADH
§ stimulates increased water permeability in the distal convoluted tubule and the
collecting duct(MCQ)
§ makes the tubular fluid isosmotic with the ISF . (MCQ)
o Aldosterone increases Na+ reabsorption and K+ secretion. (MCQ)
o These hormones regulate (MCQ)
§ K+ excretion
§ final urinary concentrations of K+, Na+, and Cl−.
o Two main cell types are present in the distal nephron.
§ Principal cells are involved with Na+ and water transport. (MCQ)
§ Intercalated cells secrete H+ and reabsorb K+.(MCQ)
o These processes allow the kidney to secrete dilute or concentrated urine as necessary to
maintain homeostasis.
o The early distal convoluted tubule is the site of action of thiazide diuretics, which inhibit
the Na+-Cl−cotransporter. (MCQ)
• Regulation of NaCl Excretion
o Because sodium salts are the predominant extracellular solutes, total body sodium determines
extracellular fluid volume. Thus, any change in the amount of sodium in the body affects the
regulation of ECF .
o The primary regulatory systems that respond to changes in body fluid volume are the
§ sympathetic nervous system
§ renin-angiotensin-aldosterone system
§ atrial natruretic factor (ANF
§ ADH or vasopressin.
o The sympathetic nervous system
§ has stretch receptors on blood vessels such as vena cava, cardiac atria, and pulmonary
vessels.

§ A decreased firing rate in the afferent nerves from these volume recep-tors
increases sympathetic outflow from cardiovascular medullary centers.
§ Increased renal sympathetic tone leads to salt reabsorption and activa-tion of the
renin-angiotensin system. (MCQ)
o Aldosterone secretion is controlled by the renin-angiotensin system
§ Granular cells in the wall of renal afferent arterioles , which are part of the
juxtaglomerular apparatus, release renin(MCQ)
§ renin is an enzyme that converts angiotensinogen from the liver to angiotensin I.
(MCQ)
§ Renin production is controlled by three mechanisms
• Decreased sodium chloride delivery past macula densa cells in the thick
ascending limb of the loop of Henle increases renin release. (MCQ)
• Baroreceptors in the wall of the afferent arteriole respond to pressure,
stretch, or shear stress by increasing renin release.
• Stimulation of Beta-adrenergic receptors on the juxtaglomerular granular cells
stimulates renin release. (MCQ)
• Factors influencing renin secretion.
o Inhibitory factors(MCQ)
§ Increased Na+ and Cl– reabsorption across macula densa
§ Increased afferent arteriolar pressure
§ Angiotensin II
§ Vasopressin
o Stimulatory factors(MCQ)
§ Increased sympathetic� �activity via renal nerves
§ Increased circulating� �catecholamines
§ Prostaglandins
• Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme.
• The plasma level of renin is the rate-limiting step in the production of angiotensin II.
• Angiotensin II enhances salt retention by
o increasing sodium reabsorption in the proximal tubule
o by its vasoconstrictor action, which reduces the GFR.
• Angiotensin II also stimulates aldosterone secretion from the zona glomerulosa of the
adrenal gland, causing enhanced Na+ reabsorption by the collecting duct. (MCQ)
• ANF , or atrial natriuretic peptide
o is a peptide released by atrial distention
o inhibits Na+ reabsorption along the collecting duct, thereby causing
natriuresis. ANF may also increase the GFR.
o ANF release is increased by volume expansion and decreased with volume depletion.
• ADH
o increases the water permeability (MCQ)of renal cells in the distal tubule and
collecting duct,
o decreases the volume and increases the osmolarity of urine.
o ADH is stimulated by intravascular volume depletion, thereby promoting
water retention.

o ADH is synthesized in supraoptic and paraventricular nuclei of the
hypothalamus and is released from the posterior pituitary. (MCQ)
• Diabetes insipidus
o a syndrome of ADH deficiency
o associated with polydipsia and polyuria.
§ Hypothalamic DI
§ Nephrogenic DI – defect in the V2 receptor gene or aquaporin 2
gene for ADH.
• Conn syndrome
o benign adenoma or hyperplasia of the zona glomerulosa of the adrenal cortex.
o It is caused by primary hyperaldosteronism due to unregulated production of
aldosterone.
o Aldosterone increases distal Na+ exchange for K+ and H+ ions, resulting in
hypernatremia
§ hypokalemia
§ Metabolic alkalosis results from loss of H+ions,which increases
reabsorption of HCO3−.(MCQ)
§ Increased blood volume inhibits Na+ reabsorption in the proximal
tubule and ADH release. (MCQ)
§ The excess reabsorption of Na+ results in hypertension.
Potassium Regulation
• K+ is filtered, reabsorbed, and secreted by the nephron. (MCQ)

• Most of the filtered K+ is reabsorbed in the proximal tubule. (MCQ)
• Twenty percent is reabsorbed in the thick ascending limb of the loop of Henle ,
through its involvement in the Na+-K+-Cl2 cotransporter. (MCQ)
• K+ balance is achieved when urinary excretion ofK+ equals dietary intake ofK+. (MCQ)
• K+ is passively secreted by the principal cells in the distal nephron via
o K+ channel
o K+-Cl2−cotransporter pathway .
• Reabsorption of K+ occurs in the distal nephron in the intercalated cells via the K+-
H+ exchanger. (MCQ)
• Increased K+ excretion occurs in response to(MCQ)
o High intakes of K+ or Na+
o Increased cell pH in the distal convoluted tubule
o Increased plasma aldosterone levels
Renal Handling of Glucose
• The glucose-filtered load is directly proportional to the plasma glucose concentration.

• Reabsorption of glucose is by secondary active transport via Na+-glucose co-
transport.
• The number of Na+-glucose carriers is, however, limited.
• At plasma glucose concentrations greater than 350 mg/dL, carriers are saturated;
this is the Tm for glucose (MCQ)
Urea Regulation
• Urea is an example of a passively transported substance.
• It is freely filterable
• about 50% of the filtered load is reabsorbed in the proximal tubule. (MCQ)
• the distal tubule and collecting ducts are usually impermeable to urea, (MCQ)
• ADH increases the permeability of the medullary collecting ducts , thereby en-
hancing the osmolality of the medullary interstitium
• Thus, in a water diuresis when ADH is low, the clearance ofurea increases. (MCQ)
• About 40% of the osmolality in the medulla is due to the presence of urea. (MCQ)
Phosphate Regulation
• Most of the filtered phosphate is reabsorbed in the proximal convoluted tubule

• distal nephron.
• Parathyroid hormone inhibits phosphate reabsorption, causing phosphaturia (MCQ)
• Phosphate is a buffer for H+ in the urine and is excreted as H2PO4. (MCQ)
• Renal Calcium Regulation
• Ninety percent of the filtered calcium is passively reabsorbed in the proximal
tubule and thick ascending limb of the loop of Henle. (MCQ)
• Loop diuretics (eg, furosemide) inhibit Ca2+ reabsorption because Ca2+ reabsorption
is coupled with Na+ reabsorption and blocked by loop diuretics. (MCQ)
• Thiazide diuretics increase Ca2+ reabsorption in the distal tubule and collecting
ducts and can be used to treat hypercalcuria
• Parathyroid hormone increases Ca2+ reabsorption in the distal tubule. (MCQ)
Magnesium Regulation
• Mg2+ is primarily reabsorbed in the proximal tubule and thick ascending limb ofthe loop of
Henle. (MCQ)
• Mg2+ and Ca2+ compete for reabsorption in the thick ascending limb. (MCQ)
• Hypercalcemia, therefore, inhibits Mg2+ reabsorption(MCQ)
• Hypermagnesemia inhibits Ca2+ reabsorption. (MCQ)
Concentrating and Diluting Mechanisms
• Generation of a corticomedullary osmotic gradient

o The purpose of the countercurrent mechanism is to increase the osmolality
of the interstitial fluid a nd concentrate urine.
o The countercurrent multiplication principle requires energy and differences
in the membrane characteristics between the two limbs of the loop of
Henle.
o Active ion reabsorption by the thick ascending limb increases the interstitial
osmotic gradient.
• Low water permeability of the ascending limb prevents dilution ofthe interstitial osmotic
gradient.
• High water permeability of the descending limb permits equilibration ofcontents with the
interstitium.
• The osmotic gradient is maintained through (MCQ)
o Passive countercurrent exchange in the vasa recta
o Low fluid flow rates in the tubules and vasa recta
o Regulation of the permeability of collecting ducts to water and urea via
ADH
Topic- Hypoxia
Hypoxemia and Hypoxia
• Hypoxemia is defined as a decrease in arterial PO2

• Hypoxia is defined as a decrease in O2 delivery to, or utilization by, the tissues.
• Hypoxemia is one cause of tissue hypoxia
Hypoxemia
• A - a gradient, or A - a difference
• useful tool for comparing causes of hypoxemia
• A - a gradient is the difference between the PO2 of alveolar gas (PAO 2 ) and the PO2 of
systemic arterial blood (PaO2).
• A - a gradient describes whether there has been equilibration of O2 between alveolar gas and
pulmonary capillary blood (which becomes systemic arterial blood).
• Normally, O2 equilibrates across the alveolar-pulmonary capillary barrier
• Normally , A - a gradient is close to zero.
• In some, but not all causes of hypoxemia, the A- a gradient is increased, or widened, signifying a
defect in O2 equilibration. (MCQ)
§ High altitude
o causes hypoxemia because barometric pressure (PB) is decreased, which decreases the PO2
of inspired air (PIO2) and of alveolar air (PAO2)
o Equilibration of O2 across the alveolar/pulmonary capillary barrier is normal, and systemic
arterial blood achieves the same (lower) PO2 as alveolar air.
o Because PAO2 and PaO2 are nearly equal, theA a gradient is normal. (MCQ)

o At high altitude, breathing supplemental O2 raises arterial PO2 by raising inspired and alveolar PO2.
§ Hypoventilation
o causes hypoxemia by decreasing alveolar PO2 (less fresh inspired air is brought into alveoli).
o Equilibration of O2 is normal, and systemic arterial blood achieves the same (lower) PO2 as
alveolar air.
o PAO2 and PaO2 are nearly equal
o A- a O2 gradient is normal. (MCQ)
o In hypoventilation, breathing supplemental O2 raises arterial PO2 by raising the alveolar
PO2. (MCQ)
§ Diffusion defects (e.g., fibrosis, pulmonary edema)
o cause hypoxemia by
§ increasing diffusion distance or
§ decreasing surface area for diffusion.
o Equilibration of O2 is impaired
o PaO2 is less than PAO2,
o A a gradient is increased, or widened. (MCQ)
o With diffusion defects, breathing supplemental O2 raises arterial PO2 by raising alveolar
PO2 and increasing the driving force for O2 diffusion. (MCQ)
§ V_/Q_ defects
o always cause hypoxemia with increased A a gradient. (MCQ)
o In V_/Q_ defects, supplemental O2 can be helpful, primarily because it raises the PO2 of
low V_/Q_ regions where blood flow is highest. (MCQ)
§ Right-to-left shunts (right-to-left cardiac shunts, intrapulmonary shunts)
o always cause hypoxemia and increased A- a gradient(MCQ)
o Shunted blood completely bypasses ventilated alveoli and cannot be oxygenated. Because
shunted blood mixes with, and dilutes, normally oxygenated blood (nonshunted blood), the
PO2 of blood leaving the lungs must be lower than normal.
o Why supplemental O2 has a limited effect on the PO2 of systemic arterial blood ? (MCQ)
§ because supplemental O2 can only raise the PO2 of normal nonshunted blood ; the
shunted blood continues to have a dilutional effect.
§ HYPOXIA
o Hypoxia is decreased O2 delivery to the tissues
o O2 delivery is the product of cardiac output and O2 content of blood
o hypoxia is caused by
§ decreased cardiac output (blood flow)
§ decreased O2 content of blood.
o O2 content of blood is determined primarily by the amount of O2-hemoglobin.

§ Carbon monoxide (CO) poisoning

o causes hypoxia because CO occupies binding sites on hemoglobin that normally are
occupied by O2 (MCQ)
o CO decreases the O2 content of blood. (MCQ)
§ Cyanide poisoning
o interferes with O2 utilization of tissue
o it is one cause of hypoxia that does not involve decreased blood flow or decreased O2
content of blood. (MCQ)
Topic- Blood Flow
§ The cardiovascular system consists of

o two pumps - left and right heart ventricles
o two circuits - pulmonary and systemic
§ Because the two circuits are connected in series, flow (mL/min) must beequal in both
§ The systemic circuit
o begins as a large vessel, the aorta, and branches into smaller vessels until capillaries are reached
within organs.
o Vascular components include arteries, arterioles, and capillaries.
o Arterioles
§ They have the highest resistance in the cardiovascular system (MCQ)
§ regulated by the autonomic nervous system.
§ Arteriolar smooth muscle tone depends on sympathetic input, local metabolites,
hormones, and other mediators.
o Capillaries
§ have the largest total cross-sectional and surface areas (MCQ)
§ are the site of exchanges of nutrients, water, and gases.
§ The venous circuit
o Veins
§ thin-walled vessels under low pressure (MCQ)
§ contain most of the blood in the cardiovascular system.
o Venules
§ most permeable components of the microcirculation.
§ Hemodynamics - Velocity and Blood Flow
§ Velocity
o inversely related to the total cross-sectional area of all vessels of a particular segment of the
cardiovascular system.
o The cross-sectional area of the aorta is approximately 2.8 cm2, whereas the area of the
combined capillaries is approximately 1357 cm2.
o The aorta, therefore, has the highest velocity, and the capillaries the lowest. (MCQ)
§ Blood flow
o it has the dimensions of volume per unit time, for example, cubic centimeters per second.
o the flow through the aorta per minute (ie, cardiac output) is equivalent to the flow to the right
atrium per minute (ie, venous return)is equivalent to the flow through the combined capillaries
per minute.
§ Hemodynamic Equivalent of Ohm’s Law
§ The equivalent relationship for a liquid in motion is
Cardiac output = mean arterial pressure – right arterial pressure
Total peripheral resistance
Where
§ CO = cardiac output
§ P = pressure difference (mm Hg) Q = volume flow (L/min)
§ R = resistance (mm Hg/L/min)
§ Resistance
o Poiseuille’s equation gives the relationship offlow, pressure, and resistance
Q = P1 −P2 ,
§ Q = blood flow (L/min)

§ P1 = upstream pressure for segment
§ P2 = pressure at end of segment
§ R = resistance of vessels between P1 and P2
o The equation states that flow (Q) is directly proportional to the driving pressure (P) and
inversely proportional to the resistance (R).
o Resistance is directly proportional to the length () of the vessel and to the viscosity of
blood (f):

o r4 = radius of the blood vessel to the fourth power.

o The greater the vessel length, the greater the resistance (MCQ)
o greater the viscosity, the greater the resistance.
o The most important factor determining resistance is the radius of the vessel
o The equation emphasizes that if the vessel radius doubles (ie, resistance decreases),
then flow will increase 16-fold, if other factors remain constant. (MCQ)
o the systemic and pulmonary circulations have approximately the
o same number of total capillaries
o with the same total cross-sectional area (1357 cm2)
o blood viscosities and flows are both equal
o lower pressure difference across the pulmonary circuit must be due to the
difference in vessel length between the pulmonary and systemic circuits.
§ Reynolds Number and Turbulence
o Laminar flow does not generate an audible sound
o Turbulent flow involves random pressure fluctuations, and sounds are heard.
o The Reynolds number (a dimensionless variable relating viscous and inertial forces) serves as a
useful indicator for the transition of laminar flow to turbulent flow . (MCQ)
o The Reynolds number is calculated from the following equation:
§ NR = Reynolds number
§ V = mean velocity (cm/s) D = tube diameter (cm)
§ p = fluid density
§ n = fluid viscosity (Poises)
o Turbulent flow usually occurs when the Reynolds number exceeds a critical value of 3000
(MCQ)
o Because the viscosity of blood is relatively high , the Reynolds number for turbulent flow is
not exceeded in most parts of the circulation.
§ Compliance
o Compliance describes the distensibility of blood vessels.
o Vascular compliance (C) is the slope of the relationship between a rise in volume in the
vessel and the rise in pressure produced by that rise; hence,

o The compliance of combined veins is about 19 times greater than the compliance found in
the combined arteries.
o Systolic pressure is a function of the stroke volume (and compliance). (MCQ)
o Diastolic pressure is a function of the heart rate and the arteriolar resis-tance, which
determines run-off into the veins . (MCQ)
§ Pressure Profile
o As blood flows through the systemic circulation, pressure decreases progressively from the
aorta, where it is highest, to the vena cava, where it is lowest
o Because the greatest resistance to flow occurs in the arterioles, the largest decrease in pressure
occurs across the arterioles.
o Local arteriolar dilation in an organ decreases arteriolar resistance, which increases blood
flow and pressure downstream
o Local arteriolar constriction increases arteriolar resistance and decreases flow and pressure
downstream.
o Atrial pressure is lower than venous pressure
o pressure is 5–10 mm Hg in the left atrium
o 15 mm Hg in peripheral venules.
§ Arterial Pressures
o Systolic arterial pressure
o highest arterial pressure during the cardiac cycle.
o It represents the pressure developed when the heart contracts most forcibly.
o As blood flows from the aorta to the peripheral arteries. (MCQ)
§ Arterial peak systolic pressure increases
§ minimum diastolic pressure falls
o Diastolic pressure
o lowest arterial pressure during the cardiac cycle
o represents the pressure when the heart is relaxed and not contracting.
o Pulse pressure
o difference between systolic and diastolic pressures (MCQ)
o determined primarily by stroke volume and arterial compliance.
o Pulse pressure and both arterial pressures increase with aging due to decreased
compliance of vessels. (MCQ)
o The pulse pressure also increases as blood moves out along the arterial tree. (MCQ)
o Mean arterial pressure
o average arterial pressure over time
o calculated by adding diastolic pressure plus one third of pulse pressure. (MCQ)
o Mean pressure, the driving force for flow,decreases as one moves out along the arterial
tree. (MCQ)
o The fall in mean pressure across the arteriolar bed means that capillary pressure is
normally nonpulsatile

Control Mechanisms and Special Circulations
§ Autoregulation
o Autoregulation is the maintenance of constant blood flow over a wide range of blood
pressures.
o Constant flow is due to
§ metabolic theory of autoregulation
• Increases or decreases in local metabolites
§ myogenic theory of autoregulation
• Smooth muscle contraction in response to increases or decreases in
pressure
§ Active Hyperemia
o Active hyperemia is defined as increased blood flow to an organ caused by increased tissue
metabolic activity and accumulation of vasodilator metabolites.
o In exercise, blood flow will increase to skeletal muscles involved to meet increased
metabolic demand.
§ Reactive Hyperemia
o If arterial inflow to a vascular bed is stopped for a few minutes, the blood flow, on release of
the occlusion, immediately exceeds the flow before the occlusion, producing reactive
hyperemia.
o A number of metabolites may mediate the metabolic vasodilation that occurs during the interval
of occlusion, such as CO2, H+, K+, lactic acid, and adenosine(MCQ)
o The increase in flow is proportional to the length of the occlusion.
§ Coronary Blood Flow
o The principal factor responsible for perfusion of the myocardium is aortic pressure.
o Changes in coronary blood flow are caused mainly by caliber changes of the coronary
resistance vessels in response to metabolic demands of the heart .
o A decrease in O2 supply or an increase in O2 demand apparently causes
o the release of a vasodilator (adenosine) that decreases coronary resistance and increases
coronary flow proportionally.
§ Cutaneous Circulation and Temperature
o The skin contains two types of resistance vessels
§ Arterioles
§ arteriovenous anastomoses.
o Arteriovenous anastomoses
§ shunt blood from the arterioles to venules and venous plexuses, bypassing the capillary
bed.
§ found primarily in fingertips, palms of the hand, soles of the feet, ears, nose, and lips (ie,
exposed regions).
§ These vessels are almost exclusively under sympathetic neural control by
temperature receptors from higher centers and become maximally dilated when their
nerve supply is interrupted.
§ They do not appear to be under metabolic contro
§ they fail to exhibit reactive hyperemia or autoregulation (MCQ)
§ Fetal Circulation at Birth

o In the fetus, blood returning to the right heart is divided into two streams by the edge of the
interatrial septum (crista dividens).
o The larger stream is shunted to the left atrium through the foramen ovale.
o The other stream passes into the right atrium, where it is joined by superior vena cava
blood returning from the upper parts of the body .
o Because of the large pulmonary resistance, due to the low fetal partial pressure of O2 in
alveolar gas, only one tenth of the right ventricular output goes through the lungs.
o The remainder right ventricular output passes through the ductus arteriosus from the
pulmonary artery to the descending aorta . (MCQ)
o Blood flows from the pulmonary artery to the aorta because the pulmonary resistance is
high and the diameter of the ductus arteriosus is as large as the descending aorta.
o At birth, the asphyxia that starts with clamping ofthe umbilical vessels activates the infant’s
respiratory center.
o As the lungs fill with air, pulmonary vascular resistance decreases to about one-tenth of the
value existing before lung expansion.
o The left atrial pressure is raised above the pressure in the inferior vena cava and right atrium
o this reversal of the pressure gradient across the atria abruptly closes the valve over the foramen
ovale.
o With the decrease in pulmonary vascular resistance, the pressure in the pulmonary artery
falls, causing a reversed blood flow through the ductus arteriosus.
o Closure of the ductus arteriosus appears to be initiated by the high O2 tension of the arterial
blood passing through it. (MCQ)
o The presence of vasodilator prostaglandins is thought to be the reason for failure of the
ductus arteriosus to close. (MCQ)
o The administration of indomethacin, which blocks prostaglandin synthesis, often leads to
closure of the ductus in infants in whom it fails to close.
§ CUSHING PHENOMENON
o Generally,cerebral blood flow to the brain is constant.
o Cerebral metabolic products(diminished O2,elevated CO2 and H+) contribute to the control
of cerebral blood flow locally in accordance with local metabolism.
o Cerebral circulation is maintained in hypertension by a combination of sympathetic
vasoconstriction, hormonal vasoconstriction, and homeostatic autoregulation.
o Cushing’s phenomenon
§ patients with brain tumors who had cerebral ischemia also have increased systemic
blood pressure with a simultaneous decrease in heart rate. (MCQ)
§ This response,called,is caused by cerebral ischemic stimulation of vasomotor regions
in the medulla that help maintain cerebral blood flow in the face of increased resistance
caused by expanding intracranial tumors.
§ Pulmonary Blood Flow
o Pressures Within the Pulmonary Circuit
§ The most important difference between the pulmonary and systemic circulations is the
low blood pressure in the pulmonary arteries.
• The pulmonary arterial systolic pressure is approximately 22 mm Hg(MCQ)
• left ventricular systolic pressure is around 120 mm Hg.
§ The pulmonary circulation is a low-resistance circuit that must accommodate the
entire cardiac output at rest and during exercise.
§ When pulmonary arterial pressure increases, vascular resistance decreases for two
reasons:
• Increased pressure increases the caliber (distention) of the arteries.
• Increased pressure causes more capillaries to open (recruitment).
o Effects of Gravity on Blood Flow
§ Because of the low blood pressures in the pulmonary circulation, gravity has a large
effect on blood flow to different parts of the lung
§ In an upright subject, the effect of gravity causes
• blood flow to be larger at the base than at the apex
• Ventilation is also larger at the base than at the apex.
§ Although the base receives the greatest ventilation, it does not match the very high
blood flow .
• Thus, the base is an underventilated region, in which theV/Q ratio is less
than 0.8. (MCQ)
• an underventilated lung unit acts like a pulmonary shunt.
§ Even though the apex receives the lowest ventilation, it is too high for the low
blood flow.
• Therefore, the apex can be considered an overventlated region, in which th
V/Q ratio is greater than 0.8. (MCQ)
• An overventilated lung unit acts like dead space
o Hypoxic Vasoconstriction
§ A decrease in alveolar PO2 produces a local vasoconstriction of pulmonary arterioles,
thereby lowering blood flow to that part of the lung.
§ In other systemic organs, hypoxia results in vasodilation of arterioles .
o Pulmonary Edema
§ The two causes of pulmonary edema are
• Increased capillary permeability
• Increased pulmonary blood pressure due to hypoxic vasoconstriction, left
heart failure, or loss of surfactant
o Circulation divisions in a vertical lung.
§ In zone 1
• no blood flow occurs
• alveolar pressure is higher than pulmonary arterial pressure
• In normal persons with adequate cardiac output, there is no zone 1 be-
cause pulmonary arterial pressure is greater than alveolar pressure
§ In zone 2
• pulmonary arterial pressure is greater than alveolar pressure
• blood flow occurs but alveolar pressure is greater than pulmonary venous
pressure.
§ In zone 3,
• pulmonary arterial and venous pressures are both greater than alveolar
pressure
• blood flow is maximal

o Shunts
§ In an absolute right-to-left shunt
• venous blood is delivered to the left side of the heart without contacting
ventilated alveoli
• this shunt produces hypoxemia
• The shunt results in a
o decrease in arterial PO2
o widening of alveolar-arterial (A-a) difference.
§ With a significant pulmonary shunt
• e.g in regional atelectasis
• breathing 100% O2 does not result in a significant increase in systemic arterial
PO2, leading to a diagnosis of a pulmonary right-to-left shunt.
• Ventilation-Perfusion Differences
• In the normal lung, the V/Q ratio is approximately 0.8.
• Physiologic dead space is defined as anatomic dead space plus the volume of all airways that
behave as if they have received no blood flow.
o In health, anatomic dead space and physiologic dead space are essentially equal.
o In ventilation-perfusion mismatch, the amount of physiologic dead space is much
greater than the amount of anatomic dead space.
o Some regions of the lung may have a hig V/Q - PO2 in these alveoli is below average.
o Bohr method measures physiologic dead space
§ measures volume of all airways in which no CO2 has been added from the blood

o In many pulmonary diseases, the physiologic shunt and the physiologic dead space
will be increased.
o The consequence of increased physiologic dead space is wasted ventilation.
• Hypoventilation
o associated with equal decreases in PO2 in the alveolar, pulmonary end capillary , and
systemic arterial compartments
o Supplemental oxygen or increased alveolar ventilation will return arterial PO2 to normal.
• Diffusion impairment
o refers to a lung structural problem (eg, increased thickness of lung membrane ).
o With significant diffusion impairment, the A-a gradient widens.
o Supplemental oxygen will increase the gradient across the alveolar membranes and return
arterial PO2 toward normal.
• Exercise increases ventilation and pulmonary blood flow
o During exercise, the VQ ratio is greater than 0.8, (MCQ)
§ ventilation increases more than cardiac output
§ base-to-apex flows become more equal.
§ High Altitude
• At high altitude, atmospheric pressure is reduced from 760 mm Hg, resulting in decreased
alveolar and arterial PO2 (hypoxemia).
• Low PO2 stimulates peripheral chemoreceptors, inducing hyperventilation, a decrease in
alveolar and arterial PCO2, and respiratory alkalosis.
• Hypoxemia stimulates erythropoietin,
o The increased Hb production increases O2 content of the blood .
• 2,3-DPG levels increase
o shifts the oxyhemoglobin dissociation curve to the right and facilitating O2 extraction by
the tissues. (MCQ)
• Hypoxemia also results in hypoxic vasoconstriction (ie, pulmonary vasoconstriction), resulting
eventually in hypertrophy of the right ventricle due to increased work of the right heart.
§ Hyperbaric Chamber
• Breathing room air (21% O2; 79% N2) in a hyperbaric environment (MCQ)
• increases the partial pressure of O2 and N2 in alveoli and arterial blood
o Elevated PO2 can produce oxygen toxicity
o high PN2 can lead to the bends (also known as caisson disease).
• Sudden decompression causes bubbles of nitrogen to accumulate in the blood and tissues.
• Treatment is recompression and gradual decompression.
Topic - Lung Volumes and Capacities
Lung Volumes
• Tidal volume
o Normal, quiet breathing involves inspiration and expiration of a tidal volume (VT).
o Normal tidal volume is approximately 500 mL (MCQ)

o tidal volume includes the volume of air that fills the alveoli plus the volume of air that fills
the airways. (MCQ)
• inspiratory reserve volume
o The subject is asked to take a maximal inspiration, followed by a maximal expiration
o The additional volume that can be inspired above tidal volume is called the inspiratory
reserve volume (MCQ)
o approximately 3000 mL(MCQ)
• expiratory reserve volume
o The additional volume that can be expired below tidal volume is called the expiratory reserve
volume
o approximately 1200 mL. (MCQ)
• residual volume
o The volume of gas remaining in the lungs after a maximal forced expiration is the residual
volume (RV),
o It is approximately 1200 mL (MCQ)
o It cannot be measured by spirometry (MCQ)
LUNG CAPACITIES
• inspiratory capacity (IC)

o composed of the tidal volume plus the inspiratory reserve volume
o approximately 3500 mL (500 mL + 3000 mL). (MCQ)
• functional residual capacity (FRC
o composed of the expiratory reserve volume (ERV) plus the residual volume
o it is approximately 2400 mL (1200 mL + 1200 mL). (MCQ)
o FRC is the volume remaining in the lungs after a normal tidal volume is expired
o It is the equilibrium volume of the lungs .
• Vital capacity (VC)
o composed of the inspiratory capacity plus the expiratory reserve volume
o it is approximately 4700 mL (3500 mL + 1200 mL) (MCQ)
• Vital capacity
o volume that can be expired after maximal inspiration
o Its value increases with (MCQ)
§ body size
§ male gender,
§ physical conditioning
o Its value decreases with age(MCQ)
• Total lung capacity (TLC)
o includes all of the lung volumes
o It is the vital capacity plus the residual volume, (MCQ)
o It is 5900 mL (4700 mL + 1200 mL). (MCQ)
o What are the lung capacities that cannot be measured by spirometry ?
§ Since residual volume cannot be measured by spirometry ,lung capacities that include
the residual volume also cannot be measured by spirometry
§ FRC and TLC cannot be measured (MCQ)
• FRC
• the volume remaining in the lungs after a normal expiration
• it is the resting or equilibrium volume of the lungs. (MCQ)
• There are two methods used to measure FRC (MCQ)
o helium dilution method
o body plethysmography

§ Dead space
o volume of the airways and lungs that does not participate in gas exchange.
§ Anatomic Dead Space
o The anatomic dead space is the volume of the conducting airways, including the nose
(and/or mouth), trachea, bronchi, and bronchioles.
o It does not include the respiratory bronchioles and alveoli. (MCQ)
o The volume of the conducting airways is approximately 150 mL(MCQ)
o To sample alveolar air, one must sample end-expiratory air(MCQ)
§ Physiologic Dead Space
o Physiologic dead space includes the anatomic dead space of the conducting airways plus a
functional dead space in the alveoli.
o The functional dead space can be thought of as ventilated alveoli that do not participate in
gas exchange.
o The most important reason that alveoli do not participate in gas exchange is a mismatch of
ventilation and perfusion,
o In normal persons, the physiologic dead space is nearly equal to the anatomic dead space.
o The ratio of physiologic dead space to tidal volume provides an estimate of how much
ventilation is “wasted” (either in the conducting airways or in nonperfused alveoli).
o Partial pressure of CO2 (PCO2 ) of mixed expired air (PECO2)
§ Used to estimate volume of the physiologic dead space (MCQ)
§ based on three assumptions:
• All of the CO2 in expired air comes from exchange of CO2 in functioning
(ventilated and perfused) alveoli
• there is essentially no CO2 in inspired air
• the physiologic dead space (non- functioning alveoli and airways) neither
exchanges nor contributes any CO2.

§ If physiologic dead space is zero, then PECO2 will be equal to alveolar PCO2
(PACO2).
§ if a physiologic dead space is present, then PECO2 will be “diluted” by dead space
air and PECO2 will be less than PACO2 by a dilution factor. (MCQ)
§ Therefore, by comparing PECO2 with PACO2, the dilution factor (i.e., volume ofthe
physiologic dead space) can be measured.
o Why is PCO2 of systemic arterial blood (PaCO2) is equal to the PCO2 of alveolar air
(PACO2).
§ Alveolar air cannot be sampled directly .
§ Alveolar air normally equilibrates with pulmonary capillary blood (which becomes
systemic arterial blood).
o Volume of physiologic dead space is calculated by the following equation: (MCQ)
§ VD = Physiologic dead space (mL)
§ VT =Tidal volume (mL)
§ PaCO2 = PCO2 of arterial blood (mm Hg)
§ PECO2 = PCO2 of mixed expired air (mm Hg)
o In words, the equation states that the volume of the physiologic dead space is the tidal
volume (volume inspired with a single breath) multiplied by a fraction.
o The fraction represents the dilution of alveolar PCO2 by dead space air (which contributes
no CO2).
VENTILATION RATES
o Ventilation rate is the volume of air moved into and out of the lungs per unit time.
o Minute ventilation
o total rate of air movement into and out of the lungs
o Minute ventilation = VT x Breaths/min(MCQ)
o Alveolar ventilation,
o corrects for the physiologic dead space. (MCQ)

ALVEOLAR VENTILATION EQUATION
o There is inverse relationship between alveolar ventilation and alveolar PCO2 (PACO2).
(MCQ)
o The alveolar ventilation equation is expressed as follows:
o if CO2 production is constant, then P ACO2 is determined by alveolar ventilation.

o For a constant level of CO2 production, there is a hyperbolic relationship between PACO2 and
alveolar ventilation.
o Increases in alveolar ventilation cause a decrease in PACO2
o Decreases in alveolar ventilation cause an increase in PACO2.
o if CO2 production doubles (e.g., during strenuous exercise), the hyperbolic relationship between
PACO2 and alveolar ventilation shifts to the right(MCQ)
o Under these conditions, the only way to maintain PACO2 at its normal value
(approximately 40 mm Hg) is for alveolar ventilation to double also.
o if CO2 production increases from 200 mL/min to 400 mL/min, PACO2 is maintained at
40 mm Hg if, simultaneously, alveolar ventilation increases from 5 L/min to 10 L/min.
o FORCED EXPIRATORY VOLUMES
o Vital capacity
§ volume that can be expired following a maximal inspiration(MCQ)
o Forced vital capacity (FVC)
§ total volume of air that can be forcibly expired after a maximal inspiration,
o FEV1
§ volume of air that can be forcibly expired in the first second is called
§ Normally, the entire vital capacity can be forcibly expired in 3 seconds, so there
is no need for “FEV4.” (MCQ)
o FEV1/FVC
§ in a normal person, FEV1/FVC is approximately 0.8(MCQ)
§ 80% of the vital capacity can be expired in the first second of forced expiration
o In a patient with an obstructive lung disease such as asthma (MCQ)
§ both FVC and FEV1 are decreased
§ FEV1 is decreased more than FVC
§ FEV1/FVC is also decreased,
o In a patient with a restrictive lung disease such as fibrosis (MCQ)
§ both FVC and FEV1 are decreased
§ FEV1 is decreased less than FVC is.
§ Thus, in fibrosis, FEV1/ FVC is actually increased
Topic - Oxygen dissociation curve
§ Saturation is the percentage of Hb-binding sites occupied by O2.

§ oxygen capacity of Hb in blood is approximately 20 mL O2/100 mL of blood or 20 vol%. (MCQ)
o Each gram of Hb has an oxygen capacity of 1.34 mL O2 , (MCQ)
o 100 mL of blood contains 15 g Hb
o completely oxygenated blood contains approximately 20 mL O2/100 mL (1.34 mL O2 15
g Hb/100 mL).
§ Physiologic implications of the oxyhemoglobin dissociation curve
o Hb combines rapidly and reversibly with O2 to form oxyhemoglobin.
o The saturation curve has a sigmoid shape because oxygenation of the first
heme group of the Hb molecule increases the affinity of O2 for the other heme
groups.
§ The O2 capacity
o maximum amount of O2 that can be bound to Hb
o determined by the Hb concentration in blood.
§ The O2 content
o total amount of O2 carried in the blood whether bound or dissolved in solution.
§ Several factors influence the oxyhemoglobin dissociation curve
o Shifts to the right (MCQ)
§ occur when the affinity of Hb-binding sites for O2 is decreased
§ it is easier for tissues to extract oxygen.
§ Causes of this shift include (MCQ)
• increased CO2 (Bohr effect)
• increased H+ (decreased pH)
• increased temperature
• increased 2,3-diphosphoglycerate (2,3-DPG).

§Anemia is characterized by a reduced Hb concentration in blood and decreased
arterial oxygen content.
o Shifts to the left (MCQ)
§ occur when there is increased affinity of Hb for O2
§ it is more difficult for tissues to extract oxygen.
§ Causes of this shift include(MCQ)
• decreased temperature
• decreased PCO2
• decreased H+ (increased pH),
• decreased 2,3-DPG.
§ Stored blood loses 2,3-DPG and fetal Hb, and both decreases shift the curve to the
left. (MCQ)
§ Polycythemia is characterized by a higher than normal concentration of Hb in the
blood, a shift to the left in the oxyhemoglobin dissociation curve, and increased
arterial oxygen content. (MCQ)
§ Carbon monoxide poisoning
o Carbon monoxide (CO) has a much greater affinity (more than 200 times) for Hb than does
O2. (MCQ)
o Thus, the amount if CO dissolved in plasma is essentially zero.
o The O2-binding capacity of Hb and the O2 content of blood decrease.
o The oxy hemoglobin dissociation curve shifts to the left. (MCQ)
o • Arterial PO2 is normal,but O2 saturation of Hb decreases.
§ Saturation versus partial pressure.
o Each saturation curve has a single P50
o which is the PO2 that gives 50% saturation
o Normal P50 = 26 mm Hg (MCQ)

§ O2 content versus partial pressure for two diffe ent hemoglobin (Hb) concentrations.
§ Curve A represents normal Hb levels in blood (15 g/100 mL).
§ Curve B represents a reduced concentration of Hb in blood (7.5 g/100 mL). The main effect
of the lower Hb concentration is a reduced carrying capacity of the blood.
§ Thus, in curve B, the total amount of O2/100 mL of blood is around 10 mL O2/100 mL,
instead ofthe normal 20 mL O2/100 mL. (MCQ)
Changes in affinity of hemoglobin (Hb) for O2 (oxyhemoglobin dissociation curve).
Topic - Blood Pressure Cardiac out put
Cardiac Muscle and Cardiac Output

§ Ventricular Action Potential V ersus Mechanical Events
o The QRS complex represent ventricular cell phase 1 depolarizations.(MCQ)
o The T wave records of all ventricular cell phase 3 repolarizations. MCQ)
o The T wave begins midway through the ejection phase and continues until the onset of the
isovolumetric relaxation phase. (MCQ)
§ Myocardial Cell Structure
o Cardiac muscle cells
§ contain numerous myofibrils
§ chains of sarcomeres, the fundamental contractile unit.
§ Myocytes are coupled to one another by intercalated disks.
§ cardiac myocytes that comprise the ventricles and atria contract almost in unison,
MCQ)
o Cell-to-cell conduction occurs through gap junctions (MCQ)
o Low resistance pathways that are a part of the intercalated discs (MCQ)
§ allow for rapid electrical spread of action potentials to cells.
o Cardiac muscle differs from skeletal muscle in the following ways:
§ Cardiac muscle contains only one or two centrally located nuclei, in contrast to the
several nuclei in skeletal muscle.
§ Gap junctions are found only in cardiac muscle. (MCQ)
§ Compared to skeletal muscle, cardiac muscle contains fewer but larger T-tubules,
particularly in the atria. (MCQ)
§ Similar Cardiac Output: Right and Left Heart
o The stroke volume (SV) of the two ventricles must, at steady state, be identical.
o The rate (HR) of the two ventricles must be identical.
o output (HR SV) of the two ventricles must also be identical.
o Cardiac output is equivalent to the venous return
§ Cardiac output increases during exercise because of the fall in skeletal muscle resis-
tance and increased venous return.
§ Excitation-Contraction Coupling
o This coupling links the electrical activities of the myocyte to the force- generating actin-
myosin reaction.
o Ca2+ enters the myocyte mainly during phase 2 of an action potential via voltage-activated
channels. (MCQ)
o This Ca2+ entry triggers the release of Ca2+ from intracellular (MCQ)sarcoplasmic reticulum
(SR) stores, increasing intracellular Ca2+ levels.
o Ca2+ binds to troponin C, moving tropomyosin away and allowing actin and myosin
binding.
o Actin and myosin bind, the thick and thin filaments slide past one another, and the myocardial cell
contracts.
o The strength of contraction correlates with the amount of SR Ca2+ release. (MCQ)
o Ca2+ removal by an active Ca2+-ATPase pump is required for relaxation. (MCQ)
§ End-diastolic Blood Pressure Changes with Change in Cardiac Output
o with an increase in sympathetic activity, the rate and the myocardial contractility (ie, stroke
volume) will increase.

o The result will be decreased ventricular end-diastolic pressure, because these induced cardiac
changes are accompanied by a concurrent increase in arteriolar resistance (ie,
vasoconstriction). (MCQ)
o With the increase in cardiac output during exercise, ventricular end-diastolic pressure
will not decrease, as a result of reduction in peripheral resistance from dilation in the
skeletal muscle beds. (MCQ)
§ Starling’s Law
o The relation between fiber length and strength of contraction is known as Starling’s law of
the heart.
o
o An increase in myocardial fiber length, as occurs with an increased ventricular filling during
diastole (ie, preload), produces a more forceful ventricular contraction because more
overlap between thick and thin filaments is exposed for cross-bridge formation. (MCQ)
o Hence, a decreased heart rate, with longer filling time, will result in an increase in stroke
volume.
o Starling’s law is active only to the point at which a maximal systolic pressure is reached at the
optimal preload.
o If diastolic pressure increases beyond the optimal preload, no further increases in developed
pressure will occur. Thus, the normal heart operates on the ascending portion of the
Frank-Starling curve.
Pressure-Volume Loop of the Left Ventricle
The external work of the heart can be approximated as the product of pressure (P) times stroke volume
(SV), which is the pressure-volume loop of the heart.

o Pressure-volume loop
o Isovolumetric contraction
§ Occur From points 1 to 2.
§ Point 1
• is diastole with the ventricular muscle relaxed
• filled with blood to about 145 mL (end-diastolic volume). (MCQ)
• Upon excitation, the ventricle contracts but no blood is ejected because
all of the valves are closed.
o Ventricular ejection
§ represented by movement from points 2 to 3.
§ At point 2
• aortic valve opens and blood is ejected into the aorta.
• The volume ejected per beat is the stroke volume
• Graphically depicted by the width of the pressure-volume loop
§ Point 3
• is the end-systolic volume. (MCQ)
o Isovolumetric relaxation
§ represented by movement from points 3 to 4
§ At point 3, as the ventricle relaxes, the aortic valve closes.
§ Ventricular volume is constant because all valves are closed.
o Ventricular filling
§ represented by movement from points 4 back to 1.
§ After left ventricular pressure decreases below left atrial pressure, the mitral
valve (AV) opens and filling begins.
§ Ventricular volume increases to about 140 mL (end-diastolic volume), of which
only 10–20% results from atrial contraction. (MCQ)
o Cardiac Work
o Cardiac work is the amount of work done by the heart on each beat.
o cardiac work is much greater for the left heart because of the greater afterload, or increase
in arterial pressure.
§ Afterload on the left ventricle is equivalent to aortic pressure.

§ Afterload on the right ventricle is equivalent to pulmonary artery pressure.
o Cardiac work is primarily a function of arterial systolic pressure and stroke volume.
o Systolic pressure is a function ofstroke volume (MCQ)
o As stroke volume increases, systolic pressure increases.
o increased afterload results in a decrease in stroke volume.
o Heart rate is an indicator of stroke volume
§ as heart rate increases, stroke volume usually decreases, due to decreased filling
time. (MCQ)
o Venous Return and Central Venous Pressure
o The venous return (ie, vascular function) relationship defines the changes in central
venous pressure evoked by changes in cardiac output.
o As cardiac output increases, blood is removed from the central veins at a greater rate, and
central venous pressure declines.
o Central venous pressure is the response, and cardiac output is the stimulus.
Topic - Exercise physiology
§ Cardiovascular responses to exercise

o involve a combination of
§ central nervous system (CNS) mechanisms
§ local mechanisms
o Central nervous system (CNS) mechanisms
§ produces increased sympathetic outflow to the heart and blood vessels
§ decreased parasympathetic outflow to the heart.
§ increase in cardiac output.
§ There is concomitant increase in venous return is accomplished by two mechanisms
• contraction of skeletal muscle around the veins has a mechanical (squeezing)
action(MCQ)
• activation of the sympathetic nervous system produces venoconstriction.
(MCQ)
§ increased sympathetic outflow causes selective arteriolar vasoconstriction
• In the circulation of the skin, splanchnic regions, kidney, and inactive
muscles, vasoconstriction occurs via a1 receptors(MCQ)
• results in increased resistance and decreased blood flow to those organs
• In the exercising skeletal muscle, however, local metabolic effects override
any sympathetic vasoconstricting effects, and arteriolar vasodilation (MCQ)
§ Other locations where vasoconstriction does not occur (MCQ)
• coronary circulation
• cerebral circulation.
§ In the cutaneous circulation, there is a biphasic response
• Initially, vasoconstriction occurs (due to increased sympathetic outflow)

•
later, however, as body temperature increases, there is selective inhibition of
sympathetic cutaneous vasoconstriction
o Local Responses in Muscle
§ Active hyperemia
§ production of vasodilator metabolites such as lactate, potassium, and
adenosine also increases. (MCQ)
§ Vasodilation of the arterioles results in increased blood flow to meet the
increased metabolic demand of the muscle.
§ This vasodilation in the exercising muscle also produces an overall decrease in
TPR.
§ Exercise and Potassium

o Exercise causes a K+ shift out of cells
§ depletion of cellular ATP stores opens K+ channels in the muscle cell membranes
(MCQ)
§ K+ shift is reversed during a subsequent period of rest.
o strenuous exercise can result in hyperkalemia. (MCQ)
§ in a person treated with a Beta2- adrenergic antagonist
§ in those with impaired renal function
o K+ shift out of cells assists in the local control of blood flo w to exercising skeletal muscle.
§ K+ is a vasodilator metabolites(MCQ)
§ Response of the respiratory system to exercise

o more O2 is supplied by increasing the ventilation rate:
o when a trained athlete is exercising,
§ his O2 consumption may increase from its resting value of 250 mL/min to 4000
mL/min, his ventilation rate may increase from 7.5 L/min to 120 L/min. (MCQ)
§ Both O2 consumption and ventilation rate increase more than 15 times the resting
level!
o Arterial PO2 and PCO2
§ Remarkably, mean values for arterial PO2 and PCO2 do not change during exercise.
§ arterial pH may decrease, because the exercising muscleproduces lactic acid
o Venous Pco2
§ The PCO2 of mixed venous blood must increase during exercise because skeletal
muscle is adding more CO2 than usual to venous blood.
o Muscle and Joint Receptors
§ Muscle and joint receptors send information to the medullary inspiratory center and
participate in the coordinated response to exercise.
§ inspiratory center is commanded to increase the ventilation rate.
o Cardiac Output and Pulmonary Blood Flow
§ Cardiac output increases during exercise to meet the tissues’ demand for O2
§ Since pulmonary blood flow is the cardiac output of the right heart, pulmonary
blood flow increases
§ There is a decrease in pulmonary resistance associated with perfusion of more

pulmonary capillary beds, which also improves gas exchange.
§ V/Q ratio becomes more “even,” (MCQ)
§ There is decrease in the physiologic dead space. (MCQ)
o O2-Hemoglobin Dissociation Curve
§ shifts to the right (MCQ)
§ reasons for this shift,
• increased tissue PCO2
• decreased tissue pH
• increased temperature.
§ The shift to the right is advantageous is associated with (MCQ)
• an increase in P50
• decreased affinity of hemoglobin for O2
• easier to unload O2 in the exercising skeletal muscle


Topic- Long tracts
Somatosensory System and Pain
• Two pathways for transmission of somatosensory information to the CNS

o dorsal column system
o anterolateral system.
• The dorsal column system processes the sensations of (MCQ)
o fine touch
o pressure
o two-point discrimination
o vibration
o proprioception (limb position)
• The anterolateral system processes the sensations of(MCQ)
o Pain
o Temperature
o light touch.
• Somatosensory pathway
o first-order neuron
§ primary afferent neuron
§ have their cell bodies in dorsal root or cranial ganglia(MCQ)
§ their axons synapse on somatosensory receptor cells (i.e., mechanoreceptors).
§ The signal is transduced by the receptor and transmitted to the CNS by the
primary afferent neuron.
o The second-order neuron
§ located in the
• spinal cord (anterolateral system)
• brain stem (dorsal column system).
§ receive information from first-order neurons
§ transmit that information to the contralateral thalamus. (MCQ)
§ Axons of the second-order neurons cross the midline
• either in the spinal cord (anterolateral system)
• or in the brain stem (dorsal column system).
o The third-order neuron
§ located in one of the somatosensory nuclei of the thalamus
o The fourth-order neuron
§ located in the somatosensory cortex, called S1 and S2.
§ The S1 somatosensory cortex
§ has a somatotopic representation, or “map,” similar to that in the thalamus.
§ This map of the body is called the somatosensory homunculus
§ The largest areas of representation of the body are the face, hands, and fingers,
which are densely innervated by somatosensory nerves and where sensitivity is
greatest. (MCQ)
• Dorsal Column System
o consists mainly of group I and II nerve fibers.
• Anterolateral System
o consists mainly of group III and group IV fibers.
o group IV fibers have the slowest conduction velocities of all the sensory nerves(MCQ)
o Fast pain (e.g., pin prick)
§ carried on A delta, group II, and group III fibers(MCQ)
§ has a rapid onset and offset
§ precisely localized
o Slow pain (e.g., burn)
§ carried on C fibers (MCQ)
§ characterized as aching, burning, or throbbing pain
§ it is poorly localized.
• Control of posture and movement by the brain stem

• Descending motor pathways are divided among the pyramidal tract and the extrapyramidal
tract
• Pyramidal tracts
o Are corticospinal and corticobulbar tracts
o They pass through the medullary pyramids and descend directly onto lower
motoneurons in the spinal cord.
• extrapyramidal tracts.
o rubrospinal tract
§ originates in the red nucleus
§ projects to motoneurons in the lateral spinal cord.
§ Stimulation of the red nucleus produces
• activation of flexor muscles (MCQ)
• inhibition of extensor muscles. (MCQ)
o pontine reticulospinal tract
§ originates in nuclei of the pons
§ projects to the ventromedial spinal cord.
§ Stimulation has a generalized activating effect on both flexor and extensor
muscles, it has predominant effect on extensors. (MCQ)
o medullary reticulospinal tract
§ originates in the medullary reticular formation
§ projects to motoneurons in the spinal cord.
§ Stimulation has a generalized inhibitory effect on both flexor and extensor
m(MCQ)uscles, with the predominant effect on extensors.
o lateral vestibulospinal tract
§ originates in the lateral vestibular nucleus (Deiters’ nucleus) (MCQ)
§ projects to ipsilateral motoneurons in the spinal cord.
§ Stimulation produces activation of extensors and inhibition of flexors. (MCQ)
o tectospinal tract
§ originates in the superior colliculus (tectum or “roof” of the brain stem)
§ projects to the cervical spinal cord
§ It is involved in control of neck muscles. (MCQ)
• Decerebrate rigidity
o Both the pontine reticular formation and the lateral vestibular nucleus have powerful
excitatory effects on extensor muscles(MCQ)
o lesions of the brain stem above the pontine reticular formation and lateral vestibular
nucleus, but below the midbrain, cause a dramatic increase in extensor tone, called
decerebrate rigidity. (MCQ)
o Lesions above the midbrain do not cause decerebrate rigidity . (MCQ)
Topic- Nerve conduction
o Conduction Velocity
o The speed at which action potentials are conducted along a nerve or muscle fiber is the
conduction velocity.
o The time constant (t)
o amount of time it takes following the injection of current for the potential to change to
63% of its final value (MCQ)
o the time constant indicates
§ how quickly a cell membrane depolarizes in response to an inward current
§ how quickly it hyperpolarizes in response to an outward current.
o Thus,

o Two factors affect the time constant.
o membrane resistance (Rm)
§ When Rm is high, current does not readily flow across the cell membrane, which
makes it difficult to change the membrane potential, thus increasing the time
constant.
o membrane capacitance (Cm)
§ the ability of the cell membrane to store charge
§ When Cm is high, the time constant is increased because injected current first
must discharge the membrane capacitor before it can depolarize the membrane.
Thus, the time constant is greatest (i.e., takes longest) when Rm and Cm are
high.
o length constant (l)
o the distance from the site ofcurrent injection where the potential has fallen by 63% of its original value.
(MCQ)
o The length constant indicates how far a depolarizing current will spread along a nerve.
o In other words, the longer the length constant, the farther the current spreads down the nerve
fiber. Thus
o Internal resistance, Ri, is inversely related to the ease of current flow in the cytoplasm of the nerve
fiber.
o Therefore, the length constant will be greatest (i.e., current will travel the farthest) when the
(MCQ)
o diameter ofthe nerve is large
o when membrane resistance is high
o when internal resistance is low.
o Changes in Conduction Velocity
o the larger the fiber, the lower the internal resistance. (MCQ)
o The largest nerves have the longest length constants, and current spreads farthest from
the active region to propagate action potentials.(MCQ)
o Myelination.
o Myelin is a lipid insulator of nerve axons that increases membrane resistance
o If the entire nerve were coated with the lipid myelin sheath, however, no action
potentials could occur because there would be no low resistance breaks in the membrane
across which depolarizing current could flow
o Therefore, at intervals of 1 to 2 mm, there are breaks in the myelin sheath, at the nodes of
Ranvier
o At the nodes, membrane resistance is low, current can flow across the membrane, and action
potentials can occur.

o Conduction of action potentials is faster in myelinated nerves than in unmyelinated nerves
because action potentials “jump” long distances from one node to the next, a process called
saltatory conduction.
o Synaptic and Neuromuscular Transmission
o Types of synapses
§ Electrical Synapses
• Electrical synapses allow current to flow from one excitable cell to the next
via low resistance pathways between the cells called gap junctions
(MCQ)
• Gap junctions
o are found in (MCQ)
§ cardiac muscle
§ some types of smooth muscle
o account for the very fast conduction in these tissues.
o rapid cell-to-cell conduction occurs in cardiac ventricular
muscle, in the uterus, and in the bladder, allowing cells in these
tissues to be activated simultaneously and ensuring that
contraction occurs in a coordinated manner.
§ Chemical Synapses
• there is a gap between the presynaptic cell membrane and the
postsynaptic cell membrane, known as the synaptic cleft.
• sequence of events occurs at chemical synapses:
o An action potential in the presynaptic cell causes Ca2+ channels
to open (MCQ)
o An influx of Ca2+ into the presynaptic terminal causes the
neurotransmitter, which is stored in synaptic vesicles, to be
released by exocytosis. (MCQ)
o The neurotransmitter diffuses across the synaptic cleft, binds to
receptors on the postsynaptic membrane
§ If the neurotransmitter is excitatory, it causes
depolarization of the postsynaptic cell
§ if the neurotransmitter is inhibitory, it causes
hyperpolarization of the postsynaptic cell.
• In contrast to electrical synapses, neurotransmission across chemical
synapses is unidirectional (from presynaptic cell to postsynaptic cell).
• The synaptic delay is the time required for the multiple steps in chemical
neurotransmission to occur.
o Neuromuscular junction—example of a chemical synapse
o Motor Units
§ Motoneurons are the nerves that innervate muscle fibers
§ A motor unit comprises a single motoneuron and the muscle fibers it innervates.
§ A single motoneuron may activate a few muscle fibers or thousands ofmuscle fibers . small
motor units are involved in fine motor activities (e.g., facial expressions)
§ large motor units are involved in gross muscular activities (e.g., quadriceps
muscles used in running).
o Sequence of Events at the Neuromuscular Junction
§ Action potentials are propagated down the motoneuron
§ Local currents depolarize each adjacent region to threshold.
§ Finally , the presynaptic terminal is depolarized
§ this depolarization causes voltage-gated Ca2+ channels in the presynaptic
membrane to open. (MCQ)
§ When these Ca2+ channels open, the Ca2+ permeability of the presynaptic terminal
increases, and Ca2+ flows into the terminal down its electrochemical gradient. (MCQ)
§ Ca2+ uptake into the terminal causes release of the neurotransmitter
acetylcholine (ACh), which has been previously synthesized and stored in synaptic
vesicles.
§ To release ACh, the synaptic vesicles fuse with the plasma membrane and
empty their contents into the synaptic cleft by exocytosis.
§ ACh is formed from acetyl coenzyme A (acetyl CoA) and choline by the action of
the enzyme choline acetyltransferase
§ ACh is stored in vesicles with ATP and proteoglycan for subsequent release.
§ Upon stimulation, the entire content of a synaptic vesicle is released into the
synaptic cleft.
§ The smallest possible amount of ACh that can be released is the content ofone
synaptic vesicle (one quantum), and for this reason, the release of ACh is said to be
quantal. (MCQ)
§ ACh diffuses across the synaptic cleft to the postsynaptic membrane.
§ This specialized region of the muscle fiber is called the motor end plate, which
contains nicotinic receptors for ACh. (MCQ)
§ ACh binds to the alpha subunits of the nicotinic receptor and causes a
conformational change.
§ It is important to note that the nicotinic receptor for ACh is an example of a
§ ligand-gated ion channel: It also is an Na+ and K+ channel.
§ When the conformational change occurs, the central core of the channel opens, and
the permeability of the motor end plate to both Na+ and K+ increases. (MCQ)
§ When these channels open, both Na+ and K+ flow down their respective
electrochemical gradients
§ Na+ moving into the end plate and K+ moving out, each ion attempting to drive the
motor end plate potential to its equilibrium potential. (MCQ)
§ Because other ion channels that influence membrane potential are present in the
end plate, the motor end plate only depolarizes to about 50 mV, which is the end
plate potential (EPP). (MCQ)
§ The EPP is not an action potential, but is simply a local depolarization of the
specialized motor end plate.
§ MEPP
• The content of a single synaptic vesicle produces the smallest possible
change in membrane potential of the motor end plate, the miniature end
plate potential (MEPP).
• MEPPs summate to produce the full-fledged EPP
• The spontaneous appearance of MEPPs proves the quantal nature of ACh
release at the neuromuscular junction.

• Each MEPP , which represents the content of one synaptic vesicle,
depolarizes the motor end plate by about 0.4 mV. (MCQ)
• An EPP is a multiple of these 0.4 mV units of depolarization. (MCQ)
• How many such quanta are required to depolarize the motor end plate
to the EPP? Because the motor end plate must be depolarized from its
resting potential of 90 mV to the threshold potential of 50 mV , it must,
therefore, depolarize by 40 mV . Depolarization by 40 mV requires 100
quanta (since each quantum or vesicle depolarizes the motor end plate by
0.4 mV).
• Depolarization of the motor end plate (the EPP) then spreads by local
currents to adjacent muscle fibers, which are depolarized to threshold and fire
action potentials. Although the motor end plate itself cannot fire action
potentials, it depolarizes sufficiently to initiate the process in the
neighboring “regular” muscle cells.
• Action potentials are propagated down the muscle fiber by a continuation
of this process.
§ The EPP at the motor end plate is terminated when ACh is degraded to choline
and acetate by acetyl- cholinesterase (AChE) on the motor end plate.
§ Approximately 50% of the choline is returned to the presynaptic terminal by Na+
-choline cotransport, to be used again in the synthesis of new ACh.
• Types of synaptic arrangements

o One-to-one synapses.
§ illustrated by the neuromuscular
o One-to-many synapses.
§ found, at the synapses of motoneurons on Renshaw cells of the spinal cord. (MCQ)
§ An action potential in the presynaptic cell, the motoneuron, causes a burst of action
potentials in the postsynaptic cells.
§ This arrangement causes amplification of activity.
o Many-to-one synapses.
§ most common arrangement in the nervous system.
• Synaptic input—excitatory and inhibitory postsynaptic potentials
o Excitatory Postsynaptic Potentials
§ Excitatory postsynaptic potentials (EPSPs)
§ EPSPs are produced by opening Na+ and K+ channels, similar to the nicotinic ACh
receptor. (MCQ)
§ Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine,
glutamate, and serotonin. (MCQ)
o Inhibitory Postsynaptic Potentials
§ IPSPs hyperpolarize the postsynaptic cell(MCQ)
§ IPSPs are produced by opening Cl– channels. (MCQ)
§ The membrane potential is driven toward the Cl equilibrium potential (approximately
90mV), which is a hyperpolarized state
§ Inhibitory neurotransmitters are g-aminobutyric acid (GABA) and glycine. (MCQ)
• Integration of synaptic information
o Spatial Summation
§ Spatial summation occurs when two or more presynaptic inputs arrive at a
postsynaptic cell simultaneously .
§ If both inputs are excitatory, they will combine to produce greater depolarization
than either input would produce separately.
§ If one input is excitatory and the other is inhibitory, they will cancel each other out. Spatial
summation may occur, even ifthe inputs are far apart on the nerve cell body, because EPSPs
and IPSPs are conducted so rapidly over the cell membrane.
o Temporal Summation
§ Temporal summation occurs when two presynaptic inputs arrive at the postsynaptic
cell in rapid succession
§ Because the inputs overlap in time, they summate.
o Other Phenomena That Alter Synaptic Activity
§ Facilitation, augmentation, and posttetanic potentiation
• phenomena that may occur at synapses
• repeated stimulation causes the response ofthe postsynaptic cell to be greater than
expected.
• The common underlying mechanism is believed to be an increased release of
neurotransmitter into the synapse, possibly caused by accumulation of Ca2+
in the presynaptic terminal (MCQ)
§ Long-term potentiation
• occurs in storage of memories
• involves both increased release of neurotransmitter from presynpatic
terminals and increased sensitivity of postsynaptic membranes to the
transmitter.
§ Synaptic fatigue
• occur where repeated stimulation produces a smaller than expected response
in the postsynaptic cell
• occur from the depletion of neurotransmitter stores from the presynaptic
terminal.
Topic- Cardiac conduction
Cardiac action potentials

o Origin and Spread of Excitation within the Heart
o Conducting cells
§ are specialized muscle cells
§ function to rapidly spread action potentials over the entire myocardium.
§ Have capacity to generate action potentials spontaneously. Except for the SA node,
however, this capacity normally is suppressed.
o The action potential spreads throughout the myocardium in the following sequence:
§ SA node.
• SA node serves as the pacemaker.
• Atrial internodal tracts and atria.
§ A V node.
• Conduction velocity through the A V node is considerably slower than in the
other cardiac tissues.
• Slow conduction through the A V node ensures that theventricles have
sufficient time to fill with blood before they are activated and contract.
§ Bundle of His, Purkinje system, and ventricles.
• The action potential is first conducted to the bundle of His through the
common bundle.
• It then invades the left and right bundle branches and then the smaller
bundles of the Purkinje system.
• Conduction through the His-Purkinje system is extremely fast, and it rapidly
distributes the action potential to the ventricles.
• The action potential also spreads from one ventricular muscle cell to the next,
via low- resistance pathways between the cells.
• Rapid conduction of the action potential throughout the ventricles is essential
and allows for efficient contraction and ejection of blood.
o To qualify as normal sinus rhythm, the following three criteria must be met:
§ The action potential must originate in the SA node.
§ The SA nodal impulses must occur regularly at a rate of 60 to 100 impulses per minute.
(MCQ)
§ The activation of the myocardium must occur in the correct sequence and with the
correct timing and delays.
o Action Potentials of Ventricles, Atria, and the Purkinje System

§ Long duration.
o In each of these tissues, the action potential is of long duration.
o These durations can be compared with the very brief duration of the action potential in
nerve and skeletal muscle (1 to 2 msec). (MCQ)
o The longer the action potential, the longer the cell is refractory to firing another action
potential. Thus, atrial, ventricular, and Purkinje cells have long refractory periods
compared with other excitable tissues. (MCQ)
§ Stable resting membrane potential.
o The cells of the atria, ventricles, and Purkinje system exhibit a stable, or constant, resting
membrane potential. (MCQ)
§ Plateau.
o The plateau is a sustained period of depolarization , which accounts for the long duration of
the action potential and, consequently , the long refractory periods. (MCQ)
§ The phases of the action potential
o Phase 0, upstroke.
§ In ventricular, atrial, and Purkinje fibers, the action potential begins with aphase of
rapid depolarization, called the upstroke.
§ As in nerve and skeletal muscle, the upstroke is caused by a transient increase inNa+
conductance (gNa), produced by depolarization-induced opening of activation
gates on the Na+ channels. (MCQ)
§ When gNa+ increases, there is an inward Na+ current (influx of Na+ into the cell), or
INa, which drives the membrane potential toward the Na+ equilibrium potential of
approximately + 65 mV .
§ However ,at the peak of the upstroke, the membrane potential is depolarized to a value
of about +20 mV – Why ?
• The membrane potential does not quite reach the Na+ equilibrium potential
because, as in nerve, the inactivation gates on the Na+ channels close in
response to depolarization (albeit more slowly than the activation gates open).
Thus, the Naþ channels open briefly and then close.
§ The rate of rise of the upstroke is called dV/dT.
• dV/dT varies, depending on the value of the resting membrane potential
• This dependence is called the responsiveness relationship
• Thus, dV/dT is greatest (the rate of rise of the upstroke is fastest) when the
resting membrane potential is most negative, or hyperpolarized (e.g., - 90
mV),
• dV/dT is lowest (the rate of rise of the upstroke is slowest) when the resting
membrane potential is less negative, or depolarized (e.g., - 60 mV).
• Reason
o This correlation is based on the relationship between membrane
potential and the position of the inactivation gates on the Na+
channel
o When the resting membrane potential is relatively hyperpolarized (e.g.,
- 90 mV),
§ the voltage-dependent inactivation gates are open
§ many Na+ channels are available for the upstroke.
o When the resting membrane potential is relatively depolarized (e.g., -
60 mV),
§ the inactivation gates on the Na+ channels tend to be closed
§ fewer Na+ channels are available to open during the upstroke.
• dV/dT also correlates with the size of the inward current (i.e., in ventricular,
atrial, and Purkinje fibers, the size of the inward Na+ current).
o Phase 1, initial repolarization.
§ for repolarization to occur, there must be a net outward current.
§ There are two explanations
• First, the inactivation gates on the Na+ channels close in response to
depolarization. When these gates close, gNa decreases, and the inward Na+
current (which caused the upstroke) ceases. (MCQ)
• Second, there is an outward K+ current, caused by the large driving force on
K+ ions: (MCQ)
§ At the peak of the upstroke, both the chemical and the electrical driving forces favor
K+ movement out of the cell
• intracellular K+ concentration is higher than extracellular K+
concentration(MCQ)
• cell interior is electrically positive (MCQ)
§ Because the K+ conductance (gK) is high, K+ flows out of the cell , down this steep
electrochemical gradient. (MCQ)
o Phase 2, plateau.
§ During the plateau, there is a long period (150 to 200 msec) of relatively stable,
depolarized membrane potential(MCQ)
§ Occur particularly in ventricular and Purkinje fibers
§ In atrial fibers, the plateau is shorter than in ventricular fibers. (MCQ)
§ There is an increase in Ca2+ conductance (gCa), which results in an inward Ca2+
current. (MCQ)
§ Inward Ca2+ current is also called slow inward current, reflecting the slower kinetics
of these channels (compared with the fast Na+ channels of the upstroke). The Ca2+
channels that open during the plateau are L-type channels (“L,” for long-lasting)
(MCQ)
• are inhibited by the Ca2+ channel blockersnifedipine, diltiazem, and
verapamil.
§ During the plateau, the inward Ca2+ current is balanced by the outward K+ current,
the net current is zero, and the membrane potential remains at a stable depolarized
value. (MCQ)
§ The significance of the inward Ca2+
• Ca2+ entry during the plateau of the action potential initiates the release of
more Ca2+ from intracellular stores for excitation-contraction coupling.
• This process of so-called Ca2+-induced Ca2+ release
o Phase 3, repolarization.
§ During phase 3, repolarization results from a combination of a
• decrease in gCa
• an increase in gK
o Phase 4, resting membrane potential, or electrical diastole.
§ The membrane potential fully repolarizes during phase 3 and returns to the resting level
of approximately - 85 mV (MCQ)
• Action Potentials in the Sinoatrial Node

o The following features of the action potential of the SA node are different from those in atria,
ventricles, and Purkinje fibers:
§ The SA node exhibits automaticity; (MCQ)
• it can spontaneously generate action potentials without neural input.
§ It has an unstable resting membrane potential, in direct contrast to cells in atrial,
ventricular, and Purkinje fibers.
§ It has no sustained plateau. (MCQ)
o The phases of the SA node action potential
§ Phase 0, upstroke.
• upstroke is not quite as rapid or as sharp as in the other types of cardiac
tissues.
• The ionic basis for the upstroke in the SA node differs as well. (MCQ)
o In the other myocardial cells, the upstroke is the result of an increase
in gNa and an inward Na+ current.
o In the SA nodal cells, the upstroke is the result of an increase in gCa
and an inward Ca2+ current.
• This inward Ca2+ current is carried predominantly in T-type Ca2+ channels
(“T,” for transient ) (MCQ)
o This is in contrast to the L-type channels responsible for the plateau in
ventricular cells
o T-type channels are not inhibited by L-type Ca2+ channel blockers
such as verapamil
§ Phases 1 and 2 are absent. (MCQ)
§ Phase 3, repolarization.
• As in the other myocardial tissues, repolarization in the SA node is due to an
increase in gK.
§ Phase 4, spontaneous depolarization or pacemaker potential.
• Phase 4 is the longest portion of the SA node action potential. (MCQ)
• This phase accounts for the automaticity of SA nodal cells
• During phase 4, the most negative value of the membrane potential (called
the maximum diastolic potential) is approximately - 65 mV , but the membrane
potential does not remain at this value. (MCQ)
• Rather, there is a slow depolarization, produced by the opening of Na+
channels and an inward Na+ current called If.
• The “f,” which stands for funny, denotes that this Na+ current differs from the
fast Na+ current responsible for the upstroke in ventricular cells.
• If is turned on by repolarization from the preceding action potential, thus
ensuring that each action potential in the SA node will be followed by
another action potential.
• Once If and slow depolarization bring the membrane potential to threshold,
the T-type Ca2+ channels are opened for the upstroke.
o The rate of phase 4 depolarization sets the heart rate.
§ If the rate of phase 4 depolarization increases, threshold is reached more quickly, the
SA node will fire more action potentials per time, and heart rate will increase.

§ Conversely , if the rate of phase 4 depolarization decreases, threshold is reached more
slowly, the SA node will fire fewer action potentials per time, and heart rate will
decrease
• Latent Pacemakers
o Latent pacemakers include the cells of the AV node, bundle of His, and Purkinje fibers.
o The rule is that the pacemaker with the fastest rate of phase 4 depolarization controls the heart
rate.
§ Normally, the SA node has the fastest rate of phase 4 depolarization, and therefore, it
sets the heart rate (MCQ)
§ Recall also that, of all myocardial cells, the SA nodal cells have the shortest action
potential duration (i.e., the shortest refractory periods). (MCQ)
§ Therefore, SA nodal cells recover faster and are ready to fire another action potential
before the other cell types are ready .
o Overdrive suppression
§ When the SA node drives the heart rate, the latent pacemakers are suppressed, a
phenomenon called overdrive suppression, (MCQ)
• Conditions in which a latent pacemaker takes over and becomes the ectopic pacemaker, or ectopic
focus
o If the SA node firing rate decreases (e.g., due to vagal stimulation) or stops completely
(MCQ)
o if the intrinsic rate of firing of one of the latent pacemakers should become faster than that
of the SA node , then it will assume the pacemaker role.
o if the conduction of action potentials from the SA node to the rest of the heart is blocked
because of disease in the conducting pathways
• Conduction velocity
o It is slowest in the AV node (0.01 to 0.05 m/sec) (MCQ)
o fastest in the Purkinje fibers (2 to 4 m/sec) (MCQ)
o It then takes a total of 220 msec for the action potential to spread through the atria, AV node,
and His-Purkinje system to the farthest points in the ventricles (MCQ)
o Conduction through the A V node (calledAV delay) requires almost one-half of the total
conduction time through the myocardium.
• Excitability and refractory periods
o Absolute refractory period.
§it occurs because most of the Na+ channels are closed. (MCQ)
§The absolute refractory period includes the upstroke, the entire plateau, and a
portion of the repolarization.
§ This period concludes when the cell has repolarized to approximately - 50 mV .
(MCQ)
o Effective refractory period.
§ it is slightly longer than, the absolute refractory period.
§ At the end of the effective refractory period, the Na+ channels start to recover (i.e.,
become available to carry inward current). (MCQ)
o Absolute VS effective refractory periods
§ absolute means absolutely no stimulus is large enough to generate another action
potential
§ effective means that a conducted action potential cannot be generated (i.e., there is
not enough inward current to conduct to the next site).
o Relative refractory period.
§ During the relative refractory period, even more Na+ channels have recovered and it
is possible to generate a second action potential, although a greater-than-normal
stimulus is required. (MCQ)
§ If a second action potential is generated during the relative refractory period, it will
have an abnormal configuration and a shortened plateau phase. (MCQ)
o Supranormal period.
§ supranormal period (SNP) follows the relative refractory period.
§ It begins when the membrane potential is - 70 mV and continues until the
membrane is fully repolarized back - 85 mV . (MCQ)
§ the cell is more excitable than normal during this period.
§ less inward current is required to depolarize the cell to the threshold potential.
§ Reason for Hyperexcitability
• Na+ channels are recovered (i.e., the inactivation gates are open again),
• because the membrane potential is closer to threshold than it is at rest, it is
easier to fire an action potential than when the cell membrane is at the resting
membrane potential.
Autonomic effects on the heart and blood vessels

o Autonomic Effects on Heart Rate

o Positive chronotropic effects
§ Norepinephrine, released from sympathetic nerve fibers, activates b1 receptors in the
SA node. (MCQ)
§ These b1 receptors are coupled to adenylyl cyclase through a Gs protein Activation
of b1 receptors in the SA node produces an increase in If, which increases the rate of
phase 4 depolarization. (MCQ)
§ Increasing the rate of phase 4 depolarization means that the SA node is depolarized to
threshold potential more frequently (MCQ)
§ It fires more action potentials per unit time (i.e., increased heart rate).
o Negative chronotropic effects
§ Acetylcholine (ACh), released from parasympathetic nerve fibers, activates muscarinic
(M2) receptors in the SA node. (MCQ)
§ Activation of muscarinic receptors in the SA node has two effects
• First, these muscarinic receptors are coupled to a type of Gi protein called GK
that inhibits adenylyl cyclase and produces a decrease in If.
o A decrease in If decreases the rate of phase 4 depolarization (MCQ)
• Second, Gk directly increases the conductance of a K+ channel called K+-ACh
and increases an outward K+ current called IK-ACh.
o Enhancing this outward K+ current hyperpolarizes the maximum
diastolic potential so that the SA nodal cells are further from
threshold potential.
§ Summary : Parasympathetic nervous system decreases heart rate through two major
effects on the SA node:
• Slowing the rate of phase 4 depolarization , (MCQ)
• Hyperpolarizing the maximum diastolic potential so that more inward
current is required to reach threshold potential.
§ As a result, the SA node is depolarized to threshold less frequently and fires fewer
action potentials per unit time (i.e., decreased heart rate)
o Dromotropic effects : Autonomic Effects on Conduction Velocity in the Atrioventricular Node

§ Conduction velocity correlates with the size of the inward current of the upstroke of
the action potential and the rate of rise of the upstroke , dV/dT.
§ Stimulation of the sympathetic nervous system
• produces an increase in conduction velocity through the A V node p ( ositive
dromotropic effect)
• The mechanism of the sympathetic effect is increased ICa, which is responsible
for the upstroke of the action potential in the AV node (as it is in the SA
node).
• Thus, increased ICa means increased inward current and increased
conduction velocity. (MCQ)
§ Stimulation of the parasympathetic nervous system

• produces a decrease in conduction velocity through the A V node n
( egative
dromotropic effect),
• it decreases the rate at which action potentials are conducted from the atria
to the ventricles.
• The mechanism of the parasympathetic effect is a combination of (MCQ)
o decreased ICa (decreased inward current)
o increased IK-ACh (increased outward Kþ current, which further reduces
net inward current).

§ Sympathetic stimulation increases the rate of phase 4 depolarization and increases the
frequency of action potentials.
§ Parasympathetic stimulation decreases the rate of phase 4 depolarization and hyperpolarizes
the maximum diastolic potential to decrease the frequency of action potentials.
Topic- Cardiac conduction
Cardiac action potentials
o Origin and Spread of Excitation within the Heart

o Conducting cells
§ are specialized muscle cells
§ function to rapidly spread action potentials over the entire myocardium.
§ Have capacity to generate action potentials spontaneously. Except for the SA node,
however, this capacity normally is suppressed.
o The action potential spreads throughout the myocardium in the following sequence:
§ SA node.
• SA node serves as the pacemaker.
• Atrial internodal tracts and atria.
§ A V node.
• Conduction velocity through the A V node is considerably slower than in the
other cardiac tissues.
• Slow conduction through the A V node ensures that theventricles have
sufficient time to fill with blood before they are activated and contract.
§ Bundle of His, Purkinje system, and ventricles.
• The action potential is first conducted to the bundle of His through the
common bundle.
• It then invades the left and right bundle branches and then the smaller
bundles of the Purkinje system.

• Conduction through the His-Purkinje system is extremely fast, and it rapidly
distributes the action potential to the ventricles.
• The action potential also spreads from one ventricular muscle cell to the next,
via low- resistance pathways between the cells.
• Rapid conduction of the action potential throughout the ventricles is essential
and allows for efficient contraction and ejection of blood.
o To qualify as normal sinus rhythm, the following three criteria must be met:
§ The action potential must originate in the SA node.
§ The SA nodal impulses must occur regularly at a rate of 60 to 100 impulses per minute.
(MCQ)
§ The activation of the myocardium must occur in the correct sequence and with the
correct timing and delays.
o Action Potentials of Ventricles, Atria, and the Purkinje System
§ Long duration.
o In each of these tissues, the action potential is of long duration.
o These durations can be compared with the very brief duration of the action potential in
nerve and skeletal muscle (1 to 2 msec). (MCQ)
o The longer the action potential, the longer the cell is refractory to firing another action
potential. Thus, atrial, ventricular, and Purkinje cells have long refractory periods
compared with other excitable tissues. (MCQ)
§ Stable resting membrane potential.
o The cells of the atria, ventricles, and Purkinje system exhibit a stable, or constant, resting
membrane potential. (MCQ)
§ Plateau.
o The plateau is a sustained period of depolarization , which accounts for the long duration of
the action potential and, consequently , the long refractory periods. (MCQ)
§ The phases of the action potential
o Phase 0, upstroke.
§ In ventricular, atrial, and Purkinje fibers, the action potential begins with aphase of
rapid depolarization, called the upstroke.

§As in nerve and skeletal muscle, the upstroke is caused by a transient increase inNa+
conductance (gNa), produced by depolarization-induced opening of activation
gates on the Na+ channels. (MCQ)
§ When gNa+ increases, there is an inward Na+ current (influx of Na+ into the cell), or
INa, which drives the membrane potential toward the Na+ equilibrium potential of
approximately + 65 mV .
§ However ,at the peak of the upstroke, the membrane potential is depolarized to a value
of about +20 mV – Why ?
• The membrane potential does not quite reach the Na+ equilibrium potential
because, as in nerve, the inactivation gates on the Na+ channels close in
response to depolarization (albeit more slowly than the activation gates open).
Thus, the Naþ channels open briefly and then close.
§ The rate of rise of the upstroke is called dV/dT.
• dV/dT varies, depending on the value of the resting membrane potential
• This dependence is called the responsiveness relationship
• Thus, dV/dT is greatest (the rate of rise of the upstroke is fastest) when the
resting membrane potential is most negative, or hyperpolarized (e.g., - 90
mV),
• dV/dT is lowest (the rate of rise of the upstroke is slowest) when the resting
membrane potential is less negative, or depolarized (e.g., - 60 mV).
• Reason
o This correlation is based on the relationship between membrane
potential and the position of the inactivation gates on the Na+
channel
o When the resting membrane potential is relatively hyperpolarized (e.g.,
- 90 mV),
§ the voltage-dependent inactivation gates are open
§ many Na+ channels are available for the upstroke.
o When the resting membrane potential is relatively depolarized (e.g., -
60 mV),
§ the inactivation gates on the Na+ channels tend to be closed
§ fewer Na+ channels are available to open during the upstroke.
• dV/dT also correlates with the size of the inward current (i.e., in ventricular,
atrial, and Purkinje fibers, the size of the inward Na+ current).
o Phase 1, initial repolarization.
§ for repolarization to occur, there must be a net outward current.
§ There are two explanations
• First, the inactivation gates on the Na+ channels close in response to
depolarization. When these gates close, gNa decreases, and the inward Na+
current (which caused the upstroke) ceases. (MCQ)
• Second, there is an outward K+ current, caused by the large driving force on
K+ ions: (MCQ)
§ At the peak of the upstroke, both the chemical and the electrical driving forces favor
K+ movement out of the cell

• intracellular K+ concentration is higher than extracellular K+
concentration(MCQ)
• cell interior is electrically positive (MCQ)
§ Because the K+ conductance (gK) is high, K+ flows out of the cell , down this steep
electrochemical gradient. (MCQ)
o Phase 2, plateau.
§ During the plateau, there is a long period (150 to 200 msec) of relatively stable,
depolarized membrane potential(MCQ)
§ Occur particularly in ventricular and Purkinje fibers
§ In atrial fibers, the plateau is shorter than in ventricular fibers. (MCQ)
§ There is an increase in Ca2+ conductance (gCa), which results in an inward Ca2+
current. (MCQ)
§ Inward Ca2+ current is also called slow inward current, reflecting the slower kinetics
of these channels (compared with the fast Na+ channels of the upstroke). The Ca2+
channels that open during the plateau are L-type channels (“L,” for long-lasting)
(MCQ)
• are inhibited by the Ca2+ channel blockersnifedipine, diltiazem, and
verapamil.
§ During the plateau, the inward Ca2+ current is balanced by the outward K+ current,
the net current is zero, and the membrane potential remains at a stable depolarized
value. (MCQ)
§ The significance of the inward Ca2+
• Ca2+ entry during the plateau of the action potential initiates the release of
more Ca2+ from intracellular stores for excitation-contraction coupling.
• This process of so-called Ca2+-induced Ca2+ release
o Phase 3, repolarization.
§ During phase 3, repolarization results from a combination of a
• decrease in gCa
• an increase in gK
o Phase 4, resting membrane potential, or electrical diastole.
§ The membrane potential fully repolarizes during phase 3 and returns to the resting level
of approximately - 85 mV (MCQ)

Topic - Action potential
Diffusion Potentials and Equilibrium Potentials
• Ion channels
o integral membrane proteins that, when open, permit the passage of certain ions. ion
channels are selective
• selectivity is based on both
o the size of the channel
o charges lining it.
• Ion channels are controlled by gates
• depending on the position of the gates, the channels may be open or closed.
• Voltage-gated channels
o open and close in response to changes in membrane potential
o activation gate on the nerve Na+ channel (MCQ)
§ opened by depolarization of the nerve cell membrane
§ opening of this channel is responsible for the upstroke of the action potential.
o inactivation gate of Na+ channel, (MCQ)
§ closed by depolarization.
o Because the activation gate responds more rapidly to depolarization than the inactivation
gate, the Na+ channel first opens and then closes.
• Ligand- gated channels
o open and close in response to binding of ligands such as hormones,neurotransmitters, or second
messengers.
o nicotinic receptor on the motor end plate is actually an ion channel that opens when
acetylcholine (ACh) binds to it(MCQ)
§ when open, it is permeable to Na+ and K+ ions. (MCQ)
• Diffusion potentials
o A diffusion potential is the potential difference generated across a membrane when an ion
diffuses down its concentration gradient.
o a diffusion potential can be generated only if the membrane is permeable to that ion.
o The magnitude of a diffusion potential depends on the size of the concentration gradient,
where the concentration gradient is the driving force.
o diffusion potentials are created by the movement of only a few ions , and they do not cause
changes in the concentration of ions in bulk solution.
• Equilibrium potentials
o The equilibrium potential is the diffusion potential that exactly balances or opposes the
tendency for diffusion down the concentration difference.
• Nernst equation
o is used to calculate the equilibrium potential for an ion at a given concentration difference
across a membrane, assuming that the membrane is permeable to that ion. By definition, the
equilibrium potential is calculated for one ion at a time.
§ R is the gas constant,

§ T is the absolute temperature

§ F is Faraday’s constant
o By convention, membrane potential is expressed as intracellular potential relative to
extracellular potential. Hence, a transmembrane potential difference of 70 mV means 70
mV, cell interior negative. (MCQ)
o Typical values for equilibrium potential for common ions
o Resting Membrane Potential

o The resting membrane potential is the potential difference that exists across the
membrane of excitable cells , such as nerve and muscle, in the period between action
potentials (i.e., at rest).
o The resting membrane potential is established by diffusion potentials, which result
from the concentraion differences for various ions across the cell membrane.
concentration differences have been established by primary and secondary active
transport mechanisms
o Each permeant ion attempts to drive the membrane potential toward its own
equilibrium potential
o Ions with the highest permeabilities or conductances at rest will make the greatest
contributions to the resting membrane potential
o The resting membrane potential of excitable cells falls in the range of –70 to –80mV
(MCQ)
o the resting membrane potential is close to the equilibrium potentials for K+ and
Cl- because the permeability to these ions at rest is high. (MCQ)
o The resting membrane potential is far from the equilibrium potentials for Na+ and
Ca2+ because the permeability to these ions at rest is low. (MCQ)
o Action Potentials
o The action potential consists of a rapid depolarization (upstroke) followed by
repolarization of the membrane potential.
o Depolarization is t(MCQ)he process of making the membrane potential less
negative.
§ the usual resting membrane potential of excitable cells is ori- ented with the
cell interior negative
§ Depolarization makes the interior of the cell less negative , or it may even
cause the cell interior to become positive.(MCQ)
o Hyperpolarization
§ the process of making the membrane potential more negative. (MCQ)
o Inward current
§ flow of positive charge into the cell.
§ inward currents depolarize the membrane potential.
§ An example of an inward current is the flow of Na+ into the cell during the
upstroke of the action potential. (MCQ)
o Outward current
§ flow of positive charge out of the cell.
§ Outward currents hyperpolarize the membrane potential.
§ An example of an outward current is the flow of K+ out of the cell during the
repolarization phase of the action potential. (MCQ)
o Threshold potential
§ membrane potential at which occurrence of the action potential is inevitable.
Because the threshold potential is less negative than the resting membrane
potential, an inward current is required to depolarize the membrane potential
to threshold.
§ At threshold potential, net inward current (e.g., inward Na+ current) becomes
larger than net outward current (e.g., outward K+ current), and the resulting
depolarization becomes self-sustaining, giving rise to the upstroke of the
action potential. (MCQ)
§ If net inward current is less than net outward current, the membrane will not
be depolarized to threshold, and no action potential will occur (all-or-none
response). (MCQ)
o Overshoot is that portion of the action potential where the membrane potential is
positive (cell interior positive).
o Undershoot, or hyperpolarizing afterpotential, is that portion of the action potential ,
following repolarization, where the membrane potential is actually more negative
than it is at rest.
o Refractory period is a period during which another normal action potential cannot be
elicited in an excitable cell. Refractory periods can be absolute or relative.
o Characteristics of action potentials
o Action potentials have three basic characteristics(MCQ)
§ stereotypical size and shape
§ propagation
§ all-or-none response.
o Stereotypical size and shape.
§ Each normal action potential for a given cell type looks identical, depolarizes
to the same potential, and repolarizes back to the same resting potential.
o Propagation.
§ An action potential at one site causes depolarization at adjacent sites,
bringing those adjacent sites to threshold
§ Propagation of action potentials from one site to the next is nondecremental.
o All-or-none response.
§ If an excitable cell is depolarized to threshold in a normal manner, then the
occurrence of an action potential is inevitable(MCQ)
§ On the other hand, if the membrane is not depolarized to threshold, no
action potential can occur. (MCQ)
o Ionic basis of the action potential
o Resting membrane potential.
§ At rest, the membrane potential is approximately 70 mV (cell interior
negative). (MCQ)
§ The K+ conductance or permeability is high (MCQ)
§ K+ channels are almost fully open (MCQ)
§allows K+ ions to diffuse out of the cell down the existing concentration
gradient.
§ This diffusion creates a K+ diffusion potential, which drives the membrane
potential toward the K+ equilibrium potential.
§ The conductance to Cl- also is high, and, at rest, Cl- also is near
electrochemical equilibrium. (MCQ)
§ At rest, the Na+ conductance is low, and, thus, the resting membrane potential
is far from the Na+ equilibrium potential. (MCQ)
o Upstroke of the action potential.
§ An inward current occurs usually the result of current spread from action
potentials at neighboring sites
§ An inward current causes depolarization of the nerve cell membrane to
threshold, which occurs at approximately 60 mV . (MCQ)
§ This initial depolarization causes rapid opening of the activation gates of the
Na+ channel, and the Na+ conductance promptly increases and becomes
even higher than the K+ conductance (MCQ)
§ The increase in Na+ conductance results in an inward Na+ current; the
membrane potential is further depolarized toward, but does not quite reach,
the Na+ equilibrium potential of +65 mV . (MCQ)
§ Tetrodotoxin , lidocaine block these voltage-sensitive Na+ channels and
prevent the occurrence of nerve action potentials. (MCQ)
o Repolarization of the action potential.
§ The upstroke is terminated, and the membrane potential repolarizes to the
resting level as a result of two events.
§ First, the inactivation gates on the Na+ channels respond to depolarization
by closing, (MCQ)
• but their response is slower than the opening of the activation gates.
• Thus, after a delay, the inactivation gates close the Na+ channels,
terminating the upstroke.
§ Second, depolarization opens K+ channels
• increases K+ conductance to a value even higher than occurs at rest.
(MCQ)
§ The combined effect of closing of the Na+ channels and greater opening of
the K+ channels makes the K+ conductance much higher than the Na+
conductance. Thus, an outward K+ current results, and the membrane is
repolarized. (MCQ)
§ Tetraethylammonium (TEA) blocks these voltage-gated K+ channels, the
outward K+ current, and repolarization.
o Hyperpolarizing afterpotential (undershoot).
§ For a brief period following repolarization, the K+ conductance is higher than
at rest, and the membrane potential is driven even closer to the K+
equilibrium potential (hyperpolarizing afterpotential). (MCQ)
§ Eventually , the K+ conductance returns to the resting level, and the
membrane potential depolarizes slightly , back to the resting membrane potential.
§ The membrane is now ready , if stimulated, to generate another action
potential.
§ Functions of activation and inactivation gates on the nerve Na+ channel. (MCQ)
o At rest, the activation gate is closed and the inactivation gate is open.
o During the upstroke of the action potential, both gates are open and Na+ flows into the
cell down its electrochemical potential gradient.
o During repolarization, the activation gate remains open but the inactivation gate is
closed.

Refractory periods
§ Absolute Refractory Period

o The absolute refractory period overlaps with almost the entire duration of the action
potential.
o During this period, no matter how great the stimulus, another action potential cannot be
elicited.
o The basis for the absolute refractory period is closure of the inactivation gates of the
Na+ channel in response to depolarization. (MCQ)
o These inactivation gates are in the closed position until the cell is repolarized back to
the resting membrane potential (MCQ)
§ Relative Refractory Period
o The relative refractory period begins at the end of the absolute refractory period and
overlaps primarily with the period of the hyperpolarizing afterpotential. (MCQ)
o During this period, an action potential can be elicited, but only if a greater than usual
depolarizing (inward) current is applied.
o The basis for the relative refractory period is the higher K+ conductance than is present at
rest. (MCQ)

o Because the membrane potential is closer to the K+ equilibrium potential, more inward
current is needed to bring the membrane to threshold for the next action potential to be
initiated. (MCQ)
§ Accommodation
o When a nerve or muscle cell is depolarized slowly or is held at a depolarized level, the
usual threshold potential may pass without an action potential having been fired.
o This process, called accommodation, occurs because depolarization closes inactivation
gates on the Na+ channels.
o If depolarization occurs slowly enough, the Na+ channels close and remain closed.
o The upstroke of the action potential cannot occur, because there are not enough Na+
channels available to carry inward current. (MCQ)
o An example of accommodation is seen in persons who have an hyperkalemia. (MCQ)
§ At rest, nerve and muscle cell membranes are very permeable to K+; an increase in
extracellular K+ concentration causes depolarization of the resting membrane (as
dic- tated by the Nernst equation).
§ This depolarization brings the cell membrane closer to threshold and would
seem to make it more likely to fire an action potential. (MCQ)
§ However, the cell is actually less likely to fire an action potential, because this
sustained depolarization closes the inactivation gates on the Na+ channels.
(MCQ)
Topic- Altitude physiology
Adaptation to high altitude
§ Ascent to high altitude causes hypoxemia. (MCQ)

o At sea level, the barometric pressure is 760 mm Hg
o at 18,000 feet above sea level
§ the barometric pressure is one-half that value, or 380 mm Hg.
§ PO2 = 70 mm Hg
§ Hyperventilation
o The most significant response to high altitude is hyperventilation
o if alveolar PO2 is 60 mm Hg, then arterial blood will have a PO2 of 60 mm Hg, in which
case the hypoxemia is severe enough to stimulate peripheral chemoreceptors in the carotid
and aortic bodies. . (MCQ)
o In turn, the chemoreceptors instruct the medullary inspiratory center to increase the
breathing rate.
o A consequence of the hyperventilation is respiratory alkalosis.
§ Offsetting effect of of respiratory alkalosis on hyperventilation
• decrease in PCO2 and the resulting increase in pH will inhibit central and
peripheral chemoreceptors and offset the increase in ventilation rate. . (MCQ)
• These offsetting effects of CO2 and pH occur initially, but within several
days HCO3- excretion increases, HCO3_ leaves the CSF, and the pH of the
CSF decreases toward normal.
• Thus, within a few days, the offsetting effects are reduced and
hyperventilation resumes.

§ The respiratory alkalosis that occurs as a result of ascent to high altitude can be
treated with carbonic anhydrase inhibitors (e.g., acetazolamide).
§ These drugs increase HCO3- excretion, creating a mild compensatory metabolic
acidosis.
§ Polycythemia
o Ascent to high altitude produces polycythemia and, as a consequence, an increase in
hemoglobin concentration.
o The increase in hemoglobin concentration means that the O2-carrying capacity is increased,
which increases the total O2 content of blood in spite of arterial PO2 being decreased. .
(MCQ)
o polycythemia increases blood viscosity, whichincreases resistance to blood flow
o The stimulus for polycythemia is hypoxemia, which increases the synthesis of erythropoietin in
the kidney .
§ 2,3-DPG and O2-Hemoglobin Dissociation Curve
o One of the most interesting features of the body’s adaptation to high altitude is an increased
synthesis of 2,3-DPG by red blood cells.
o The increased concentration of 2,3-DPG causes the O2 hemoglobin dissociation curve to
shift to the right. . (MCQ)
o This right shift is advantageous in the tissues, since it is associated with
o increased P50, decreased affinity , and increased unloa ing of O2.
o However, the right shift is disadvantageous in the lungs because it becomes more difficult to
load the pulmonary capillary blood with O2.
§ Pulmonary Vasoconstriction
o At high altitude, alveolar gas has a low Po2, which has a direct vasoconstricting effect on the
pulmonary vasculature (i.e., hypoxic vasoconstriction).. (MCQ)
o s pulmonary vascular resistance increases, pulmonary arterial pressure also must increase
to maintain a constant blood flow .
o The right ventricle must pump against this higher pulmonary arterial pressure and may
hypertrophy in response to the increased afterload. . (MCQ)
§ Acute Altitude Sickness
o The initial phase of ascent to high altitude is associated with a constellation of complaints,
including headache, fatigue, dizziness, nausea, palpitations, and insomnia.
o The symptoms are attributable to the initial hypoxia and respiratory alkalosis, which abate
when the adaptive responses are established. . (MCQ)
Topic- eeg
Electroencephalogram (EEG)
• EEG waves originate from alternating excitatory and inhibitory synaptic potentials that produce
sufficient extracellular current flow across the cortex to be detected by surface electrodes.
• EEG waves are not action potentials. . (MCQ)
• Beta rhythm
o 13–30 Hz . (MCQ)
o dominant frequency in a normal, awake adult with eyes open

o recorded over the parietal and occipital lobes . (MCQ)
o consists of desynchrononous low-voltage, high-frequency waves.
• Alpha rhythm
o 8–13Hz
o dominant frequency with eyes closed . (MCQ)
o has more synchronous waves of higher voltage and lower frequency.
• Slow-wave sleep
o As a person falls asleep, he or she passes through four stages of slow-wave sleep.
o In Stage 1
§ the alpha waves seen in an awake adult with eyes closed are interspersed withlower-
frequency theta waves. (MCQ)
o In Stage 2
§ low-frequency waves are interspersed with
§ high-frequency bursts called sleep spindles and
§ large, slow potentials called K complexes. (MCQ)
o In Stage 3
§ there are very low-frequency delta waves and occasional sleep spindles.
o Stage 4
§ characterized by delta waves. (MCQ)
• REM sleep
o Approximately every 90 minutes, the slow-wave sleep pattern changes to rapid eye
movement (REM) sleep. (MCQ)
o EEG becomes desynchronized, with low-voltage, high- frequency waves that resemble
those in an awake per-son.
o REM sleep is sometimes called paradoxical sleep:
§ Even though the EEG is most similar to that of the awake state, the person is
(paradoxically) most difficult to awaken.
o REM sleep is characterized by . (MCQ)
§ loss of muscle tone ,
§ notably in the eye muscles resulting in rapid eye movements
§ loss of temperature regulation
§ pupiary constriction
§ penile erection
§ fluctuations in heart rate, blood pressure, and respiration.
o Most dreams occur during REM sleep. . (MCQ)
o The proportion of slow-wave sleep and REM sleep varies over the life span.
§ Newborns spend half of their sleep in REM sleep . (MCQ)
§ young adults spend about 25% of sleep in REM sleep
§ elderly have little REM sleep

Electroencephalo- gram of an awake subject and of subjects in Stages 1, 2, 4, and REM sleep
Topic – Ovulation
Female Reproductive Hormones
• Fetal Life
o No HY antigen is produced; therefore, the indifferent gonad develops into an ovary.
o Lack of MIH allows the Müllerian ducts to develop into the uterus and fallopian tubes.
(MCQ)

o Lack of testosterone causes Wolffian ducts to degenerate and prevents development of
male structures.
• Synthesis of Estrogens
o Theca cells are the major sources of 17-alpha -hydroxyprogesterone and of an-
drostenedione (the principle androgen produced by the ovary). (MCQ)
o Granulosa cells are the major source of estradio l (E2). (MCQ)
o LH stimulates progesterone synthesis from pregnenolone. (MCQ)
o Significant amounts of estrogens are produced by the peripheral aromatization of
androgens.
o In human males, the peripheral aromatization of testo terone to E2 accounts for 80% of
the production rate of estrogens . (MCQ)
o In females, as much as 50 % of the E2 produced during pregnancy comes from the
aromatization of the adrenal androgen DHEA sulfate. (MCQ)
o The conversion of androstenedione to estrone (E1) , is the major source of estrogens in
postmenopausal women(MCQ)
o Aromatase activity is present in adipose cells and in liver, skin, and other tissues.
• Physiologic Effects of Estrogen
o Estrogen is responsible for development of female secondary sex characteristics
including
§ Narrow shoulders
§ Broad hips and wider carrying angle
§ Divergent arms
§ Convergent thighs and wider pelvic inlet
o Estrogen has the following endocrine organ effects:
§ It increases keratinization of the vaginal lining for protection.
§ It increases profuse watery secretion of cervix long threads (spinnbarkheit) used
clinically to indicate that ovulation is imminent. (MCQ)
§ It enhances the growth of the endometrial (secretory) layer , making it 3–4 times
thicker.
§ Increased actin and myosin of myometrium and sensitivity to oxytocin content to
promote spontaneous contractions to facilitate sperm transport.
§ Estrogen enhances spontaneous contractility of uterine tubules to facilitate
sperm movement for fertilization.
§ The number of LH receptors on ovarian follicles increases, and follicular growth
increases. (MCQ)
§ Estrogen enhances ductal development (ie, number and size) in the breast. (MCQ)
o Estrogen has the following metabolic effects:
§ It lowers blood levels of cholesterol and inhibits atherogenesis
§ High doses, however, promote thrombosis.
§ It increases Ca2+ retention. Thus, at menopause, Ca2+ loss occurs. (MCQ)
§ Estrogen also promotes growth spurts and then closure of epiphyseal plates.
§ Estrogen increases the number of steroid-binding proteins (eg, thyroglobulin)
synthesized by the liver.
• Progesterone
o Progesterone has the following endocrine effects:
§ It increases leukocyte infiltration in vaginal epithelium.
§ It produces a thick cervical mucous resistant to the penetration of spermatozoa
(natural fertilization barrier).
§ It decreases uterine spontaneous activity and sensitivity to oxytocin, while
increasing endometrial gland secretion.
§ It stimulates lobular alveolar gland growth in the breast. (MCQ)
o Progesterone has the following metabolic effects:
§ It induces natriuresis (Na+ loss from the kidney) by competing for aldosterone
receptors. (MCQ)
§ It makes the respiratory system more sensitive to CO2, thereby increasing
respiratory rate. (MCQ)
§ It increases the basal body temperature by about 1C.
• Ovarian Cycle: Hormonal Regulation of Oogenesis
o The cycle begins with 15–30 follicles developing due to FSH stimulation.
o On day 6, one follicle begins to produce antifollicular compounds, which lead to atresia
of other follicles.
o The dominant follicle produces estrogen, which decreases FSH and LH by negative
feedback. (MCQ)
o Near midcycle, about 48 hours prior to ovulation, a huge increase in estrogen
production results in a positive feedback that causes a surge of gonadotropins
(primarily LH), leading to rupture of the follicle and ovulation 16–24 hours later. (MCQ)
o After ovulation, the follicular cavity fills with yellowish luteal cells due to luteinization of
the theca and granulosa cells (corpus luteum) resulting from LH stimulation.
o The corpus luteum produces progesterone and E2 for 8–9 days.
o The increased plasma levels of E2 and progesterone negatively feed back to keep FSH
and LH levels low. (MCQ)
o If fertilization does not occur, the corpus luteum then regresses (luteolysis).
o Days 1–14 of the ovarian cycle are called the follicular phase (preovulatory).
o The follicular phase is the most variable (MCQ)
o After ovulation, the luteal phase (postovulatory) begins with corpus luteum functioning.
o luteal phase is always 14 days.
§ Thus, the day of ovulation can be estimated by subtracting 14 days from the total
length of the menstrual cycle.
o LH levels continue to decline during the luteal phase, whereas FSH levels rise during the
late luteal phase due to a decline in E2 and progesterone secretion and removal of
negative feedback effects on the hypothalamo-hypophyseal complex. (MCQ)
• Uterine Cycle
o Menstruation occurs during days 1–5.
o Days 5–14
§ represent the proliferative phase
§ endometrium shed at menstruation is restored.
§ The endometrial lining increases in thickness three to four times
§ cells become edematous and more highly vascularized at ovulation.
§ The length of this phase is highly variable.
o Days 14–28
§ represent the secretory phase,
§ uterus prepares for implantation of the fertilized ovum .
§ After ovulation, glands become coiled and endometrial secretions increase.
(MCQ)
§ This phase always lasts 14 days. (MCQ)
§ If fertilization does not occur, hormonal support of the endometrium ceases
§ endometrium regresses, and a new cycle begins with first day of menstruation.
§ Hormonal Control of the Ovary
o GnRH stimulates production of FSH and LH. (MCQ)
o FSH and LH act on the ovary to stimulate follicular development and estrogen
production.
o Low levels of estrogen negatively feed back to the hypothalamus and anterior pituitary to
inhibit LH production(MCQ)
o Inhibin secretion exerts negative feedback on FSH secretion. (MCQ)
o High levels of estrogen also feed back positively to cause an LH surge.
o At midcycle, both negative feedback and positive feedback are present.
o High levels of estrogen dominate for at least 36 hours to positively feed back to the
pituitary , causing the LH and FSH surge that results in ovulation
o Most oral contraceptives contain a synthetic progestin and estrogen, which combine to
prevent gonadotropin release. (MCQ)
o Oral contraceptives are administered for 21 days, then withdrawn for 5–7 days to permit
menstrual flow to start again.
§ Indicators of Ovulation
o The approximate 1C temperature rise observed after ovulation is associated with
progesterone secretion by the corpus luteum.
o Cervical mucus increases and becomes watery, and spinnbarkheit can be formed,
associated with the estrogen peak prior to ovulation.
o Mittelschmerz (pain in the middle) may be felt; it is caused by irritated membranes at
ovulation.
o Spotting is associated with the fall of hormone support for the endometrium at midcycle.
Topic- Temperature regulation
Body Temperature Regulation
• Body Temperature Values

o Normal body temperature (from oral measurements) is 37C (98.6F).
o An individual’s temperature varies 0.5–0.7C throughout the day.
o Circadian variation.
§ Temperatures are lowest early in the morning and highest in the evening.
• Heat Production by the Body
o The specific dynamic action of ingested food is diet-induced thermogenesis
o Muscle activity is a major factor in determining metabolic rate and heat production.
o The increase in metabolic rate and heat production by catecholamines is termed the chemical
thermogenic action.
o When body temperature drops, there is increased sympathetic discharge and increased
release of epinephrine and norepinephrine from the adrenal medulla
o Thyroid hormones
§ increase metabolic rate and heat production

§ stimulate Na+/K+-ATPase activity. (MCQ)
§ in hyperthyroidism, temperature may be elevated 0.5C
§ in hypothyroidism, temperature may be depressed 0.5C.
o Brown fat
§ Brown fat cells are richly innervated by sympathetic nerve fibers. (MCQ)
§ Cold temperatures activate the sympathetic nervous system and activate
etareceptors in brown fat, thereby increasing metabolic rate and heat production.
(MCQ)
§ In human infants, brown fat may serve as a physiologic electric blanket.
• Heat Loss
o Sixty percent of heat loss is by radiation in the form of infrared heat waves when the
ambient temperature increases. (MCQ)
o Cutaneous vasodilation shifts blood to skin so that more heat can be lost.
o Conduction accounts for another 18% of heat loss.
o Convection currents replace warmed air with cooler air.
o Evaporation accounts for about 22% of heat loss and is due to sweating.
o Sweating
§ is primarily a sympathetic cholinergic response (MCQ)
§ postganglionic fibers release acetylcholine to activate sweat glands.
• Temperature Regulation Mechanisms
o The anterior hypothalamus contains temperature-sensitive cells. (MCQ)
o These cells increase their firing with increased temperature and decrease their firing with
decreased temperature.
o They may defend against increased body temperature by stimulating sweat-ing,
vasodilation, and sympathetic outflow to sweat glands.
o There are skin receptors for cold and hot.
§ The ratio of cold-to-hot receptors is about 10:1.
§ Interaction between cutaneous cold receptors and hypothalamic temperature-
sensitive cells is thought to be responsible for the body’s response to cold
temperatures.
o When anterior hypothalamus temperature-sensitive cells fire, they send signals thatinhibit the
cold-response centers in the posterior hypothalamus. (MCQ)
o With decreased temperatures, anterior hypothalamic cells decrease their firing and
posterior hypothalamic inhibition is removed. (MCQ)
o Stimulation of cold-response centers causes shivering, cutaneous vaso-
o constriction, and increased metabolism.
• Set Point
o If the body core temperature is below the set point, the posterior hypothalamus activates
heat-generating mechanisms (eg, shivering). (MCQ)
o If the body core temperature is above the set point, the posterior hypothalamus stimulates
heat loss mechanisms (eg, vasodilation of cutaneous vessels). (MCQ)
• Fever
o Endotoxin, a cell-wall lipopolysaccharide of gram-negative bacteria, is a potent exogenous
pyrogen.
o Phagocytic leukocytes act on exogenous pyrogens to produce endogenous pyrogens.
o Other endogenous pyrogens include
§ tumor necrosis factor-a
§ Beta and Gamma interferon
§ interleukin-6 (IL-6).
o Endogenous pyrogens are thought to act on the thermoregulatory center to change the set
point.
o IL-1 may act on cells in the hypothalamus and increase the release of prostaglandin E2,
which increases the set point. (MCQ)
o Prostaglandin release explains the antipyretic (fever-reducing) property ofaspirin.
o Steroids reduce fever by blocking arachidonic acid release from brain phospholipids, thus
preventing prostaglandin production.
• Cold-Induced Vasodilation
o The initial response to a cold environmental temperature is usually cutaneous
vasoconstriction. (MCQ)
o As body surface areas cool, vasodilation can occur.
o This vasodilation may be a protective response that prevents freezing of the body surface
(frostbite).
o The primary mechanism has been attributed to cold-induced paralysis of
o vascular smooth muscle.
o An example of cold-induced vasodilation in the human is the facial flush or “rosy cheeks”
of an individual on a cold day.
• DISORDERS OF THERMOREGULATION
o Hypothermia
§ It is defined as a core temperature below 35C. (MCQ)
o Heat stroke
§ body’s heat loss mechanisms fail(MCQ)
§ temperature rises to the point of tissue damage (eg, cerebral edema).
o Heat exhaustion
§ result of dehydration (MCQ)
§ occur due to excessive sweating
§ characterized by fatigue and dizziness.
o Malignant hyperthermia i
§ observed in individuals susceptible to inhalation anesthetic agents.
§ The increased heat production is due to increased muscle contraction and muscle
metabolism triggered by excessive Ca2+ release during stress. (MCQ)
Topic – Calcitonin
Hormones in Calcium Regulation
§ Three major systemic hormones are involved in calcium regulation

o parathyroid hormone (PTH)
o calcitonin
o calcitriol (1,25(OH)2D3)—the hormonally active metabolite of vitamin D3.
§ Calcium Balance
o Calcium intake averages 1000 mg/d in healthy adults (MCQ)
o about 350 mg are absorbed from the small intestine and enter the ECF each day . Roughly
150 mg are returned in gastric secretions.
o Thus, net absorption equals about 200 mg/d. (MCQ)
o Normally, 98% of the calcium filtered by the kidney is reabsorbed.
o Urinary loss equals about 200 mg/d. Thus, intestinal absorption is balanced by urinary
excretion.
o Nearly 99% of total body calcium is found in bone.
o A rapidly exchangeable pool of skeletal calcium is in equilibrium with calcium in the
ECF .
§ Plasma Calcium
o Plasma calcium exists in three forms:
§ Approximately 40% is bound to plasma protein, (primarily albumin)
§ 60% remains unbound and ultrafiltrable. (MCQ)
§ Ten percent of the total is bound to anions such as PO43−, citrate, and isocitrate.
(MCQ)
o Ionized or free Ca2+ makes up about 50% of the tota l and is the active plasma fraction.
o The equilibrium between ionized and protein-bound calcium depends on blood pH.
§ Acidosis decreases binding and increases ionized Ca2+ (MCQ)
§ Alkalosis increases binding and decreases ionized Ca2+. (MCQ)
§ Bone Cells
o Osteoblasts
§ found on the surfaces of bone
§ primarily responsible for bone formation.
§ As bone formation proceeds, osteoblasts become surrounded by bone matrix.
o Osteocytes
§ bone cells surrounded by calcified matrix.
§ They send processes into the canaliculi, which spread throughout the bone.
o Osteoclasts
§ large multinucleated cells responsible for bone resorption.
o The osteoid of bone
§ Composed of collagen and mucopolysaccharides.
§ Collagen is the most abundant protein found in humans.
§ Parathyroid Hormone
o PTH is a polypeptide produced in the parathyroid glands.
o Secretion is stimulated by a low plasma Ca2+ level and suppressed by a high plasma
Ca2+ level. (MCQ)
o The primary skeletal action of PTH is stimulation of osteoclastic bone resorption.
o In addition to stimulation of osteoclast activity, PTH also increases osteoclast numbers.
(MCQ)
o Resorption of bone by osteoclasts is dependent on
§ an increased H+ concentration in the resorption zone
§ increased release of lysosomal enzymes to promote breakdown of the bone matrix.
o PTH decreases the kidney tubular reabsorption of PO43−(MCQ)
o PTH increases the kidney tubular reabsorption of Ca2+. (MCQ)
o PTH stimulates increased intestinal Ca2+ absorption. (MCQ)
§ Calcitriol
o 7-Dehydrocholesterol is converted to cholecalciferol (vitamin D3) by sun- light

o Vitamin D3 is transported by a sterol binding protein to the liver where it is hydroxylated
to form 25-(OH)D3, the primary circulating form of vitamin D3.
o 25-(OH)D3 is transported to the kidney where hydroxylation occurs to form calcitriol,
the active metabolite of vitamin D3.
o Absence of calcitriol causes rickets (uncalcified osteoid).
o Factors that increase formation of vitamin D3 include (MCQ)
§ PTH
§ Low serum Ca2+
§ Hypophosphatemia (low serum phosphate)
§ Prolactin, GH, and insulin (though not as primary regulators)
o Calcitriol functions include (MCQ)
§ Increased Ca2+ and PO43- absorption by the small intestine
§ Increased tubular reabsorption of Ca2+ in the kidney
§ Stimulation of bone resorption with high concentrations
§ Calcitriol mediates the PTH effect of increased intestinal Ca2+ absorption.
§ Calcitonin
o Calcitonin is a polypeptide
o synthesized by parafollicular C cells of the thyroid gland. (MCQ)
o Excess plasma Ca2+ stimulates calcitonin release to block bone reabsorption. (MCQ)
o The nervous system releases calcitonin gene–related peptide (CGRP), a potent
vasodilator substance. (MCQ)
o Although calcitonin is a tumor marker for thyroid medullary carcinoma, calcitonin
deficiency and excess have no clinical manifestations.
Disorders affecting bone formation
§ Paget disease
o characterized by increased osteoclastic activity . (MCQ)
o Calcitonin is used clinically to decrease the high bone turnover associated with this
condition.
o Calcitonin can be used to treat hypercalcemia. (MCQ)
o The initial effect of calcitonin is to decrease bone resorption, lowering serum Ca2+
levels.
§ Hypoparathyroidism (MCQ)
o low PTH
o hypocalcemia
o hyperphosphatemia
o decreased PO 3- excretion.
§ Primary hyperparathyroidism causes (MCQ)
o Increased total plasma calcium (hypercalcemia)
o Increased ionized Ca2+ in the plasma
o Decreased plasma PO 3−(hypophosphatemia)
o Increased urinary PO 3−excretion (phosphaturia) 4
o Increased urinary Ca2+ when the plasma Ca2+ increases beyond the concentration the
kidney can reabsorb
§ Vitamin D deficiency is characterized by
o low serum Ca2+,which stimulates PTH secretion. (MCQ)

o This results in a form of secondary hyperparathyroidism.
§ Hypocalcemia
o Low extracellular free Ca2+ levels can result in hypocalcemic tetany .(MCQ)
o Extensive spasms of the skeletal muscles can occur.
o Laryngospasm can become so severe that the airway passage is obstructed and fatal
asphyxia produced.
Topic- Insulin
• Endocrine pancreas
o The beta cells compose 65% of the islet and secrete insulin.
o alpha cells com-pose 20% of the islet and secrete glucagon.
o delta (delta) cells compose 10% of the islet and secrete somato-statin.
o The remaining cells secrete pancreatic polypeptide or other peptides.
• INSULIN
o Structure and Synthesis of Insulin
§ Insulin is a peptide hormone
§ consists of two straight chains
• A chain (21 amino acids)
• B chain (30 amino acids).
§ Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is
located within the A chain. (MCQ)
§ The synthesis of insulin is directed by a gene on chromosome 11(MCQ)
§ The mRNA directs ribosomal synthesis of preproinsulin
§ preproinsulin contains four peptides: a signal peptide, the A and B chains ofinsulin , and a
connecting peptide (C peptide).
§ The signal peptide is cleaved very early in the biosynthetic process yielding proinsulin
§ The secretion of connecting peptide (C peptide) is the basis of a test for b-cell
function in persons with type I diabetes mellitus who are receiving injections of
exogenous insulin.
§ Insulin is metabolized in the liver and kidney by enzymes that break disulfide bonds.
(MCQ)

o Regulation of Insulin Secretion

o Mechanism of glucose induced insulin secretion
§ Transport of glucose into the b cell.
• The b-cell membrane contains GLUT 2 (MCQ)
• GLUT 2 , a specific transporter for glucose that moves glucose from the blood
into the cell by facilitated diffusion (MCQ)
§ Metabolism of glucose inside the b cell.
• Once inside the cell, glucose is phosphorylated to glucose-6- phosphate by
glucokinase
• glucose- 6-phosphate is subsequently oxidized
• ATP, one of the products of this oxidation step, appears to be the key factor
that regulates insulin secretion.
§ ATP closes ATP-sensitive K+ channels.(MCQ)
• K+ channels in the b-cell membrane are regulated (i.e., opened or closed) by
changes in ATP levels.

• When ATP levels inside the b cell increase, the K+ channels close which
depolarizes the b-cell membrane
§ Depolarization opens voltage-sensitive Ca2+ channels. (MCQ)
• Ca2+ channels are opened by depolarization and closed by
hyperpolarization.
§ Increased intracellular Ca2+ causes insulin secretion.
o Oral glucose is a more powerful stimulant for insulin secretion than intravenous glucose.
§ Reason for this difference : Oral glucose stimulates the secretion of glucose-
dependent insulinotropic peptide (GIP), a gastrointestinal hormone that has an
independent stimulatory effect on insulin secretion (MCQ)
o Glucagon
§ activates a Gq protein coupled to phospholipase C (MCQ)
§ it leads to a rise in intracellular Ca2+ (i.e., IP3/Ca2+), causing exocytosis of insulin.
o The sulfonylurea drugs (e.g., tolbutamide; glyburide)
§ stimulate insulin release from beta cells
§ by closing the ATP-dependent K+ channels, depolarizing the cell, and mimicking
the depolarization induced by glucose.
o Mechanism of Action of Insulin
o insulin receptor is a tetramer composed of two a subunits and two b subunits
o The b subunits have tyrosine kinase activity . (MCQ)
§ Activated tyrosine kinase phosphorylates several other proteins or enzymes including
protein kinases, phosphatases, phospholipases, and G proteins. (MCQ)
§ Phosphorylation either activates or inhibits these proteins to produce the various
metabolic actions of insulin.
o Insulin downregulates its own receptor by decreasing the rate of synthesis and increasing the
rate of degradation of the receptor.
§ Down-regulation of the insulin receptor is in part responsible for the decreased
insulin sensitivity of target tissues in obesity and type II diabetes mellitus.
o Actions of Insulin
o Decreases blood glucose concentration.
§ Insulin increases glucose transport into target cells such as muscle and adi-pose by
directing the insertion of glucose transporters (GLUT 4) into the cell membranes.
(MCQ)
§ Insulin promotes the formation of glycogen from glucose in the liver and in muscle
and, simultaneously, inhibits glycogenolysis (MCQ)
§ Insulin inhibits gluconeogenesis (synthesis of glucose) by increasing the production
of fructose 2,6-bisphosphate, which increases phosphofructokinase activity.
(MCQ)
• In effect, substrates are directed away from the formation of glucose.

§ Glucagon
o Mechanism of action of glucagon on its target cells
§ hormone bindS to a cell membrane receptor, which is coupled to adenylyl cyclase via
a Gs protein. (MCQ)
§ The second messenger is cAMP , which activates protein kinasesthat phosphorylate
various enzymes; (MCQ)
§ the phosphorylated enzymes then mediate the physiologic actions of glucagon.
o The major actions of glucagon are on the liver (in contrast to insulin, which acts on liver,
adipose, and muscle tissue).

§ SOMATOSTATIN
o Pancreatic somatostatin
§ a polypeptide with 14 amino acids
§ secreted by the delta cells of the islets of Langer- hans.
§ Secretion of somatostatin is stimulated by (MCQ)
• ingestion of all forms of nutrients (i.e., glucose, amino acids, and fatty acids),
• by several gastrointestinal hormones
• by glucagon
• by beta-adrenergic agonists.
§ Secretion of somatostatin is inhibited by insulin (MCQ)
Topic- Peristalsis
• Swallowing
o Swallowing is coordinated by the medullary swallowing center
o It is stimulated by sensory input from the mouth via cranial nerves V, IX, and X. (MCQ)
o 2 Phases
§ The oropharyngeal phase
• characterized by movement of food to the rear of mouth, elongation of the
soft palate
• During this phase , the following events occur
o Nasopharynx is closed off
o inhibition of respiration (MCQ)
o tipping over of the epiglottis to block the airway
o upward movement of the hyoid bone and larynx
o relaxation of the upper esophageal sphincter. (MCQ)
§ The esophageal phase
• characterized by a primary peristaltic wave that pushes the bolus toward the
stomach, and relaxation ofthe lower esophageal sphincter (LES) allows food to enter the
stomach.
• A secondary peristaltic wave clears residual material left behind.
• The LES
o a barrier to the reflux of the stomach contents into the esophagus
o in the resting state maintains a pressure higher than in the stomach.
• Foods that decrease LES pressure include chocolate, peppermint ,alcohol
(MCQ)
• high-protein meals increase LES pressure. (MCQ)
• Important hormones that decrease LES pressure include
o Progesterone (MCQ)
o CCK, (MCQ)
§ a GI peptide released from the small intestine in response to fat and
protein meals.
o The contraction and relaxation of the LES is mediated by neurotransmitters (both released by
parasympathetic innervation only)
§ acetylcholine, causes LES contraction (MCQ)
§ VIP and nitric oxide (NO), which cause LES relaxation. (MCQ)
• Gastric Motor Function A. Fed Motor Pattern
o After a meal, peristaltic waves move toward the antrum to the pyloric sphincter, slowly
propelling the mixture of food and gastric acid into the duodenum.
o Basic electrical rhythm (BER)
§ Peristalsis is controlled by a wave of partial depolarization known as the basic
electrical rhythm (BER) or slow wave.
§ The BER begins in a group of pacemaker cells in the greater curvature and sweeps
over the outer longitudinal muscle toward the pylorus. (MCQ)
§ The BER may or may not be accompanied by contraction ofunderlying circular muscle.
§ For example, when vagal fibers are activated by distention of the stomach, circular
muscle fibers are depolarized enough to bring them to threshold so that they have
action potentials and contraction occurs. (MCQ)
§ Contractions of circular muscle occur in step with the BER-induced depolarization
wave moving over the antrum.
§ Gastric waves occur only when BER depolarizations reach the threshold for action
potential discharges.
§ A BER reaching threshold is determined by a combination of stretch, neural (vagal),
and humoral (gastrin) stimuli.
o 3 major gastric motor activities of the fed stomach (A Very High yield topic for MD Entrance )
§ The three major gastric motor activities of the fed stomach include receptive
relaxation, mixing, and emptying.
§ With each swallow, the proximal stomach stretches to receive food from the
esophagus, which involves only a small rise in intragastric pressure (receptive
relaxation).
§ Receptive relaxation of the proximal stomach is a vagally mediated reflex.
§ The distal stomach grinds and mixes food to reduce bolus size so that it can be moved to
the small intestine through the pyloric sphincter.
§ Muscle contractions of the antrum control the amount of food that leaves the
stomach so as not to overload the digestive ability of the small intestine.
§ The amount of chyme (semi-fluid material produced by gastric digestion of food)
emptied depends on the
• strength ofthe peristaltic wave and the
• pressure gradient between the antrum and duodenum.
§ The pylorus limits the size of particles emptied and acts to prevent reflux ofduodenal
contents into the stomach.
§ The volume and composition (ie, osmolality, pH, and caloric content) of gastric
contents influence gastric emptying.
o Fasting Motor Pattern: Migrating Motor Complex (MMC)
§ The MMC is the pattern of a fasting or interdigestive state that is divided into three
phases
• Phase I
o quiescent period
o lasts 45–60 minutes
• phase II
o lasts 30–45 minutes
o 50% of slow waves are assoc ated with contractions.
• phase III
o 100% of slow waves are associated with strong contractions.
o this phase lasts only 5–10 minutes

o gastric material is moved large distances.
§ The MMC moves stomach contents through the intestine to the ileocecal valve during
overnight fasting. (MCQ)
§ The MMC performs a housekeeping function by sweeping gastric acid to the ileum to
prevent bacterial overgrowth in the gut. (MCQ)
§ The GI regulatory peptide, motilin, is associated with initiation of MMCs in the
stomach (MCQ)
§ Feeding interrupts MMC activity (MCQ)
• Control of Gastric Emptying
o Volume
§ Emptying of isotonic, noncaloric fluids is proportional to the volume or distention ofthe
stomach.
o Osmolality
§ Hypertonic and hypotonic fluid empty more slowly than isotonic fluids (MCQ)
o pH:
§ The lower the pH, the slower the emptying.
o Caloric content:
§ The duodenum regulates the delivery of calories .
o Particle size:
§ Large particles decrease the emptying rate.
o Intragastric pressure:
§ The greater the antral peristalsis and intragastric pressure, the faster the emptying.
o Pyloric sphincter resistance:
§ Greater resistance slows emptying and vice versa.
o Duodenal pressure
§ Increased duodenal pressure slows emptying and vice versa.
o Negative feedback
§ Control of emptying is mediated by neural and humoral factors activated by nutrients.
• Motility of the Small Intestine
o The small intestine is divided into three sections: the duodenum, jejunum, and ileum
§ Ninety-five percent of nutrients are usually absorbed by the time a meal reaches the
distal jejunum.
§ The remainder of the intestine is devoted primarily to absorption of water and
electrolytes.
§ The ileum has specific absorptive mechanisms for cobalamin (vitamin B12) and bile
acids. (MCQ)
§ Transit time through the small intestine is 2–4 hours for chyme.
o Normal contractile behavior of the small intestine.
§ Intestinal slow waves determine the frequency and patterns of contractions
§ The frequency of slow waves is highest in the proximal small intestine (12/min).
§ There is a stepwise decrease in frequency from the duodenum (12/min) to the
ileum (8/min). (MCQ)
§ Fed motor activities are associated with contractions are segmentation (mixing) and
peristalsis (propulsion)
• In the small intestine, contraction of circular muscle results from a temporary
removal of the inhibitory effects of the enteric nervous system.
• The timing of contractions is determined by slow wave depolarization.
• Segmentation
o characterized by isolated contractions
o moves chyme in both directions
o most common type of intestinal contraction.
o Segmentation increases the exposure of chyme to enzymes and
contact with absorbing cells.
o Peristalsis is not considered to be an important component of
intestinal transit because it moves chyme only a few centimeters at a time.
o In fasting motor activity , the purpose of MMCs is to keep the small intestine swept clean of
bacteria, undigestible meal residua, desquamated cells, and secretions.
§ When a segment of the intestine is severed, it generates spontaneous MMCs at a
rate higher than in the intact intestine.
§ Not every MMC progresses all the way to the terminal ileum.
§ Feeding (MCQ)
• interrupts the interdigestive MMC
• initiates the fed pattern of motility , which is more conducive to absorption than
the fasting pattern.
• infusion of neurotensin, a GI peptide released with feeding, is associated
with inhibition of MMCs
• Motility of the Colon and Rectum
o The colon conserves water and electrolytes
o Haustra, or colonic sacculations
§ result from the anatomic arrangement of the longitudinal muscle, which is
concentrated in three bundles, or teniae coli, instead of a solid sheath in the upper GI
tract.
§ There are no haustra in the lower colon or rectum because the longitudinal muscle
forms a uniform coat again.
o food transit through the colon is measured in days.
o The majority of mixing and delay in transit occurs in the right colon.
o The frequency of slow waves in the colon increases from proximal to distal incontrast to
that of the small bowel.
o Haustral segmentation contractions occur 90% of the time , shuttling contents slowly back
and forth to enhance absorption of water and electrolytes. (MCQ)
o Multihaustral segmentation, in which several haustra contract together and move contents a
short distance, occurs 10% of the time.
o Mass movements
§ occur usually after the first meal of the day and move material a long distance, often
stimulating the urge to defecate. (MCQ)
§ Mass movements are associated with the
• gastrocolic reflex, initiated by distention ofthe stomach with food,
• orthocolic reflex , stimulated by standing after reclining overnight.
o Defecation

§ Defecation urge is stimulated by distention of the rectal sigmoid area elicits the
rectosphincteric reflex, or relaxation ofthe internal anal sphincter, and voluntary contraction
of the external anal sphincter.
§ If defecation is not socially appropriate
• both the external and internal anal sphincter contract
• an adaptive relaxation reflex, or decreased sensitivity to rectal wall
distention, occurs.
§ If defecation is socially appropriate
• the internal and external anal sphincters relax
• a Valsalva maneuver, or forced expiration against a closed glottis, is
performed.
§ Mechanoreceptors in the rectal wall can discriminate between solid, liquid, or gas.
• This ability is lost in persons with ulcerative colitis due to mucosal damage.
o The contractile activity of the colon is inhibited by the enteric nervous system as in the small
intestine.
§ Stimulation of parasympathetic innervation increases colonic contraction. (MCQ)
§ Stimulation of sympathetic nerves to the colon suppress motility.
§ Fatty chyme in the ileum or colon releases peptide YY, which inhibits colonic and gastric
motility and gastric and pancreatic secretions. (MCQ)
Topic – Acidosis
• Acid-Base Balance
o An acid is a proton donor
o A base is a proton acceptor
o H+ is the acid and A−is the conjugate base in HA, a conjugate acid-base pair.
• Buffering Systems
o Buffers resist changes in pH when H+ ions are added to or removed from a solution.
o The capacity of a buffering system is related to its concentration and it pK (relative to pH).
o The major extracellular buffer is HCO3.(MCQ)
o Phosphate is a minor extracellular buffer that plays its most important role as a urinary
buffer.
o Intracellular buffers include organic phosphates (eg, ATP , ADP , and AMP) andproteins (of
which hemoglobin is a major one). .(MCQ)
o The Henderson-Hasselbalch equation is used to calculate pH:

• where
o pH = −log10 [H+]
o pK= −log10 equilibrium constant (pH units)
o [A−] = base form of buffer (mM);
o H+ acceptor [HA] = acid form of buffer (mM); H+ donor
o When the concentration of HA and A−are equal, the pH of the solution
equals the pK of the buffer.
• Acid Production in the Body

o Arterial pH is slightly alkaline (7.4) despite the production of large amounts of acid on a
daily basis.
o This acid production has two forms:
§ volatile acid (carbon dioxide, CO2)
§ nonvolatile, or fixed, acid.
o CO2
§ CO2, or volatile acid, is the end product of aerobic metabolism in the cells (MCQ)
§ generated at a rate of 13,000 to 20,000 millimoles daily (mmol/day).
§ CO2 itself is not an acid.
§ However, when it reacts with water (H2O), it is converted to the weak acid carbonic
acid, H2CO3: catalyzed by the enzyme carbonic anhydrase.
§ H2CO3 dissociates into H+ and HCO3-, and the H+ generated by this reaction must
be buffered.
§ CO2 produced by the cells is added to venous blood, converted to H+ and HCO3-
within the red blood cells, and carried to the lungs.
§ In the lungs, the reactions occur in reverse, and CO2 is regenerated and expired.
CO2 is therefore called a volatile acid
§ Thus, buffering of the H+ that comes from CO2 is only a temporary problem for
venous blood.
o FIXED ACID
§ Catabolism of proteins and phospholipids results in the production of approximately
50 mmol/day of fixed acid. (MCQ)
§ Proteins with the sulfur-containing amino acids (e.g., methionine, cysteine, and
cystine) generate sulfuric acid (MCQ)
§ phospholipids generate phosphoric acid.
§ fixed acids first must be buffered in the body fluids until they can be excreted by the kidneys.
§ pathophysiologic states where fixed acids can be produced in excessive quantities.
• ketoacids that are generated in untreated diabetes mellitus
o beta-hydroxybutyric acid
o acetoacetic acid
• lactic acid
o generated during strenuous exercise
o generated when the tissues are hypoxic
o fixed acids may be ingested,
• salicylic acid (from aspirin overdose)
• formic acid (from methanol ingestion),

• glycolic and oxalic acids (from ethylene glycol ingestion).
§ Extracellular fluid buffers
o The major buffers of the ECF are bicarbonate and phosphate. (MCQ)
§ For bicarbonate, the A- form is HCO3- and the HA form is CO2 (in equilibrium
with H2CO3).
§ For phosphate, the A- form is HPO4-and the HA form is H2PO4-
o HCO3-/CO2 Buffer
§ The most important extracellular buffer is HCO3- /CO2. (MCQ)
§ It is utilized as the first line of defense when H+ is gained or lost from the body.
§ Characteristics account for importance of HCO3- /CO2 as an ECF buffer:
• The concentration of the A- form, HCO3- , is high at 24mEq/L. (MCQ)
• The pK of the HCO3- /CO2 buffer is 6.1, which is fairly close to the pH of
ECF (MCQ)
• CO2, the acid form of the buffer, is volatile and can be expired by the
lungs
o HPO4-2/H2PO4- Buffer
§ Inorganic phosphate also serves as a buffer.
§ pK of the HPO4-/H2PO4- buffer is 6.8 (MCQ)
§ linear portion of its curve extends from pH 5.8 to 7.8.
§ inorganic phosphate would be a more important physiologic buffer than HCO3-
since its effective buffering range is closer to 7.4, the pH of blood.
§ However, two features of the HCO3- /CO2 buffer make it the more effective
buffer
• HCO3- is in much higher concentration (24 mmol/L) than phosphate (1
to 2 mmol/L).
• The acid form of the HCO3- /CO2 buffer is CO2, which is volatile and
can be expired by the lungs.
§ Intracellular fluid buffers
o There are vast quantities of intracellular buffers, which include
§ organic phosphates
§ proteins.
o To utilize these ICF buffers in acid-base disturbances, H+ firstmust cross the cell
membrane by one of the following 3 mechanisms
§ In conditions where there is an excess or a deficit ofCO2 , CO2 itself can cross the cell
membranes.
§ In conditions where there is an excess or a deficit offixed acid , H+ can enter or leave
the cell with an organic anion, such as lactate.
§ In other cases of excess or deficit of fixed H+ in which there is no
accompanying organic anion, H+ exchanges with K+ to preserve
electroneutrality.
o Although they are not present in ICF, plasma proteins also buffer H+.
§ A relationship exists between plasma proteins, H+, and calcium (Ca2+), which
results in changes in ionized Ca2+ concentration when there is an acid-base
disturbance. (MCQ)

§ Negatively charged groups on plasma proteins (e.g., albumin) can bind either
H+ or Ca2+. (MCQ)
§ Protein-binding of Ca2+ is extensive and accounts for 40% of total Ca2+. (MCQ)
§ In acidemia, there is an excess of H+ in blood. (MCQ)
• Because more H+ is bound to plasma proteins, less Ca2+ is bound,
producing an increase in free Ca2+ concentration.
§ In alkalemia, there is a deficit of H+ in blood. (MCQ)
• Because less H+ is bound to plasma proteins, more Ca2+ is bound,
producing a decrease in free Ca2+ concentration (hypocalcemia).
• Symptoms of hypocalcemia commonly occur in respiratory alkalosis and
include tingling, numbness, and tetany.
o Organic Phosphates
§ Organic phosphates in ICF include ATP , ADP , AMP , glucose-1-phosphate, and
2,3-diphosphoglycerate (2,3-DPG). (MCQ)
§ H+ is buffered by the phosphate moiety of these organic molecules.
§ The pKs for these organic phosphates range from 6.0 to 7.5, ideal for effective
physiologic buffering.
o Proteins
§ Intracellular proteins serve as buffers because they contain a large number of acidic
or basic groups such as COOH/COO - or NH3+/NH2.
§ Of all the dissociable groups on proteins, those with a pK in the physiologic range
are the imidazole group of histidine (pK 6.4 to 7.0) and the alpha amino groups
(pK 7.4 to 7.9). (MCQ)
§ The most significant intracellular buffer is hemoglobin, (MCQ)
• Each hemoglobin molecule has a total of 36 histidine
• The pK of oxyhemoglobin is 6.7, which is in the range for effective
physiologic buffering.
• Deoxyhemoglobin, however, is an even more effective buffer with a pK of
7.9. The change in the pK of hemoglobin when it releases oxygen (O2)
has physiologic significance.
• As blood flows through the systemic capillaries, oxyhemoglobin releases
O2 to the tissues and is converted to deoxyhemoglobin.
• At the same time, CO2 is added to systemic capillary blood from the
tissues.
• This CO2 diffuses into the red blood cells and combines with H2O to
form H2CO3. The H2CO3 then dissociates into H+ and HCO3- .
• The H+ generated is buffered by hemoglobin, which now is conveniently in
its deoxygenated form.
• Deoxyhemoglobin certainly must be an excellent buffer for H+: (MCQ)
• The pH of venous blood is 7.37, which is only 0.03 pH units more acidic
than the pH of arterial blood despite the addition of large amounts of acid as
CO2. (MCQ)
• Renal Mechanisms in Acid-Base Balance
o The kidneys play two major roles in the maintenance of normal acid-base balance
§ reabsorption of HCO3-
§ excretion of H+.
o There are two mechanisms for excretion of this fixed H+:
§ excretion of H+ as titratable acid (i.e., buffered by urinary phoshate)
§ excretion of H+ as NH4+
o Reabsorption of filtered HCO3-
§ Almost 99.9% of the filtered HCO3- is reabsorbed,
§ If the glomerular filtration rate (GFR) is 180L/day and the plasma HCO3-
concentration is 24 mEq/L, then the filtered load is 4320 mEq/day (180 L/day 24
mEq/L). (MCQ)
§ The measured excretion rate of HCO3 - is merely 2 mEq/day.
§ Therefore, the reabsorption rate of HCO3- is 4318 mEq/day, which is 99.9% of the
filtered load. (MCQ)
§ Most filtered HCO3- reabsorption occurs in the proximal tubule (MCQ)
o Mechanism of HCO3- Reabsorption in the Proximal Tubule

§ The luminal membrane contains an Na+-H+ exchanger, which is one of several Na+-
dependent secondary active transport mechanisms in the early proximal tubule.
(MCQ)
§ As Na+ moves from the lumen into the cell down its electrochemical gradient, H+
moves from the cell into the lumen against its electrochemical gradient.
§ H+ secreted into the lumen combines with filtered HCO3- to form H2CO3.
§ The H2CO3 then decomposes into CO2 and H2O, catalyzed by a brush border
carbonic anhydrase. (MCQ)
§ The CO2 and H2O that are formed in this reaction readily cross the luminal
membrane and enter the cell.
§ Inside the cell, the reactions occur in reverse
• CO2 and H2O recombine to form H2CO3, catalyzed by intracellular carbonic
anhydrase.
• H2CO3 is converted back to H+ and HCO3- .
o The fates of the H+ and HCO3- are different.
§ H+ is secreted by the Na+-H+ exchanger to aid in the reabsorption of another
filtered HCO3-

§ The HCO3- is transported across the basolateral membrane into the blood (i.e., the
HCO3- is reabsorbed) by two mechanisms:
• Na+-HCO3- cotransport
• Cl- HCO3- exchange.
o 2 very important features of the mechanism for reabsorption of filtered HCO3- (MCQ)
§ The process results in net reabsorption of Na+ and HCO 3 .
• Thus, a portion of the Na+ reabsorption in the proximal tubule is linked
directly to the reabsorption of filtered HCO3-.
• The rest of the Na+ reabsorption is linked to reabsorption of glucose, amino
acids, Cl- , and phosphate.
§ There is no net secretion of H+ via this mechanism.
• Each H+ secreted by the Na+-H+ exchanger in the luminal membrane
combines with a filtered HCO3- to form CO2 and H2O, which enter the cell
and are converted back to H+ and HCO3- .
• The H+ is recycled across the luminal membrane on the Na+-H+ exchanger
to reabsorb more filtered HCO3- .
• Because there is no net secretion of H+ by this mechanism, it produces little
change in tubular fluid pH.
o Effect of Filtered Load of HCO3-
§ The filtered load of HCO3 is the product of GFR and the plasma HCO3
concentration
§ when the plasma HCO3 concentration is greater than 40mEq/L, the filtered load
becomes so high that the reabsorption mechanism is saturated; any filtered HCO3- that
cannot be reabsorbed is excreted. (MCQ)
o Effect of Extracellular Fluid Volume on Metabolic alkalosis
§ Since HCO3- is part of this isosmotic reabsorption , changes in ECF volume alter
HCO3- reabsorption in a predictable way .
• ECF volume expansion inhibits isosmotic reabsorption in the proximal tubule
and, therefore, inhibits HCO3- reabsorption. (MCQ)
• Conversely , ECF volume contraction stimulates isosmotic reabsorption in the
proximal tubule and stimulates HCO3- reabsorption. (MCQ)
§ A second mechanism, involving angiotensin II, participates in the response of HCO3-
reabsorption to ECF volume contraction. (contraction alkalosis) (MCQ)
§ What is meant by contraction alkalosis
• contraction alkalosis means metabolic alkalosis that occurs secondary to ECF
volume contraction
• decreases in ECF volume activate the renin–angiotensin II–aldosterone
system.
• Angiotensin II stimulates Na+-H+ exchange in the proximal tubule, thus
stimulating HCO3- reabsorption and increasing the blood HCO3-
concentration.
• Contraction alkalosis occurs (MCQ)
o during treatment with loop diuretics or thiazide diuretics
o it is a complicating factor in the metabolic alkalosis caused by
vomiting.
•
Contraction alkalosis is treated by infusing isotonic NaCl to restore ECF
volume
o Effect of PCO2
§ Chronic changes in PCO2 alter the reabsorption of filtered HCO3-
§ the phenomenon of renal compensation for chronic respiratory acid-base disorders
(MCQ)
• Increases in PCO2 increase the reabsorption of HCO3-
• Decreases in PCO2 decrease the reabsorption of HCO3-
§ Explanation
• In respiratory acidosis, the PCO2 is increased. (MCQ)
o Because more CO2 is available in the renal cells to generate H+ for
secretion by the Na -H exchanger, more HCO3 can be reabsorbed.
o Thus, the plasma HCO3_ concentration increases, which increases
the arterial pH (a compensation).
• In respiratory alkalosis, the PCO2 is decreased. (MCQ)
o As less CO2 is available in the renal cells to generate H+ for secretion,
less HCO3_ is reabsorbed.
o In this case, the plasma HCO3 concentration decreases, which

decreases the arterial pH (a compensation)
o Excretion of H+ as titratable acid
§ By definition, titratable acid is H+ excreted with urinary buffers.

§ Inorganic phosphate is the most important of these buffers because
• its relatively high concentration in urine
• its ideal pK.
§ there is a significant amount of phosphate in urine
§ because only 85% of the filtered phosphate is reabsorbed; 15% of the filtered
phosphate is left to be excreted as titratable acid. (MCQ)

Mechanism for excretion of H+ as titratable acid
Mechanism of Excretion of Titratable Acid
• Titratable acid is excreted primarily in the a-intercalated cells of the late distal tubule and collecting
ducts. (MCQ)
• The luminal membrane of alpha-intercalated cells contains 2 primary active transport mechanisms for
secreting H+ into tubular fluid.
• The first mechanism for H+ secretion is H+ ATPase
o It is stimulated by aldosterone. (MCQ)
o Aldosterone not only acts on the principal cells in stimulation ofNa+ reabsorption and K+ secretion ,
but also stimulates H+ secretion in the alpha-intercalated cells. (MCQ)
o The H+ secreted by the H+ - ATPase is produced in the renal cells from CO2 and H2O,
which combine to form H2CO3 in the presence of intracellular carbonic anhydrase.
o H2CO3 dissociates into H+, which is secreted, and HCO3- which is reabsorbed into the
blood via Cl-HCO3-exchange. (MCQ)
o For each H+ excreted as titratable acid, one new HCO3- synthesized and reabsorbed.
o This new HCO3- replenishes extracellular HCO3- , which previously had been depleted from
buffering fixed H+.
• The other mechanism for H+ secretion is H+-K+ ATPase
o the transporter responsible for K+ reabsorption in alpha-intercalated cells
o In the lumen, the secreted H+ combines with the A- form of the phosphate buffer, HPO4-2,
to produce the HA form of the buffer, H2PO4-
o H2PO4- is titratable acid, which is excreted.

o For this mechanism to be useful, it is essential that most of the filtered phosphate be in the
form that can accept an H+; that is, in the HPO4-2 form. Is this so?
o concentration of HPO4- 2 is almost fourfold the concentration of H2PO4-
• Amount of Urinary Buffer

o The amount of H+ excreted as titratable acid depends on the amount of urinary buffer
available
o the minimum urine pH is 4.4. (MCQ)
o Since blood pH is 7.4, a urine pH of 4.4 represents a 1000-fold difference in H+ concentration across
the renal tubular cells.
o This 1000-fold difference is the largest concentration gradient against which H+ can be
secreted by the H+ -ATPase. (MCQ)
o When the urine pH is reduced to 4.4, net secretion of H+ ceases.
• pK of Urinary Buffers
o The pK of the urinary buffers also affects the amount of H+ that is excreted.
o for a given quantity of urinary buffer, more H+ was excreted when the buffer was phosphate
than when the buffer was creatinine
• EXCRETION OF H+ AS NH + 4
• fixed H+ production from protein and phospholipid catabolism is approximately 50 mEq/day
• only 20 mEq/day of this fixed H+ is excreted as titratable H+ (MCQ)
• The remaining 30 mEq/day is excreted by a second mechanism, NH4+. (MCQ)
• Mechanism of Excretion of H+ as NH4+
• Three segments of the nephron participate in the excretion of H+ as NH4+
§ the proximal tubule
• In the proximal tubule, NH4+ is secreted by the Na+-H+ exchanger. (MCQ)
§ the thick ascending limb ofHenle’s loop
• In the thick ascending limb, NH4+ that was previously secreted by the proximal tubules
is reabsorbed and added to the corticopapillary osmotic gradient (MCQ)
§ alpha-intercalated cells of the collecting ducts.
• In the a-intercalated cells of the collecting duct, NH3 and H+ are secreted
into the lumen, combine to form NH4 , and are excreted. (MCQ)

• Proximal tubule.
§ In the cells of the proximal tubule, glutamine is metabolized to NH3 and a-

ketoglutarate (MCQ)
§ In turn, a-ketoglutarate is metabolized to glucose, which is metabolized to CO2 and

H2O and then to HCO3-.
§ In the cell, NH3 is converted to NH4+, which is secreted into the lumen on the Na+-
H+ exchanger (NH4+ substitutes for H+).
§ The HCO3- is reabsorbed into the blood via Na+- HCO3+ cotransport
• For each H+ secreted, one new HCO3- is reabsorbed.
§
The fate of the NH4 , once in the lumen of the proximal tubule, is complicated.
• A portion of the NH4 + is excreted directly in the urine.
• The remainder follows a circuitous route and is excreted indirectly:
• It is first reabsorbed by the thick ascending limb, then deposited in the
medullary interstitial fluid, and then secreted from the medullary interstitial
fluid into the collecting ducts for final excretion.
o Thick ascending limb.
§ a portion of the NH4+ that is secreted in the proximal tubule and delivered to the
loop of Henle is reabsorbed by the thick ascending limb. (MCQ)
§ At the cellular level, NH4+ is reabsorbed by substituting for K+ on the Na+-K+-2Cl-
cotransporter.
§ As a result of this substitution, NH4+ participates in countercurrent multiplication
(much like NaCl) and is concentrated in the interstitial fluid of the inner medulla and
papilla of the kidney.

o Collecting duct - diffusion trapping

§ luminal membrane of alpha-intercalated cells of the collecting duct contains two
transporters that secrete H+ into tubular fluid (MCQ)
• H+ ATPase
• H+-K+ ATPase.
o The H+ ATPase is stimulated by aldosterone.
§ What is meant by diffusion trapping
• As H+ is secreted into tubular fluid, NH3 diffuses from its high concentration in
the medullary interstitial fluid into the lumen ofthe collecting duct , where it combines
with the secreted H+ to form NH4+.
§ Why does only the NH3 form of the NH3/NH4+ buffer diffuse from the
medullary interstitium?
• while both NH4+ and NH3 are present in the medullary interstitial fluid, only
the NH3 form is lipid soluble and can diffuse across the collecting duct cells
into tubular fluid.
• Once in the tubular fluid, NH3 combines with the secreted H+ to form
NH4+. NH4+ is not lipid soluble and, thus, is trapped in the tubular fluid and
excreted.
• The overall process is termed diffusion trapping because the lipid-soluble
form of the buffer (NH3) diffuses and the water-soluble form of the buffer
(NH4+ is trapped and excreted. (MCQ)
§ The source of the H+ secreted by the a-intercalated cells is CO2 and H2O.
• For each H+ produced in the cells and secreted, one new HCO3- is
synthesized and reabsorbed.
• As with the titratable acid mechanism, this new HCO3- helps to replenish
depleted HCO3 stores.
§ Effect of Urinary pH on Excretion of NH4+

o As urinary pH decreases, the excretion of H+ as NH4+ increases .

o In acidosis, where urine pH tends to be low, there are large quantities of H+ to be
excreted.
o Reason – it is explained on basis of diffusion trapping of NH3/NH4+.
§ As the pH of urine decreases, more of the urinary buffer is present in the NH4+
form and less is present in the NH3 form.
§ The lower the luminal concentration of NH3, the larger the gradient for diffusion
of NH3 from medullary interstitial fluid into tubular fluid.
§ Thus, the lower the pH of tubular fluid , the greater the amount of NH3
diffusion and the greater the amount of H+ excreted as NH4+.
§ Effect of Acidosis on NH3 Synthesis
o The rate of NH3 synthesis changes, depending on the quantity of H+ that must be
excreted.
o In chronic acidosis, there is an adaptive increase in NH3 synthesis in the cells of the
proximal tubule. (MCQ)
o Mechanism
§ a decrease in intracellular pH, induces the synthesis of enzymes involved in
glutamine metabolism
§ When NH3 synthesis is augmented in this way
• more H+ is excreted as NH4+,
• more new HCO3- is reabsorbed.
o Example
§ in diabetic ketoacidosis, fixed acid production is increased.
§ The ability of the kidneys to excrete this additional fixed acid load is attributable,
in large part, to an adaptive increase in NH3 synthesis.
§ Effect of Plasma K+ Concentration on NH3 Synthesis
o Plasma K+ concentration also alters NH3 synthesis
o Hyperkalemia (MCQ)
§ inhibits NH3 synthesis (MCQ)
§ Reason
• In hyperkalemia, K+ enters the renal cells and H+ leaves.
• The resulting increase in intracellular pH inhibits NH3 synthesis from
glutamine
§ reduces the ability to excrete H+ as NH4+
§ causes type 4 renal tubular acidosis (RTA). (MCQ)
o Hypokalemia (MCQ)
§ stimulates NH3 synthesis (MCQ)
§ Reason
• In hypokalemia, K+ leaves renal cells and H+ enters.
• The resulting decrease in intracellular pH stimulates NH3 synthesis
from glutamine.
§ increases the ability to excrete H+ as NH4+
Comparison of titratable acid and NH4+ excretion

§ In normal persons eating a relatively high protein diet

o approximately 50 mEq of fixed H+ is produced daily.
o The kidneys excrete all (100%) of the fixed acid that is produced
o 40% is excreted as titratable acid (20 mEq/day)
o 60% as NH4+ (30 mEq/day).
§ In persons with diabetic ketoacidosis,
o fixed acid production may be increased as much as 10-fold, to 500 mEq/day.
o To excrete this additional acid load, excretion of both titratable acid and NH4+ is increased.
o NH4+ excretion is increased (MCQ)
§ Reason
• acidosis induces the enzymes involved in glutamine metabolism
• thereby increases NH3 synthesis
• As more NH3 is produced by the renal cells, more H+ is excreted as NH4+.
o Why titratable acid excretion is increased.
§ beta-OH butyric acid and acetoacetic acid are overproduced
§ The salts of these ketoacids (i.e., butyrate and acetoacetate) are themselves filtered
and serve as urinary buffers, similar to phosphate
§ It increases the total amount of H+ excreted as titratable acid.
§ Chronic renal failure
§ A person in chronic renal failure who continues to eat a relatively high protein diet will produce 50
mEq of fixed acid daily
§ progressive loss of nephrons impairs renal mechanisms for excreting fixed acid
§ The total fixed acid excretion in chronic renal failure is only 15 mEq/day (MCQ)
o 10 mEq as titratable acid
o 5 mEq as NH4+
§ Logically , persons with chronic renal failure are placed on a low protein diet to reduce daily fixed
acid production.
§ The Urinary Anion Gap
o The cations normally present in urine are Na+, K+, NH4+, Ca++ and Mg++.
o The anions normally present are Cl-, HCO3-, sulphate, phosphate and some organic anions.
o Only Na+, K+ and Cl- are commonly measured in urine so the other charged species are the
unmeasured anions (UA) and cations (UC).
o Because of the requirement for macroscopic electroneutrality, total anion charge always
equals total cation charge, so:
• Cl- + UA = Na+ + K+ + UC
o Urinary Anion Gap = ( UA - UC ) = [Na+]+ [K+] - [Cl-]
• Serum Anion Gap (AG) and Metabolic Acidosis

o Total cation changes in the plasma always equal the total anion changes.
o The AG represents unmeasured ions (ie, protein, phosphate citrate, sulfate) in serum.
o Normal AG is 5–12 mEq/L. (MCQ)
o Metabolic acidosis is subdivided into increased AG and normal AG.
o Increased AG is anything greater than 12 mEq/L. (MCQ)
o If the fall in HCO3−is less than the rise in AG, coexisting metabolic alkalosis is suspected.
(MCQ)
o An AG of 12 means that 12 anions are unaccounted for (normally albumin, phosphate, and organic
acids). (MCQ)
o If AG is increased, then other ions (eg, phosphate, lactate, -hydroxybutyrate) must be
in the system to replace HCO3−.
o Increased AG is most useful in diagnosing the cause of metabolic acidosis
o with the accumulation of organic anions, such as lactic acidosis, diabetic ketoacidosis, and
the ingestion of sulfate.
o In type I renal tubular acidosis (MCQ)
§ H+ cannot be secreted in the distal tubule,
§ inhibits HCO3 reabsorption and promotes K+-Na+ exchange,
§ results in hypokalemia.
o In type II renal tubular acidosis (MCQ)
§ HCO3 reabsorption is defective in the proximal tubule
§ results in an increased negative charge in tubular urine
• depletes HCO3
• it draws out positive charged ions such as K+, and causes hypokalemia
• The urinary anion gap can help to differentiate between GIT and renal causes of a
hyperchloraemic metabolic acidosis. (MCQ)
o Urinary Anion Gap (UAG) provides a rough index of urinary ammonium excretion.
o Ammonium is positively charged so a rise in its urinary concentration (ie increased unmeasured cations)
will cause a fall in UAG
o Step ONE: Metabolic acidosis can be divided into two groups based on the anion gap (AG):
§ High anion gap acidosis
§ Normal anion gap (or hyperchloraemic) acidosis.
o Step Two: Consider the hyperchloraemic group for further analysis. Hyperchloraemic acidosis
can be caused by:
§ Loss of base via the kidney (eg renal tubular acidosis)
§ Loss of base via the bowel (eg diarrhoea).
§ Gain of mineral acid (eg HCl infusion).
o Step Three: Bowel or kidney as the cause?

§ If the acidosis is due to loss of base via the bowel then the kidneys can response
appropriately by increasing ammonium excretion to cause a net loss of H+ from the
body .
• The UAG would tend to be decreased
• That is: increased NH4+ (with presumably increased Cl-) => increased UC
=>decreased UAG.
§ If the acidosis is due to loss of base via the kidney , then as the problem is with the
kidney it is not able to increase ammonium excretion and the UAG will not be decreases.
o Negative UAG VS Positive UAG
§ In a patient with a hyperchloraemic metabolic acidosis:
• A negative UAG suggests GIT loss of bicarbonate (eg diarrhoea) (MCQ)
• A positive UAG suggests impaired renal distal acidification (ie renal tubular
acidosis). (MCQ)
• As a memory aid, remember ‘neGUTive’ - negative UAGin bowel causes
§ Primary Acid-Base Disturbances
o Respiratory acidosis
§ caused by hypoventilation, which increases CO2 levels (MCQ)
§ results in a decrease in pH and a slight increase in HCO3−.
§ Respiratory acidosis is diagnosed when PCO2 is greater than 40.
§ A possible cause is barbiturate overdose.
o Respiratory alkalosis
§ caused by hyperventilation, which decreases CO2 levels
§ results in increased pH and a slight decrease in HCO3−.
§ Respiratory alkalosis is diagnosed when PCO2 is less than 40.
§ Possible causes include (MCQ)
• Hyperventilation
• high altitude
• salicylates (a few grams/day)
• endotoxins.
o Metabolic acidosis
§ caused by a gain in fixed acid or a loss of HCO3−and decreased pH.
§ Metabolic acidosis is diagnosed when HCO3 is less than 24. (MCQ)
§ Possible causes include
• diabetic ketoacidosis
• methanol poisoning
• uremia.
o Metabolic alkalosis
§ caused by a loss in H+ as fixed acid
§ results in an increase in HCO3−and increased pH.
§ Metabolic alkalosis is diagnosed when HCO3 is greater than 24 hrs
§ Possible causes include (MCQ)
• vomiting (when H+ is lost)
• diuretic abuse.

• Compensatory Mechanisms
o Renal compensation for respiratory acidosis: (MCQ)
§ The primary defect is increased PCO2 and reduced plasma pH.
§ The kidney produces HCO3−and secretes it into the blood.
§ For every HCO3−produced by the kidney , one H+ will be excreted in the urine
(producing acidic urine).
o Renal compensation for respiratory alkalosis (MCQ)
§ The primary defect is reduced PCO2 and elevated plasma pH.
§ The kidney excretes HCO3−in the urine (producing alkaline urine).
§ For every HCO3−excreted in the urine, one H+ is returned to the blood.
§ Plasma HCO3−decreases slowly as plasma H+ increases.
o Respiratory compensation for metabolic acidosis (MCQ)
§ Hyperventilation reduces CO2 levels, shifting the reaction to the left and consuming
H+.
o Respiratory compensation for metabolic alkalosis: (MCQ)
§ Hypoventilation increases CO2 levels, shifting the reaction to the right and
producing H+.
• Diagnostic Hints for Acid-Base Disorders
o Decreased pH indicates acidosis. (MCQ)
§ Increased CO2 indicates respiratory acidosis.
§ Normal CO2 with decreased HCO3 indicates metabolic acidosis.
§ Increased CO2 with decreased HCO3 indicates combined respiratory and metabolic acidosis.
o Increased pH indicates alkalosis. (MCQ)
§ Decreased CO2 indicates respiratory alkalosis.
§ Normal CO2 with elevated HCO3 indicates metabolic alkalosis.

§Decreased CO2 with elevated HCO3 indicates combined respiratory and
metabolic alkalosis.
o If CO2 and HCO3 change in opposite directions, a combined disturbance is present.


Topic - Coagulation
• Mechanism of Blood Coagulation

o clotting takes place in three essential steps:
§ In response to rupture of the vessel or damage to the blood itself , a complex of
activated substances collectively calledprothrombin activator forms
• rate-limiting factor in causing blood coagulation (MCQ)
§ The prothrombin activator catalyzes conversion of prothrombin into thrombin.
§ The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh
platelets, blood cells, and plasma to form the clot. (MCQ)

o Prothrombin
§ a plasma protein, an alpha2-globulin (MCQ)
§ It is an unstable protein that can split easily into smaller compounds
§ formed continually by the liver, and it is continually being used throughout the body
for blood clotting.
§ If the liver fails to produce prothrombin, in a day or so prothrombin concentration in
the plasma falls too low
§ Vitamin K is required by the liver for normal formation of prothrombin
o Fibrinogen
§ formed in the liver(MCQ)
§ Because of its large molecular size, little fibrinogen normally leaks from the blood
vessels into the interstitial fluids
§ interstitial fluids ordinarily do not coagulate. (MCQ)
• . Clot Retraction—Serum.
§ Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the
fluid from the clot within 20 to 60 minutes.
§ The fluid expressed is called serum
§ all the fibrinogen in serum and most of the other clotting factors have been removed; in this
way, serum differs from plasma.
§ Serum serum because it lacks these factors. (MCQ)
§ Platelets are necessary for clot retraction to occur. Therefore,failure of clot retraction is an
indication that the number of platelets in the circulating blood might be low.
Initiation of Coagulation: Formation of Prothrombin Activator
§ Prothrombin activator is formed in two ways

o by the extrinsic pathway that begins with trauma to the vascular wall and surrounding
tissues
o by the intrinsic pathway that begins in the blood itself.
§ Tissue factor initiates the extrinsic pathway(MCQ)

§ contact of Factor XII and platelets with collagen in the vascular wall initiates the intrinsic
pathway . (MCQ)
§ extrinsic pathway can be explosive; once initiated(MCQ)
o its speed ofcompletion to the final clo t is limited only by the
o amount of tissue factor released from the traumatized tissues
o quantities of Factors X, VII, and V in the blood.
o With severe tissue trauma, clotting can occur in as little as 15 seconds.
§ The intrinsic pathway is much slower to proceed (MCQ)
o usually require 1 to 6 minutes to cause clotting.
1.
Extrinsic pathway for initiating blood clotting.

Intrinsic pathway for initiating blood clotting.
§ Role of Calcium Ions in the Intrinsic and Extrinsic Pathways

o Except for the first two steps in the intrinsic pathway , calcium ions are required
o in the absence of calcium ions , blood clotting by either pathway does not occur.
o when blood is removed from a person, it can be prevented from clotting by adding
§ citrate ion
§ oxalate ion.
§ Prevention of Blood Clotting
o in the Normal Vascular System— Intravascular Anticoagulants
o Endothelial Surface Factors
§ most important factors for preventing clotting in the normal vascular system are
• the smoothness of the endothelial cell surface
o prevents contact activation of the intrinsic clotting system
• a layer of glycocalyx on the endothelium
o repels clotting factors and platelets, thereby preventing activation of
clotting
• thrombomodulin
o a protein bound with the endothelial membrane,
o binds thrombin.
o Slow the clotting process by removing thrombin
o thrombomodulin-thrombin complex also activates a plasma protein,
protein C (MCQ)
§ Activated protein C acts as an anticoagulant by inactivating
activated Factors V and VIII.
o Antithrombin Action of Fibrin and Antithrombin III.
§ Factors that remove thrombin from the blood.
• the fibrin fibers that themselves are formed during the process of clotting
§ While a clot is forming, about 85 to 90 per cent of the thrombin formed from the
prothrombin becomes adsorbed to the fibrin fibers as they develop. (MCQ)
• This helps prevent the spread of thrombin into the remaining blood and,
therefore, prevents excessive spread of the clot.
§ an alpha-globulin called antithrombin III or antithrombin-heparin cofactor.
§ antithrombin III inactivates the thrombin itself during the next 12 to 20 minutes.
o Heparin – Mechanism of action
§ The heparin molecule is a highly negatively charged conjugated polysaccharide.
§ it combines with antithrombin III, the effectiveness of antithrombin III for removing
thrombin increases by a hundredfold to a thousandfold, and thus it acts as an anticoagulant.
(MCQ)
§ The complex of heparin and antithrombin III removes several other activated coagulation
factors in addition to thrombin, further enhancing the effectiveness of anticoagulation.
The others include activated Factors XII, XI, X, and IX. (MCQ)
§ Heparin is produced by
• basophilic mast cells located in the pericapillary connective tissue
throughout the body . (MCQ)
• basophil cells of the blood , which are functionally almost identical to the mast
cells, release small quantities of heparin into the plasma. (MCQ)
§ Lysis of Blood Clots—Plasmin
o The plasma proteins contain a euglobulin called plasminogen (or profibrinolysin)
plasminogen when activated, becomes a substance called plasmin (or fibrinolysin). Plasmin is
a proteolytic enzyme that resembles trypsin,
o Plasmin digests
§ fibrin fibers
§ protein coagulants such as fibrinogen, F actor V, Factor VIII, prothrombin,and Factor XII.
• Activation of Plasminogen to Form Plasmin: Then Lysis of Clots.

o When a clot is formed, a large amount of plasminogen is trapped in the clot along with
other plasma proteins.
o The injured tissues and vascular endothelium very slowly release a powerful activator
called tissue plasminogen activator (t-PA)
o After a few days later, after the clot has stopped the bleeding, eventually converts
plasminogen to plasmin, which in turn removes the remaining unnecessary blood clot.
o In fact, many small blood vessels in which blood flow has been blocked by clots are
reopened by this mechanism
Topic - Erythropoiesis
• In the early weeks of embryonic life, primitive, nucleated red blood cells are produced in the yolk
sac. (MCQ)
• During the middle trimester of gestation , the liver is the main organ for production of red blood
cells (MCQ)
• During the last month or so of gestation and after birth, red blood cells are produced exclusively in
the bone marrow.
• the bone marrow of essentially all bones produces red blood cells until a person is 5 years old.
• The marrow of the long bones , except for the proximal portions ofthe humeri and tibiae, becomes quite
fatty and produces no more red blood cells after about age 20 years. (MCQ)
• Beyond 20 years age, most red cells continue to be produced in the marrow of the membranous
bones, such as the vertebrae, sternum, ribs, and ilia.
• interleukin-3, promotes growth and reproduction of virtually all the different types of
committed stem cells (MCQ)
• Stages of Differentiation of Red Blood Cells
o The first cell that can be identified as belonging to the red blood cell series is the
proerythroblas
o The first-generation cells are called basophil erythroblasts
o Because of the short life of the reticulocytes , their concentration among all the red cells of
the blood is normally slightly less than 1 per cent.

• Regulation of Red Blood Cell Production—Role of Erythropoietin

o Tissue Oxygenation Is the Most Essential Regulator of Red Blood Cell Production.
o Erythropoietin
§ Stimulates Red Cell Production
§ Its formation Increases in Response to Hypoxia.
§ 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed
mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is
formed. (MCQ)
§ important effect of erythropoietin is to stimulate the production of
proerythroblasts from hematopoietic stem cells in the bone marrow . (MCQ)
Topic - SECOND MESSENGER
Mechanisms of Hormone Action and Second Messengers
• The mechanisms of hormone action on target cells are the

o adenylyl cyclase mechanism
§ in which cAMP is the second messenger
o the phospholipase C mechanism
§ in which IP3/Ca2+ is the second messenger
o steroid hormone mechanism.
o tyrosine kinase mechanism
§ insulin and insulin-like growth factors (IGFs)
o guanylate cyclase,
§ cyclic GMP , or cGMP is the second messenger
Topic- Surfactant
• Surface Tension of Alveoli

• a large alveolus (one with a large radius) will have a low collapsing pressure and, therefore, will
require only minimal pressure to keep it open (MCQ)
• a small alveolus (one with a small radius) will have a high collapsing pressure and require more
pressure to keep it open.
• The pressure generated by a sphere is given by the law of Laplace:
• where
o P = Collapsing pressure on alveolus dynes/cm2 or Pressure required to keep alveolus
open dynes/cm2
o T = Surface tension dynes/cm2
o R= Radius of the alveolus /cm2
• Surfactant
o How do small alveoli remain open under high collapsing pres-sures?
§ The answer to this question is found in surfactant
o Surfactant
§ a mixture of phospholipids that line the alveoli
§ reduce their surface tension.
§ By reducing surface tension, surfactant reduces the collapsing pressure for a given
radius.
§ synthesized from fatty acids by type II alveolar cells. (MCQ)
§ most important constituent is dipalmitoyl phosphatidylcholine (DPPC). (MCQ)
§ increases lung compliance (MCQ)
§ reduces the work of expanding the lungs during inspiration.
o Mechanism by which DPPC reduces surface tension
§ phospholipid molecules has amphipathic nature
§ DPPC molecules align themselves on the alveolar surface
• Occur with their hydrophobic portions attracted to each other
• their hydrophilic portions repelled.
§ Intermolecular forces between the DPPC molecules break up the attracting forces
between liquid molecules lining the alveoli (which had been responsible for the high
surface tension).
• Neonatal respiratory distress syndrome
• surfactant is lacking.
• In the developing fetus, surfactant synthesis begins as early as gestational week 24, and it is
almost always present by week 35. (MCQ)
• Infants born before gestational week 24 will never have surfactant (MCQ)
• Infants born between weeks 24 and 35 will have uncertain surfactant status.
• Without surfactant
o small alveoli have increased surface tension and increased pressures, (MCQ)
o small alveoli will collapse (atelectasis)
o Collapsed alveoli are not ventilated and, therefore, cannot participate in gas exchange causing
hypoxemia
o lung compliance will be decreased (MCQ)
o work of inflating the lungs during breathing will be increased.
Topic- Autonomic nervous system
Autonomic Nervous System
• Organization
o The autonomic nervous system (ANS) has two divisions: sympathetic and
parasympathetic.
o Synapses between neurons are made in autonomic ganglia.
§ Parasympathetic ganglia are located in or near the effector organs.
§ Sympathetic ganglia are located in the paravertebral chain

o Each division has two neurons in the peripheral distribution of the motor innervation
o A preganglionic neuron has its cell body in the central nervous system
(CNS).
§ Preganglionic sympathetic neurons originate in the thoracolumbar (MCQ)

§ spinal cord segments T1–L3. (MCQ)
§ Preganglionic parasympathetic neurons originate in the nuclei of cranial nerves
(CNs) III, VII, IX, and X and in spinal cord segments S1–S4. (MCQ)
o A postganglionic neuron has its cell body in a ganglion in the peripheral nervous system
(PNS).
o The adrenal medulla is a specialized ganglion of the sympathetic nervous system.
§ Preganglionic fibers synapse directly on chromaffin cells, which act like
postganglionic cell bodies.
§ Chromaffin cells contain phenylethanolamine N-methyltransferase, (MCQ)
§ which converts norepinephrine to epinephrine.
o Thus, the adrenal medulla secretes 80% epinephrine and 20% norepi-nephrine. (MCQ)
• Neurotransmitters
o In all sympathetically innervated organs, except sweat glands, adrenergic neurons
release norepinephrine.
o Whether in the sympathetic or parasympathetic nervous system, cholinergic neurons release
acetylcholine.
o Peptidergic neurons in the parasympathetic nervous system release neurocrine peptides
such as vasoactive inhibitory peptide
• Adrenergic Receptors
o alpha1 Receptors
§ dominant alpha receptor subtype on the postsynaptic target cell membrane.
(MCQ)
§ They are located on (MCQ)
• vascular smooth muscle
• gastrointestinal (GI) and bladder sphincters
• radial muscle of the eye.
§ They are excitatory and produce contraction through activation of phospholipase
C, leading to formation of inositol triphosphate (IP3) and an increase in
intracellular Ca2+. (MCQ)
o Alpha 2-Receptors
§ dominant -receptor type on the presynaptic side of adrenergic nerve
terminals.
§ They are located in
• presynaptic nerve terminals
• platelets, fat cells, and walls ofthe gut .
§ They are inhibitory (MCQ)
§ produce relaxation by inhibition ofadenylate cyclase and by decreasing cyclic AMP (cAMP).
(MCQ)
o Beta1-Receptors,
§ are found mostly in cardiac muscle cells

§ are excitatory
§ produce increased heart rate and contractility
§ activate of adenylate cyclase and by increasing cAMP levels. (MCQ)
o Beta 2-Receptors
§ are found in smooth muscle and in secretory effectors.
§ They are inhibitory
§ produce relaxation (eg, dilation of bronchioles) by increasing cAMP levels. (MCQ)
§ They are more sensitive to epinephrine than norepinephrine. (MCQ)
o Beta 3-Receptors have limited distribution.
§ Low levels are present in adipose tissue and the GI tract. (MCQ)
§ They are excitatory
§ stimulate lipolysis and GI motility by increasing cAMP levels. (MCQ)
• Cholinergic Receptors
o Nicotinic receptors
§ postsynaptic receptors in ganglia located in the heart, smooth muscle, and exocrine glands.
§ They are activated by low concentrations of acetylcholine or nicotine
§ They are inhibited by ganglionic blockers (eg, hexamethonium) and high
concentrations of acetylcholine.
§ They produce excitation by acting as nonspecific cation channels, increasing the
influx of Na+ and K+ down their electrochemical gradients. (MCQ)
o Muscarinic receptors
§ responsible for most parasympathetic postsynaptic effects
§ located in the heart, smooth muscle, and glands.
§ They are activated by acetylcholine and muscarine
§ They are inhibited by atropine.
§ They are inhibitory in the heart (eg, decreasing heart rate)
§ They are excitatory in smooth muscle and glands (eg, increasing secretion).
§ They produce inhibition by decreasing cAMP , which leads to opening of K+
channels (MCQ)
§ They produce excitement by increasing IP3-mediated release of Ca2+ from
intracellular stores. (MCQ)
• Central Coordination
o Electrical information reaches the medulla-pons area primarily through the nucleus
tractus solitarius, (MCQ)
o chemical information reaches medulla-pons area mostly through the area postrema.
o The medulla-pons area contains the vasomotor, respiratory, pneumotaxic, and
swallowing and vomiting centers.
o Efferent autonomic information leaves central nuclei in sympathetic and
parasympathetic tracts.
o Sympathetic efferents descend in the intermediolateral column of the spinal cord and
are transferred from there to sympathetic preganglionic neurons.
o Parasympathetic efferents leave the central nuclei primarily by way of the vagus nerves.
o Fibers of the sacral region of the spinal cord descend in the mediolateral area.
o The nucleus tractus solitarius and area postrema have extensive communi- cations with
nuclei that generate efferent information: the nucleus ambiguus, the dorsal motor nucleus, and the
rostral and caudal ventrolateral medulla nuclei. (MCQ)
Topic - Cardiac Cycle
Cardiac Cycle
• The cycle is divided into seven phases

• ATRIAL SYSTOLE (A)
o Atrial systole is atrial contraction
o It is preceded by the P wave on the ECG (MCQ)
o Contraction of the left atrium causes an increase in left atrial pressure.
o increase in atrial pressure is reflected back to the veins as thea wave.
o The left ventricle is relaxed during this phase, and because the mitral valve (A V valve of the left
side of the heart) is open, the ventricle is filling with blood from the atrium, even prior to atrial
systole.
o Atrial systole causes a further increase in ventricular volume as blood is actively ejected from
the left atrium to the left ventricle through the open mitral valve.
o The corresponding “blip” in left ventricular pressure reflects this additional volume added
to the ventricle from atrial systole.
o The fourth heart sound (S4) (MCQ)
§ not audible in normal adults
§ may be heard in ventricular hypertrophy, where ventricular compliance is
decreased(MCQ)
§ When present, S4 coincides with atrial contraction. (MCQ)
§ The sound is caused by the atrium contracting against, and trying to fill, a stiffened
ventricle. (MCQ)
• ISOVOLUMETRIC VENTRICULAR CONTRACTION (B)
o Isovolumetric ventricular contraction begins during the QRS complex
o When the left ventricle contracts, left ventricular pressure begins to increase.
o As soon as left ventricular pressure exceeds left atrial pressure, the mitral valve closes. (In the
right heart, the tricuspid valve closes.)
o Closure of the A V valves produces the first heart sound (S1)
o Ventricular pressure increases dramatically during this phase, but ventricular volume remains
constant since all valves are closed (the aortic valve has remained closed from the previous cycle).
• RAPID VENTRICULAR EJECTION (C)
o The ventricle continues to contract, and ventricular pressure reaches its highest value (MCQ)
o When ventricular pressure becomes greater than aortic pressure, the aortic valve opens.
o Now blood is rapidly ejected from the left ventricle into the aorta through the open aortic
valve, driven by the pressure gradient between the left ventricle and the aorta. Most of the
stroke volume is ejected during rapid ventricular ejection, dramatically decreasing ventricular
volume (MCQ)
o Concomitantly , aortic pressure increases as a result of the large volume ofblood that is suddenly
added to the aorta.
o During this phase, atrial filling begins, and left atrial pressure slowly increases as blood is
returned to the left heart from the pulmonary circulation.
o The end of this phase coincides with the end of the ST segment (or the beginning of the T
wave) on the ECG and with the end of ventricular contraction . (MCQ)
• REDUCED VENTRICULAR EJECTION (D)
o During reduced ventricular ejection, the ventricles begin to repolarize,
o marked by the beginning of the T wave on the ECG. (MCQ)
o Ventricular pressure falls because the ventricles are no longer contracting.
o Because the aortic valve is still open, blood continues to be ejected from the left ventricle
into the aorta, albeit at a reduced rate
o ventricular volume also continues to fall, but at a reduced rate.
o Even though blood continues to be added to the aorta from the left ventricle,blood is
“running off” into the arterial tree at an even faster rate, causing aortic pressure to
fall(MCQ)
o Left atrial pressure continues to increase as blood returns to the left heart from the lungs.
• ISOVOLUMETRIC VENTRICULAR RELAXATION (E)
o begins after the ventricles are fully repolarized, marked by the end of the T wave on the ECG.
(MCQ)
o Because the left ventricle is relaxed, left ventricular pressure decreases dramatically
o When left ventricular pressure falls below aortic pressure, the aortic valve closes. The aortic
valve closes slightly before the pulmonic valve, producing thesecond heart sound (S2).
o At the point where the aortic valve closes, theaortic pressure curve shows a “blip,” called the
dicrotic notch or incisura. (MCQ)
o Since all valves are closed again, no blood can be ejected from the left ventricle, nor can the
left ventricle fill with blood from the atria.
o Therefore, during this phase, ventricular volume is constant (isovolumetric). (MCQ)
• RAPID VENTRICULAR FILLING (F)
o When ventricular pressure falls to its lowest level (and slightly below left atrial pressure), the
mitral valve opens (MCQ)
o Once the mitral valve opens, the ventriclebegins to fill with blood from the left atrium, and
ventricular volume increases rapidly .
o Ventricular pressure remains low, however, because the ventricle is still relaxed and compliant.
o The rapid flow of blood from the atria to the ventricles produces the third heart sound
(S3), (MCQ)
§ S3 is normal in children but is not heard in normal adults; in middle-aged or older
adults(MCQ)
§ presence of S3 indicates volume overload, as in congestive heart failure or advanced
mitral or tricuspid regurgitation(MCQ)
o During this phase (and for the remainder of the cardiac cycle), aortic pressure decreases as
blood runs off from the aorta into the arterial tree, to the veins, and then back to the heart.
(MCQ)
• REDUCED VENTRICULAR FILLING (G)
o Reduced ventricular filling or diastasis is the longest phase of the cardiac cycle (MCQ)
o The end of diastasis marks the end of diastole , at which point ventricular volume is equal to
end-diastolic volume. (MCQ)
o Changes in heart rate alter the time available for diastasis, since it is the longest phase of the
cardiac cycle.
o For example, increases in heart rate reduce the time interval before the next P wave (i.e., the
next cycle) and reduce, or even eliminate, this final portion of ventricular filling.
o If diastasis is reduced by such an increase in heart rate, ventricular filling will be
compromised, end-diastolic volume will be reduced, and, as a consequence, stroke volume also
will be reduced (recall the Frank-Starling relationship).

Topic – Adh
Antidiuretic hormone
o ADH has three actions on the renal tubule

o It increases the water permeability of the principal cells of the late distal tubule and
collecting ducts. (most important function ) (MCQ)
o It increases the activity of the Na+-K+-2Cl- cotransporter of the thick ascending limb
(MCQ)
§ thereby it enhances countercurrent multiplication and the size of the
corticopapillary osmotic gradient (MCQ)
o It increases urea permeability in the inner medullary collecting ducts (but not in the
cortical or outer medullary collecting ducts)
§ thereby it enhances urea recycling and the size of the corticopapillary osmotic
gradient. (MCQ)
o In the absence of ADH, the principal cells are impermeable to water. (MCQ)
o In the presence of ADH, water channels, or aquaporins, are inserted in the luminal membrane of the
principal cells, making them permeable to water. (MCQ)
o The following steps are involved in the action of ADH on the principal cells
o When circulating levels of ADH are high, ADH is delivered to the principal cells via the
peritubular capillary blood

o V2 receptors for ADH, present in the basolateral membrane, are coupled to adenylyl cyclase
via a stimulatory G protein (Gs). (MCQ)
o When ADH binds to the receptors, adenylyl cyclase is activated and catalyzes the conversion
of ATP to cAMP . (MCQ)
o cAMP activates protein kinase A.
o Activated protein kinase A then causes phosphorylation ofintracellular structures .
o phosphorylation causes vesicles containing water channels are shuttled to and inserted into
the luminal membrane of the principal cell, thus increasing its water permeability.
o The specific water channel that is controlled by ADH isaquaporin 2 (AQP2).
o Regulation of Antidiuretic Hormone Secretion
o Increased plasma osmolarity is the most important physiologic stimulus for increasing
ADH secretion(MCQ)
§ For example, when a person is deprived of water, serum osmolarity increases.
§ The increase is sensed by osmoreceptors in the anterior hypothalamus.
§ Action potentials are initiated in cell bodies of the nearby ADH neurons and
propagated down the axons, causing the secretion of ADH from nerve terminals in the
posterior pituitary.
o Hypovolemia, or volume contraction (e.g., due to hemorrhage),
§ a potent stimulus for ADH secretion.
§ Decreases in extracellular fluid (ECF) volume of 10% or more cause a decrease in
arterial blood pressure (MCQ)
§ Low BP is sensed by baroreceptors in the left atrium, carotid artery, and aortic arch.
(MCQ)
§ This information about blood pressure is transmitted via the vagus nerve to the
hypothalamus, which directs an increase in ADH secretion. (MCQ)
§ ADH then stimulates water reabsorption in the collecting ducts, attempting to
restore ECF volume.
§ Importantly, hypovolemia stimulates ADH secretion, even when plasma osmolarity
is lower than normal (MCQ)
§ Conversely , hypervolemia (volume expansion) inhibits ADH secretion, even when
plasma osmolarity is higher than normal. (MCQ)
o
o ADH (vasopressin) has two actions
o Increase in water permeability .
o Contraction of vascular smooth muscle.
o The receptor for ADH on vascular smooth muscle is a V1 receptor, which is coupled to
phospholipase C via a Gq protein. (MCQ)
o The second messenger for this action is IP3/Ca2+,
produces (MCQ)
o contraction of vascular smooth muscle

o constriction of arterioles
o increased total peripheral resistance.
o Hyperosmotic urine is produced when the circulating levels of ADH are high, as occurs in (MCQ)
o water deprivation
o SIADH
o SIADH
o circulating levels of the hormone ADH are abnormally high owing to either
o Causes (MCQ)
§ head injury
§ lung tumors
o ADH is secreted autonomously, without an osmotic stimulus
o high levels of ADH increase water reabsorption by the late distal tubule and collecting
ducts, making the urine hyperosmotic and diluting the plasma osmolarity. (MCQ)
o Normally, a low plasma osmolarity would inhibit secretion of ADH ; however, in SIADH,
this feedback inhibition does not occur because ADH is secreted autonomously (MCQ)
o Treatment
§ demeclocycline, which inhibits the ADH action on the renal principal cells. (MCQ)
o Central Diabetes Insipidus
o follow head injury,
o Because circulating levels of ADH are low or zero, the entire distal tubule and collecting
ducts are impermeable to water. (MCQ)
o large volumes (as much as 15 L/day) of very dilute urine are excreted.
o Plasma osmolarity increases to abnormally high values as excessive amounts of water are
excreted in the urine which is the water that would have beenreabsorbed if ADH were
present
o The high plasma osmolarity would normally stimulate ADH secretion, but in central diabetes
insipidus, there is no ADH to be secreted from the posterior pituitary gland. (MCQ)
o Treatment of central diabetes insipidus consists of administration of an ADH analogue, such as
1-deamino-8-D-arginine vasopressin (dDAVP). (MCQ)
o Nephrogenic Diabetes Insipidus
o a defect in the response of the kidneys to ADH
o Although ADH secretion from the posterior pituitary gland is normal, a defect in the receptor,
the Gs protein, or adenylyl cyclase makes the principal cells unresponsive to ADH.
(MCQ)
o As a result, ADH fails to increase water permeability in the late distal tubule and
collecting ducts(MCQ)
o As in central diabetes insipidus, water cannot be reabsorbed by these segments, and large
volumes of dilute urine are excreted.
o The plasma osmolarity increases, which stimulates the posterior pituitary to secrete even more
ADH. (MCQ)
o Circulating ADH levels are higher than normal in nephrogenic diabetes insipidus, but these
high levels of ADH still are ineffective on principal cells.
o Nephrogenic diabetes insipidus is treated with thiazide diuretics
o Rationale for using thiazide diuretics (MCQ)
§ first consider the fundamental problem in nephrogenic diabetes insipidus: Because the
principal cells are unresponsive to ADH, there isexcretion of large volumes of dilute
urine.
§ Thiazide diuretics are helpful as follows (MCQ)
• They inhibit Na+ Cl- cotransport in the early distal tubule, thereby
preventing dilution of the urine in this segment.
o As more NaCl is excreted, the urine is less dilute than it would be
without treatment.
• Thiazide diuretics produce a decrease in GFR and, secondary to decreased Na+
reabsorption, a decrease in ECF volume
o The decrease in ECF volume causes an increase in proximal tubule
reabsorption via effects on Starling forces.
o The combination of less water filtered and more water reabsorbed in
the proximal tubule means that the total volume ofwater excreted is decreased.
§ FREE-WATER CLEARANCE
o Free water is defined as distilled water that is free of solutes (or solute-free water).
o In the nephron, free water is generated in the diluting segments, where solute is reabsorbed
without water.
o The diluting segments of the nephron are the water-impermeable segments: (MCQ)
§ the thick ascending limb
§ the early distal tubule.

o Measurement of free-water clearance (CH2O) provides a method for assessing the ability of
the kidneys to dilute or concentrate the urine.
o When ADH levels are low(MCQ)
§ all of the free water generated in the thick ascending limb and early distal tubule is
excreted (since it cannot be reabsorbed by the collecting ducts).
§ The urine is hyposmotic, and free-water clearance is positive.
o When ADH levels are high(MCQ)
§ all of the free water generated in the thick ascending limb and the early distal tubule is
reabsorbed by the late distal tubule and collecting duct.
§ The urine is hyperosmotic, and free-water clearance is negative.
Measurement of CH2O
Free-water clearance (CH2O) is calculated by the following equation:
§ Significance of CH2O
§ CH2O is zero.
o CH2O is zero when no solute-free water is excreted.
o Under these conditions, urine is isosmotic with plasma (called isosthenuric
o it can occur during treatment with a loop diuretic - Mechanism
§ NaCl reabsorption is inhibited in the thick ascending limb.
§ When solute reabsorption is inhibited in the thick ascending limb, no free water is
generated at this site:
§ If free water is not generated, it cannot be excreted.
§ Therefore, the ability to dilute the urine during water drinking is impaired in a per-
son who is treated with a loop diuretic.
o With Loop diuretics , the ability to concentrate the urine during water deprivation is
impaired because loop diuretics also interfere with generation of the corticopapillary
osmotic gradient (by inhibiting Na+-K+-2Cl- cotransport and countercurrent multiplication).
§ CH2O is positive. (MCQ)
o CH2O is positive when
§ ADH levels are low
§ ADH is ineffective and the urine is hyposmotic.
o The solute-free water, which is generated in the thick ascending limb and early distal tubule, is
excreted in the urine because the late distal tubules and collecting ducts are impermeable
to water under these conditions
§ CH2O is negative. (MCQ)
o CH2O is negative when ADH levels are high and the urine is hyperosmotic.
o All of the solute-free water generated in the thick ascending limb and early distal tubule (and
more) is reabsorbed by the late distal tubules and collecting ducts. negative CH2O is called
free-water reabsorption
§ Example
o A man has a urine flow rate of 15 mL/min, a urine osmolarity of 150 mOsm/L, and a plasma
osmolarity of 300 mOsm/L. What is his free-water clearance, and what is its significance?
o SOLUTION.
§ The man’s free-water clearance is calculated as follows:
§ CH2 O = V - Cosm
= V - (U) osm x V
Posm
= 15 mL/min - 150 mOsm/Lx 15 mL/min
300 mOsm/L
= 15 mL/min – 7.5 mL/min
= + 7.5 mL/ min
§ CH2O is a positive value, which means that free water is being excreted.
§ The solute-free water generated in the thick ascending limb and early distal tubule is not
reabsorbed by the collecting ducts, but it is excreted.
§ This situation occurs when circulating ADH levels are low, as in water drinking or central
diabetes insipidus (or if ADH is ineffective, as in nephrogenic diabetes insipidus).
Topic - Nerve fibre classification
o Two classification systems

o Erlanger and Gasser
§ applies to both sensory (afferent) and motor (efferent) nerve fibers
§ uses a lettered nomenclature of A, B, and C .
o Lloyd and Hunt,
§ applies only to sensory nerve fibers
§ uses a Roman numeral nomenclature of I, II, III, and IV .

Topic - Basal ganglia
BASAL GANGLIA
• The basal ganglia are the deep nuclei of the telencephalon:

o caudate nucleus
o putamen,
o globus pallidus
o amygdala.
• There also are associated nuclei, including the (MCQ)
o ventral anterior and ventral lateral nuclei of the thalamus
o subthalamic nucleus of the diencephalon
o substantia nigra of the midbrain.
• Basal ganglia –functions (MCQ)
o The main function is to influence the motor cortex via pathways through the thalamus.
o aid in planning and execution of smooth movements
o contribute to affective and cognitive functions.
• Indirect pathway vs Direct Pathway
o Almost all areas of the cerebral cortex project topographically onto the striatum, including a
critical input from the motor cortex.
o The striatum then communicates with the thalamus and then back to the cortex via two
different pathways.
o Indirect pathway(MCQ)
§ striatum has inhibitory input to the external segment of the globus pallidus
§ external segment of the globus pallidus has inhibitory input to the subthalamic
nuclei.
§ subthalamic nuclei project excitatory input to the internal segment of the globus
pallidus and the pars reticulata of the substantia nigra
§ internal segment of the globus pallidus and the pars reticulata of the substantia nigra
send inhibitory input to the thalamus.
§ The thalamus then sends excitatory input back to the motor cortex.
§ In this pathway, the inhibitory neurotransmitter is GABA, and the excitatory neurotransmitter is
glutamate. (MCQ)
§ The overall output of the indirect pathway is inhibitory(MCQ)
o Direct pathway(MCQ)
§ the striatum sends inhibitory input to the internal segment of the globus pallidus
and the pars reticulata of the substantia nigra
§ internal segment of the globus pallidus and the pars reticulata of the substantia nigra
send inhibitory input to the thalamus.
§ As in the indirect pathway , the thalamussends excitatory input back to the motor
cortex.
§ The overall output of the direct pathway is excitatory(MCQ)
o Additional pathway between striatum and the pars compacta of the substantia nigra
§ The neurotransmitter for the connection back to the striatum isdopamine.
§ dopamine will be (MCQ)
• inhibitory (via D2 receptors) in the indirect pathway
• excitatory (via D1 receptors) in the direct pathway.

§ Diseases of the Basal Ganglia

§ Parkinson’s disease(MCQ)
o cells of the pars compacta of the substantia nigra degenerate
§ reduce inhibition via the indirect pathway
§ reduce excitation via the direct pathway.
§ Huntington’s disease is caused by destruction of (MCQ)
o striatal and cortical cholinergic neurons
o inhibitory GABAergic neurons.
Topic - BILIRUBIN METABOLISM
§ Average life span red blood cells - 120 days (MCQ)

§ The hemoglobin is first split into globin and heme
§ heme ring is opened to give
o free iron, which is transported in the blood by transferrin
o a straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will
eventually be formed
§ The first substance formed is biliverdin, but this is rapidly reduced to free bilirubin,
§ The free bilirubin immediately combines strongly with plasma albumin and is transported in this
combination throughout the blood and interstitial fluids
§ In liver cells
o Bilirubin is conjugated about
§ 80 per cent with glucuronic acid to form bilirubin glucuronide,
§ about 10 per cent with sulfate to form bilirubin sulfate
§ about 10 per cent with a multitude of other substances
o the bilirubin is excreted from the hepatocytes by an active transport process into the bile
canaliculi and then into the intestines.
§ Formation and Fate of Urobilinogen.

o Once in the intestine, about half of the “conjugated” bilirubin is converted by bacterial action
into the substance urobilinogen, which is highly soluble. (MCQ)
o Some of the urobilinogen is reabsorbed through the intestinal mucosa back into the blood.
o Most of this is re-excreted by the liver back into the gut, but about 5 per cent is excreted by
the kidneys into the urine.
o After exposure to air in the urine, the urobilinogen becomes oxidized to urobilin;
alternatively, in the feces, itbecomes altered and oxidized to form stercobilin..
Diagnostic Differences Between Hemolytic and Obstructive Jaundice.
§ In hemolytic jaundice, almost all the bilirubin is in the “free” form

§ in obstructive jaundice, bilirubin is mainly in the “conjugated” form.
§ When there is total obstruction of bile flow
o no bilirubin can reach the intestines to be converted into urobilinogen by bacteria.
Therefore, no urobilinogen is reabsorbed into the blood,
o none can be excreted by the kidneys into the urine.
o Consequently, in total obstructive jaundice, tests for urobilinogen in the urine are completely
negative(MCQ)
o the stools become clay colored owing to a lack of stercobilin and other bile pigments.
(MCQ)
§ Another major difference between free and conjugated bilirubin
o kidneys can excrete small quantities of the highly soluble conjugated bilirubin but not
the albumin-bound free bilirubin. (MCQ)
o Therefore, in severe obstructive jaundice, significant quantities ofconjugated bilirubin
appear in the urine. (MCQ)
o This can be demonstrated simply by shaking the urine and observing the foam, which
turns an intense yellow. (MCQ)
Topic – Cerebellum
The Cerebellum
§ The cerebellum is dorsal to the pons and medulla

§ involved in the planning and fine tuning of skeletal muscle contractions.
§ It can be divided into three major lobes by transverse fissures:(MCQ)
o The anterior fissure separates the anterior and posterior lobes.
o The posterolateral fissure separates the small flocculonodular lobe from
the posterior lobe.
o The flocculonodular lobe, or vestibulocerebellum, controls balance and eye

movement. (MCQ)
o Input is to the vestibular nuclei.
§ A functional separation consists of a midline zone (vermis), which separates the two lateral cerebellar
hemispheres.
§ The vermis and intermediate zones, or spinocerebellum, control rate,
force, and direction of movemen t with principal input to the spinal cord.
§ The hemisphere, or pontocerebellum, is involved in the planning and initiation of

movements; principal input is to the cerebral cortex. (MCQ)
§ The cerebellar cortex has three layers:
o The molecular layer (MCQ)
§ outer layer
§ contains basket and stellate cells, as well as parallel fibers, which are the axons of the
granule cells.
§ Dendrites of the Purkinje cell extend into this layer.
o The Purkinje layer (MCQ)
§ middle and most important layer because all inputs to the cerebellum are directed
toward influencing the firing of the Purkinje cells
§ only Purkinje cell axons leave the cerebellar cortex.
§ Output is always inhibitory .
o The granular layer (MCQ)
§ innermost layer
§ comprises Golgi type II cells, granule cells, and glomeruli.
§ Each glomerulus has a granule cell, which is the only excitatory neuron in the
cerebellar cortex.
§ The cerebellar cortex has two major afferents:
o Climbing fibers (MCQ)
§ originate from the inferior olivary nuclear complex on the contralateral side of the
medulla. (MCQ)
§ Climbing fibers provide excitatory input to Purkinje cells by synapsing on them.
(MCQ)
§ They play a role in cerebellar motor learning(MCQ)
o Mossy fibers (MCQ)
o represent axons from all other sources of cerebellar input. (MCQ)
o They provide an indirect, diffuse excitatory input to Purkinje cells as well as inhibitory
neurons (ie, stellate, basket, and Golgi type II cells).(MCQ)
o All mossy fibers exert an excitatory effect on granule cells, which give rise to parallel
fibers that stimulate Purkinje cells. (MCQ)
§ The cerebellar cortex has four major efferents
o Purkinje cells (MCQ)
§ are the only output
§ are always inhibitory via the neurotransmitter Gamma-aminobutyric acid (GABA).
(MCQ)
o The spinocerebellum
§ has efferents to the red nucleus and reticular formation
§ influences lower motoneurons, via the reticulospinal and rubrospinal tracts(MCQ)
§ adjust posture and effect movement. (MCQ)
o The pontocerebellum
§ has efferents first to the thalamus and then to the cortex
§ influences lower motoneurons via the corticospinal tract. (MCQ)
§ These efferents produce precise, sequential voluntary movements. (MCQ)
o The vestibulocerebellum
§ has efferents to the vestibular nucleus
§ elicits positional changes of the eyes and trunk in response to head movements.
(MCQ)
Topic- Electrolytes
§ Composition of Intracellular Fluid and Extracellular Fluid

o The major cation in ECF is sodium (Na+) (MCQ)
o balancing anions in ECF are chloride (Cl-) and bicarbonate (HCO3-).
o The major cations and the in ICF are potassium (K+) and magnesium (Mg2+) (MCQ)
o the balancing anions in ICF are proteins and organic phosphates.
o Typically , ICF has a very low concentration of ionized Ca2+(MCQ)
§ the Ca2+ concentration in ECF is higher by approximately four orders of magnitude. ICF
is more acidic (has a lower pH) than ECF .
o the total solute concentration (osmolarity) is the same in ICF and ECF . (MCQ)
o This equality is achieved because water flows freely across cell membranes.
§ Creation of Concentration Differences across Cell Membranes
o Na+-K+ ATPase (Na+-K+ pump), (MCQ)
§ transports Na+ from ICF to ECF
§ simultaneously transports K+ from ECF to ICF . (MCQ)
§ Both Na+ and K+ are transported against their respective electrochemical gradients; therefore, an
energy source, ATP , is required.
§ The Na+-K+ ATPase is responsible for creating the large concentration gradients for
Na+ and K+ that exist across cell membranes
• the low intracellular Na+ concentration (MCQ)
• high intracellular K+ concentration(MCQ)
o Cell membrane Ca2+ ATPase
§ pumps Ca2+ against its electrochemical gradient.
§ intracellular Ca2+ concentration is maintained at a level much lower than the
extracellular Ca2+ concentration (MCQ)
§ uses ATP as a direct energy source.
o transporters that establish concentration differences across the cell membrane by utilizing
the transmembrane Na+ concentration gradient (established by the Na+-K+ ATPase) as an
energy source.
§ These transporters create concentration gradients for glucose, amino acids, Ca2+,
and H+ without the direct utilization of ATP .
o every important physiologic functions dependent on differences in composition between ICF
and ECF
§ The resting membrane potential of nerve and muscle critically depends on the
difference in concentration of K+ across the cell membrane (MCQ)
§ The upstroke of the action potential of these same excitable cells depends on the
differences in Na+ concentration across the cell membrane(MCQ)
§ Excitation- contraction coupling in muscle cells depends on the differences in Ca2+
concentration across the cell membrane and the membrane of the sarcoplasmic
reticulum(MCQ)
§ Absorption of essential nutrients depends on the transmembrane Na+ concentration
gradient
• glucose absorption in the small intestine (MCQ)
• glucose reabsorption in the renal proximal tubule (MCQ)
§ Concentration Differences between Plasma and Interstitial Fluids
o ECF consists of two subcompartments: interstitial fluid and plasma.
o The most significant difference in composition between these two compartments is the
presence of proteins (e.g., albumin) in the plasma compartment.
o Plasma proteins do not readily cross capillary walls because of their large molecular size and,
therefore, are excluded from interstitial fluid.
o Secondary consequences of the exclusion of proteins from interstitial fluid. - Gibbs-Donnan
equilibrium
o The plasma proteins are negatively charged, and this negative charge causes a
redistribution of small, permeant cations and anions across the capillary wall
o The plasma compartment contains the impermeable, negatively charged proteins.
Because of the requirement for electroneutrality , the plasma compartment must have a
slightly lower concentration of small anions (e.g., Cl-) and a slightly higher concen-
tration of small cations (e.g., Na+ and K+) than that of interstitial fluid. (MCQ)
o the Cl- concentration in plasma is slightly less than the Cl- concentration in interstitial
fluid (due to the effect of the impermeant plasma proteins(MCQ)

Topic – Pituitary
§ Hypothalamic-Pituitary Relationships
o Pituitary gland, is called the hypophysis,
§ posterior pituitary is also called the neurohypophysis
§ anterior pituitary is also called the adenohypophysis.
§ Relationship of the hypothalamus to the posterior pituitary
o The connections between the hypothalamus and the posterior lobe of the pituitary are
neural
o a hormone-secreting neuron has its cell body in the hypothalamus and its axons in the
posterior lobe of the pituitary.
o the hormones secreted by the posterior lobe (ADH and oxytocin) are actually neuropeptides;
in other words, they are peptides released from neurons.
o The cell bodies of ADH and oxytocin-secreting neurons are located in supraoptic and
paraventricular nuclei within the hypothalamus.
§ ADH is primarily associated with surpraoptic nuclei (MCQ)
§ oxytocin is primarily associated with paraventricular nuclei. (MCQ)
§ Relationship of the hypothalamus to the anterior pituitary
o The anterior pituitary secretes six peptide hormones: thyroid-stimulating hormone (TSH), follicle-
stimulating hormone (FSH), luteinizing hormone (LH), growth hormone, prolactin, and adrenocortico- tropic
hormone (ACTH).
o The hypothalamus and anterior pituitary are linked directly by thehypothalamic-hypophysial
portal blood vessels, which provide most of the blood supply to the anterior lobe.
o There are two important implications of the portal blood supply to the anterior lobe of the
pituitary
§ The hypothalamic hormones can be delivered to the anterior pituitary directly and in
high concentration
§ the hypothalamic hormones do not appear in the systemic circulation in high
concentrations. The cells of the anterior pituitary, therefore, are theonly cells in the
body to receive high concentrations of the hypothalamic hormones.
§ Anterior Lobe Hormones
§ TSH, FSH, AND LH FAMILY
o TSH, FSH, and LH are all glycoproteins (MCQ)
o sugar moieties covalently linked to asparagine residues in their polypeptide chains.. The alpha
subunits of TSH, FSH, and LH are identical and are synthesized from the same mRNA.
(MCQ)
o The b subunits confer the biologic specificity (MCQ)
o The placental hormone human chorionic gonadotropin (HCG) is structurally related to alpha
chain of the TSH-FSH- LH family(MCQ)
§ ACTH FAMILY
o The ACTH family is derived from a single precursor, pro-opiomelanocortin (POMC).
o The ACTH family includes ACTH, gamma- and beta-lipotropin, beta-endorphin,
andmelanocyte-stimulating hormone (MSH). (MCQ)
o The preprohormone for this group, prepropiomelanocortin, is transcribed from a single
gene.
o Addison’s disease (primary adrenal insufficiency), POMC and ACTH levels are increased by
negative feedback. (MCQ)
o Because POMC and ACTH contain MSH activity, skin pigmentation is a symptom of this
disorder. (MCQ)
§ Growth hormone
o It is the single most important hormone for normal growth to adult stature. (MCQ)
o The gene for growth hormone is a member of a family of genes for related peptides, prolactin
and human placental lactogen.
o Human placental lactogen, has 80% homology with Growth Hormone. (MCQ)

o Regulation of Growth Hormone Secretion

o Growth hormone is secreted in a pulsatile pattern
§ bursts of secretion occurring approximately every 2 hours. (MCQ)
§ The largest secretory burst occurs within 1 hour of falling asleep (during sleep stages
III and IV). (MCQ)
o At puberty , there is an enormous secretory burst
§ induced in females by estrogen and in males by testosterone.
o Actions of Growth Hormone
o Actions of growth hormone result from the hormone’s direct effect on target tissues such as
skeletal muscle, the liver, or adipose tissue.
o Other actions of growth hormone are mediated indirectly through the production of
somatomedins (or insulin- like growth factors [IGFs]) in the liver.
o The most important of the somatomedins is somatomedin C or IGF-1. Somatomedins act on
target tissues through IGF receptors that are similar to the insulin receptor, having tyrosine-
kinase activity and exhibiting autophosphorylation. (MCQ)
o The growth-promoting effects of growth hormone are mediated largely through production of
somatomedins.
o The actions of growth hormone
§ Diabetogenic effect.
• causes insulin resistance (MCQ)
• decreases glucose uptake and utilization by target tissues such as muscle and
adipose tissue.
• increases lipolysis in adipose tissue.
• causes an increase in blood insulin levels.
§ Increased protein synthesis and organ growth
• increases the uptake of amino acids (MCQ)
• stimulates the synthesis of DNA, RNA, and protein.
• increase lean body mass
• increase organ size.
§ Increased linear growth.
• The most striking effect of growth hormone is its ability to increase linear
growth.
• Mediated by the somatomedins, growth hormone alters every aspect of
cartilage metabolism (MCQ)
o stimulation of DNA synthesis
o RNA synthesis
o protein synthesis.
• In growing bones, the epiphyseal plates widen, and more bone is laid down at
the ends of long bones.
• There also is increased metabolism in cartilage-forming cells and proliferation
of chondrocytes.
§ Prolactin

§ Actions of Prolactin
o Breast development.
§ At puberty , prolactin, with estrogen and progesterone, stimulates proliferation and
branching ofthe mammary ducts . (MCQ)
§ During pregnancy , prolactin (again with estrogen and progesterone) stimulates growth
and development of the mammary alveoli, which will produce milk once parturition
occurs.
o Lactogenesis (milk production).
§ The major action of prolactin is
• stimulation of milk production
o by inducing the synthesis of the components of milk, including lactose
casein and lipids.
• secretion in response to suckling.
o Inhibition of ovulation.
§ In females, prolactin inhibits ovulation by inhibiting the synthesis and release of
gonadotropin-releasing hormone (GnRH) (MCQ)
§ Inhibition of GnRH secretion and, secondarily, inhibition of ovulation account for
the decreased fertility during breast-feeding.
§ In males with high prolactin levels (e.g., due to a prolactinoma), there is a parallel
inhibitory effect on GnRH secretion and spermatogenesis, resulting in infertility.
(MCQ)
§ Why the lactation does not occur even though prolactin levels are very high during
pregnancy , (MCQ)
• because the high levels of estrogen and progesterone down-regulate
prolactin receptors in the breast and block the action of prolactin.
• At parturition, estrogen and progesterone levels drop precipitously, and their
inhibitory actions cease.Prolactin can then stimulate lactogenesis, and
lactation can occur.
§ Posterior Pituitary Hormones
o Antidiuretic hormone (ADH)
§
synthesized in the hypothalamus
§
primarily in the supraoptic nucleus(MCQ)
§
stored and released from the posterior pituitary.
§
ADH increases water permeability of the renal collecting duct by placing water
channels in the membrane. (MCQ)
o Oxytocin
§ originates primarily in the paraventricular nuclei of the hypothalamus (MCQ)
§ causes milk flow (ie, letdown) from the breast.
§ Oxytocin release is stimulated by suckling at the breast, sexual activity, or emotional
factors (eg, hearing the infant cry). (MCQ)
§ Oxytocin causes contraction of the myoepithelial cells of the mammary gland and
uterine contractions at term.
Topic - SENSORY RECEPTORS
• TYPES OF SOMATOSENSORY RECEPTORS

• Mechanoreceptors
o “very rapidly adapting” (MCQ)
§ pacinian corpuscle
o “rapidly adapting” (MCQ)
§ Meissner’s corpuscle and hair follicles
o “slowly adapting” (MCQ)
§ Ruffini’s corpuscle
§ Merkel’s receptors
§ tactile discs
o Very rapidly and rapidly adapting receptors
§ detect changes in the stimulus
§ detect changes in velocity
o Slowly adapting receptors
§ respond to intensity and duration of the stimulus.
o Pacinian corpuscles (MCQ)
§ encapsulated receptors
§ found in the subcutaneous layers of nonhairy and hairy skin and in muscle
§ They are the most rapidly adapting of all mechanoreceptors.
§ Because of their very rapid on-off response , they can (MCQ)
• detect changes in stimulus velocity
• encode the sensation of vibration.
o Meissner’s corpuscles (MCQ)
§ encapsulated receptors
§ found in the dermis of nonhairy skin
§ most prominently on the fingertips, lips (MCQ)
§ locations where tactile discrimination is especially good.
§ They have small receptive fields
§ can be used for two-point discrimination. (MCQ)
§ rapidly adapting receptors that encode point discrimination, precise location,
tapping, and flutter.

o Hair-follicle receptors
§ arrays of nerve fibers surrounding hair follicles in hairy skin.
§ When the hair is displaced, it excites the hair-follicle receptors. (MCQ)
§ rapidly adapting
§ detect velocity and direction of movement across the skin.
o Ruffini’s corpuscles(MCQ)
§ located in the dermis of nonhairy and hairy skin and in joint capsules
§ have large receptive fields (MCQ)
§ stimulated when the skin is stretched.
§ stimulus may be located some distance from the receptors it activates.
§ slowly adapting receptors. (MCQ)
§ When the skin is stretched, the receptors fire rapidly, then slowly adapt to a new
level of firing that corresponds to stimulus intensity .
§ Ruffini’s corpuscles detect stretch and joint rotation. (MCQ)
o Merkel’s receptors
§ slowly adapting receptors (MCQ)
§ found in nonhairy skin and have very small receptive fields.
§ These receptors detect vertical indentations of the skin
§ response is proportional to stimulus intensity .
o Tactile discs (MCQ)
§ similar to Merkel’s receptors but are found in hairy, rather than nonhairy , skin.
(MCQ)
• Thermoreceptors
o slowly adapting receptors (MCQ)
o two classes - cold receptors and warm receptors
o at 36C, both receptors are active
o When the skin is warmed above 36C, the cold receptors become quiescent(MCQ)
o when the skin is cooled below 36C, the warm receptors become quiescent.
o If skin temperature rises to damaging levels (above 45C)
§ warm receptors become inactive
§ polymodal nociceptors will be activated.
o extremely cold (freezing) temperatures also activate nociceptors.
• Nociceptors
o respond to noxious stimuli that can produce tissue damage.
o two major classes of nociceptors
§ thermal or mechanical nociceptors (MCQ)
• supplied by finely myelinated A-delta afferent nerve fibers (MCQ)
• respond to mechanical stimuli such as sharp, pricking pain.
§ polymodal nociceptors.
• supplied by unmyelinated C fibers (MCQ)
• respond to high-intensity mechanical or chemical stimuli and hot and
cold stimuli.
o Damaged skin releases a variety of chemicals, including bradykinin, prostaglandins,
substance P , K+, and H+(MCQ)
§ initiate the inflammatory response.
§ The blood vessels become permeable,
§ there is local edema and redness of the skin.
o Mast cells near the site of injury release histamine that activates nociceptors(MCQ)
•
Topic - Skeltal muscle physiology
Structure of Skeletal Muscle
• Skeletal muscle is organized into progressively smaller anatomical units.

• Muscle fibers are surrounded by a plasma membrane more commonly called the sarcolemma.
• Muscle fibers are composed of a bundle offibrous structures called myofibrils,
• Each myofibril is a linear arrangement of repeating structures called sarcomeres.
• Sarcomeres are the fundamental contractile unit ofskeletal muscle and are characterized by their highly
ordered appearance under a polarizing light microscope
• Thick filaments – Myosin (MCQ)
o Thick filaments in the A band are composed primarily of the protein myosin. (MCQ)
o There are two essential light chains and two myosin regulatory light chains.
o Each heavy chain is associated with a globular head
§ The two globular heads of myosin heavy chains can hydrolyze ATP to ADP and
inorganic phosphate (MCQ)
§ also have the intrinsic ability to interact with actin.
• Thin filaments - : actin, tropomyosin, and troponin(MCQ)
o are composed of three primary proteins: actin, tropomyosin, and troponin.
o Actin is composed of G-actin and F-actin
o Each G-actin monomer contains binding sites for myosin, tropomyosin, and troponin I.
(MCQ)
o Tropomyosin is an elongated protein that lies within the two grooves formed by the double
stranded F-actin
o Each thin filament contains 40–60 tropomyosin molecules. (MCQ)
o Troponin is a complex of three separate proteins: (MCQ)
§ Troponin T binds the other two troponin subunits to tropomyosin
§ Troponin C binds Ca2+, the crucial regulatory step in muscle contraction. (MCQ)
§ Troponin I is responsible for the inhibitory conformation of the tropomyosin-
troponin complex observed in the absence of Ca2+.(MCQ)
o Tubules, a tubular network, are located at thejunctions of A bands and I bands and contain a
protein called the dihydropyridine receptor. (MCQ)

• The sarcoplasmic reticulum (SR)
o site of Ca2+ storage near the transverse tubules (T-tubules). (MCQ)
o It contains a Ca2+-release channel known as the ryanodine receptor. (MCQ)
• Several steps are involved in the mechanics of muscle contraction:
• Action potentials in muscle cell membrane cause depolarization of the T-tubules, which opens
Ca2+-release channels in the SR and increases intracellular Ca2+.(MCQ)
• Ca2+ releases the troponin-tropomyosin inhibitory influence so that the active sites on each
G-actin monomer are uncovered. (MCQ)
• The myosin globular heads that protrude from the thick filament bind with G-actin active
sites, thus forming crossbridges. (MCQ)
§ How is power stroke generated
o Intramolecular forces (stored energy) within the myosin molecules allow myosin to flex in
the so-called hinge regions.
o These areas are the two proteolytic enzyme–sensitive regions in the myosin molecule. The
action of flexing of the myosin molecule causes the globular heads (still attached to actin) to tilt
toward the center of the sarcomere.
o This movement, called the power stroke, creates tension that results from shortening of
individual sarcomeres.
o Immediately after the tilt, the crossbridge is broken and the globular heads snap back to the
upright position.
o At this point, a new crossbridge can be formed ifATP and Ca2+ are available in the vicinity of
thick and thin filaments. (MCQ)
o In the absence of Ca2 +, crossbridge formation is not possible.
o Relaxation occurs when Ca2+ uptake into the SR lowers intracellular Ca2+.(MCQ)
§ Biochemical events that occur during a muscle contraction cycle involve
an active complex and the rigor complex.
o Myosin with ATP bound to it (myosin-ATP complex) has a low affinity for
o the G-actin active sites.
o When Ca2+ binds to troponin and tropomyosin, tropomyosin rotates out of the way so that
the active sites on G-actin are uncovered.
o Myosin-ATP is simultaneously hydrolyzed to myosin-ADP, which has a high affinity for the
G-actin active sites.
o Consequently, an active complex, or crossbridge, is formed between actin and myosin-ADP .
o ADP is released from myosin, and the globular heads tilt toward the center of the sarcomere ,
producing tension
o At this stage, the rigor complex is formed between actin and myosin.
o ATP then binds to myosin, and the myosin-ATP complex breaks the crossbridge and the
globular heads snap back to the upright position.
o The cycle is ready to start again in the presence of Ca2+.
§ Skeletal muscle enters a state of prolonged stiffness termed rigor mortis at death.
§ Rigor mortis occurs because, with death, muscle cells are no longer able to
synthesize ATP . (MCQ)
§ In the absence of ATP , the crossbridges between myosin and actin are unable
to dissociate.
§ After 15–25 hours, proteolytic enzymes released from lysosomes begin to
break down actin and myosin.
o Relationship between muscle length and tension.

o Isometric contraction
§ muscle length is held constant during the development of force.
§ An example would be an individual pushing against an immovable object such as the wall of a
house.
o In an isotonic contraction
§ muscle shortens while exerting a constant force. (MCQ)
§ An example would be an individual lifting a Weight with his biceps
o Active tension
§ The tension that a stimulated muscle develops when it contracts isometrically (MCQ)
§ (total tension) and the passive tension exerted by the unstimulated muscle vary
with the length of the muscle fiber
§ The difference between the two values is the tension produced by the contractile
process, the active tension
§ The amount of active tension developed with a contraction decreases from its
maximum as the muscle is either shortened or lengthened prior to the contractile
stimulus.
§ Active tension developed is proportional to the number of crossbridges formed. (MCQ)
§ Tension is reduced when the sarcomere is shortened to a point where thin filaments
overlap and prevent one another from forming crossbridges with myosin.
§ Thus, isometric tension produced depends on the degree ofoverlap ofthe thick and thin
filaments, which dictates the number of crossbridges that can be formed. (MCQ)
o Force-velocity relationship
§ refers to the relationship between the load (or weight) placed on a muscle and the
velocity at which that muscle contracts while lifting the load.
§ Velocity is the distance an object moves per unit time.
o Load
§ A load can be thought of as a weight that the muscle is attempting to move via an
isotonic contraction, for example, when a weightlifter tries to lift a series of
progressively heavier weights.
§ A muscle can contract most rapidly with no load (MCQ)
§ As loads increase, however, the velocity at which the muscle lifts the weight
decreases.
§ When the weight equals the maximum amount of force that the muscle can generate,
the velocity becomes zero. In this case the contraction becomes isometric (eg, the
muscle contracts but does not shorten). (MCQ)
o The functional unit of a muscle is called a motor unit.
o Increased tension development in skeletal muscle is attained by wave summation (eg,
increasing stimulus frequency of a single motor
neuron).
o Summation, or recruitment, of motor units.

§ Besides increasing tension development, recruitment allows a movement to be continuous
and smooth because different motor units fire asynchronously; that is, while one motor
unit is contracting, another might be at rest.
§ A contraction can be a single, brief contraction or a maintained contraction due to
continuous excitation of muscle fibers.
§ A single contractile event (eg, twitch) is initiated by a single action potential from a
motor neuron reaching the neuromuscular junction. (MCQ)
§ If a second stimulus is applied before the muscle fibers in the motor unit have relaxed,
the second contractile event builds on the first.
§ It can be said that the two contractions summate.
§ This summation of contractions occurs when stimulation frequencies reach about 10
per second.
§ As the frequency of stimulation is increased, the developed force continues to sum until
a maximum developed force is reached.
§ At this point, the individual contraction-relaxation cycles fuse to produce a single
smooth curve called tetanus
§ Tetanus occurs in skeletal musclebecause the refractory period is short relative to the
contraction time. (MCQ)
Topic - Spermatogenesis
• Male Reproductive Hormones

o Fetal Life
§ In normal males, an SRY antigen released from the Y chromosome stimulates the
medullary portion ofthe indifferent gonad to develop into a testis. (MCQ)
§ Wolffian and Müllerian ducts are initially present in both male and female fetuses.
§ In the absence of hormonal input (ie, in the normal female fetus), female internal and
external structures develop (ie, Müllerian ducts develop). (MCQ)
§ Normal male development requires the presence of three hormones:

• Testosterone
• dihydrotestosterone (DHT
• Müllerian-inhibiting factor (MIH).

§ Sertoli cells secrete MIH, which inhibits Müllerian duct development. (MCQ)
§ Hormone chorionic gonadotropin (hCG) and LH stimulate Leydig cells to secrete

testosterone, which stimulates Wolffian duct development. (MCQ)
§ In certain tissues (eg, prostate)
• 5-alpha-reductase converts testosterone to DHT, which stimulates the
development of organs from the urogenital sinus and genital tubercle.
(MCQ)
• In the absence of MIH, the Müllerian ducts develop, which differentiate into
female internal structures.

§ Wolffian ducts differentiate into the majority of male internal structures , namely,
epididymis, vasa deferentia, and seminal vesicles.
§ The urogenital sinus and genital tubercle differentiate into the scrotum, penis, and
prostate gland.
o Puberty
§ Hypothalamic control of gonadotropin secretion is by GnRH.
§ GnRH is secreted in episodic bursts, which causes pulsatile release of FSH and LH
from the anterior pituitary . (MCQ)
§ At puberty , the amplitude of the LH pulses becomes greater, particularly during sleep,
driving the mean level of LH higher.
§ This increased LH stimulates the Leydig cells to again secrete testosterone. (MCQ)
o Major Cell Types of the Testis
§ LH receptors are located on the cell membranes of the interstitial cells of Leydig.
(MCQ)
§ LH stimulation results in increased synthesis and secretion of testosterone.
§ Blood testosterone provides a negative feedback signal to both the hypothalamus and
the anterior pituitary to regulate LH secretion.
§ Much of the testosterone synthesized by the Leydig cells diffuses into adjacent Sertoli
cells. (MCQ)
§ An androgen-binding protein synthesized by the Sertoli cells and secreted into the lumen ofthe
seminiferous tubules helps maintain a high local concentration of testosterone . (MCQ)
§ FSH increases the synthesis of androgen-binding protein
§ Testosterone acts locally to facilitate spermatogenesis via testosterone receptors on
the nuclear chromatin of the Sertoli cell.
§ Membranes of the Sertoli cells surround the germ cells, and nutrients destined for
the germ cells must pass through these membranes.
§ FSH is essential for the initiation of spermatogenesis. (MCQ)
§ FSH occupies receptors located on the plasma membrane of Sertoli cells to increase the
production of proteins .
§ Both FSH and testosterone are required for normal spermatogenesis.
§ Sertoli cells are the source of MIH. (MCQ)
§ Sertoli cells also secrete aromatase, which converts androgens to estrogens, and
Sertoli cell tumors are associated with feminization (MCQ)
o Anabolic Actions of Androgens
§ Androgens increase GH secretion, which drives IGF-1 to increase long bone growth,
stimulating a growth spurt.
§ IGF-1 is the major stimulus for cell division of the cartilage-synthesizing cells located
in the epiphyseal plates of long bones. (MCQ)
§ Thus, androgens stimulate the growth of long bones and are responsible for the
greater average height of men compared to women.
§ Near the end of puberty , androgens promote the mineralization (fusion or closure) of
the epiphyseal plates of long bones.
§ Protein synthesis is stimulated in muscle, causing the larger muscle mass in men as
compared with women.
§ Erythropoietin secretion is stimulated by the kidneys and increases red blood cell
production.
o Androgenic Effects of Androgens
§ Androgens induce development of male accessory reproductive organs.
§ They increase development of male secondary sex characteristics.
§ They are required for libido and potency.
§ Androgens inhibit GnRH via the hypothalamus and LH secretion via the anterior
pituitary. (MCQ)
§ They are required for maintenance of spermatogenesis.
o Regulation of Testicular Function
§ GnRH from the hypothalamus stimulates FSH and LH release from the anterior
pituitary. (MCQ)
§ A pulsatile release of GnRH is required to up-regulate its own pituitary receptors
and to prevent down-regulation of its receptors.
§ FSH acts on Sertoli cells to regulate spermatogenesis(MCQ)
§ Sertoli cells secrete inhibin, a protein that regulates FSH secretion from the anterior
pituitary by negative feedback. (MCQ)
§ LH stimulates Leydig cell testosterone secretion. (MCQ)
§ Testosterone inhibits LH by inhibiting release of GnRH from the hypothalamus and
LH release from the anterior pituitary. (MCQ)
o Regulation of Spermatogenesis
o The scrotum provides an environment 4C cooler than the abdominal cavity via a
countercurrent heat exchanger located in the spermatic cord.
• Male Sexual Response
o Erection
§ is caused by dilation of the blood vessels in the erectile tissue of the penis.
§ The increased blood flow compresses veins, blocking outflow.
§ Efferent parasympathetic fibers and nonadrenergic noncholinergic fibers mediate
erection. (MCQ)
§ Important neurocrine mediators are vasoactive intestinal peptide or nitric oxide.
(MCQ)
o Emission
§ is the movement of semen from the epididymis, vas deferens, sem nal vesicles, and
prostate to the ejaculatory ducts
§ mediated by sympathetic adrenergic transmitters.
§ A sympathetic adrenergic-mediated contraction of the internal sphincter of the
bladder prevents retrograde ejaculation of semen into the bladder. (MCQ)
§ Destruction of this sphincter by prostatectomy often results in retrograde ejaculation.
(MCQ)
o Ejaculation
§ caused by the rhythmic contraction of the bulbospongiosus and ischiocavernous
muscles of the urogenital diaphragm.
Topic – ECF
• Body Fluids
o Humans are composed primarily of water.
o Body composition depends on age and sex
o Total body water (TBW) is divided into two major compartments: theintracellular fluid (ICF)
and the extracellular fluid (ECF)
§ The ICF compartment is approximately two thirds of TBW . (MCQ)
§ The ECF compartment represents approximately one third of TBW . (MCQ)
o ECF is further divided into
§ Blood plasma (blood without cells)
§ Interstitial fluid (ISF) (fluid between cells)
§ Transcellular fluid (synovial intraocular, pericardial, cerebrospinal, and epithelial fluids)
o Adipose tissue is low in water content
o obese individuals have a lower fraction of body weight that is water than do normal weight
individuals. (MCQ)
o Substances used to determine the volume ofbody fluid compartments must have the following
characteristics:
§ They must be nontoxic.
§ They must not be synthesized or metabolized in the compartment measured.
§ They must not induce shifts in fluid distribution among different compartments.
§ They must be easily and accurately measured.
o Tritiated water and deuterium oxide are used to measure TBW (MCQ)
o Inulin, mannitol, and sulfate are used to measure ECF. (MCQ)
o plasma volume can be measured using radioiodinated serum albumin (131I-albumin, or RISA) or
Evans blue dye. (MCQ)
o TBW−ECF = ICF
o ECF −plasma volume = ISF

• TBW daily
turnover
due to water
intake and loss
(Very High
Yield Topic)
o Water intake averages about 2 L/d, (MCQ)

o Insensible water loss is approximately 0.74 L/d due to water evaporation through the skin
and due to respiration. (MCQ)
o Water loss through the skin (0.3–0.4 L/d) is not dependent on sweating and occurs in people
born with no sweat glands
o The rate of water loss is minimized because of the cornified layer of the skin.
o When this skin layer is lost following severe burns, the rate of water loss increases
dramatically to about 3–5 L/d.
o Water loss due to respiration is about 0.3–0.4 L/d. (MCQ)
o Water vapor pressure in the lung is approximately 47 mm Hg.
o Inspired air becomes saturated with moisture because it has a lower vapor pressure. In cold
weather, vapor pressure in the air decreases even further, enhancing water loss.
o At rest, water loss due to sweating is approximately 0.1 L/d, but this amount increases
dramatically during heavy exercise (up to 1–2 L/h).
o Feces accounts for approximately 0.1–0.2 L/d. (MCQ)
o Urine accounts for approximately 0.5–1.5 L/d (MCQ)
• Fluid shifts between compartments follow several basic principles:
o ICF and ECF are in osmotic equilibrium.
o Na+ is the major cation of the ECF . (MCQ)
o K+ is the major cation of the ICF . (MCQ)
o The distribution of Na+ and K+ is maintained by Na+-K+-ATPase.
o Equilibration between the ICF and ECF occurs through water movement,
not through movement of osmotically active particles.
Topic - Respiratory cycle
o Forces Acting on the Lungs

o Lung recoil
§ refers to forces that develop in the lung wall during expansion.
§ Recoil increases as the lung enlarges.
§ Recoil always acts to collapse the lung.
o Intrapleural pressure (also called pleural pressure, or PPL)
§ the pressure in the thin film of fluid between the lung and chest wall
§ PPL is generally subatmospheric (~ −5 cm H20). (MCQ)
§ Negative subatmospheric pressures act to expand the lung
§ positive pressures act to collapse the lung. (MCQ)
§ When PPL exceeds recoil ,forces the lungs expand.
§ When recoil forces exceed PPL the lungs decrease in volume.
o Alveolar pressure (PA)
§ It is the pressure of the alveolar air
§ PA drives airflow into and out of the lungs.
§ If PA equals 0 (ie, no airflow), then PA is the same as atmospheric pressure. (MCQ)
§ PA is less than 0 during inspiration(MCQ)
§ PA is greater than 0 during expiration. (MCQ)
.
• Alveolar and intrapleural pressures during normal breathing.

o Intrapleural pressure remains negative during inspiration and expiration. (MCQ)
o Alveolar pressure is negative during inspiration and positive during expiration. (MCQ)

o Transpulmonary pressure (PTP)

o difference between the pressure inside the lung (alveolar pressure) and the pressure
outside the lung (intrapleural pressure).
o PTP determines the degree of inflation of the lung.
o PTP is greater in the upper regions of the lung , (MCQ)
o PPL is more negative and holds the lungs in a more expanded position. (MCQ)
o The upper regions of the lungs also have greater volumes than the lower regions. Further
increases in volume per unit increase in PTP are smaller in the upper than lower regions of
the lungs because the upper expanded lung is stiffer (ie, less compliant).

o Lung Compliance
o Compliance (CL) is the stretching of the lungs and is calculated as follows
o Compliance (CL) = change in lung volume

transpulmonary pressure
o Compliance is the change in lung volume per unit change in airway pressure
o High CL means more air will flow for a given change in pressure. (MCQ)
o Low CL means less air will flow for a given change in pressure(MCQ)

o If PTP becomes more negative, more air will flow into the system, (MCQ)
o if PTP becomes more positive more air will flow out of the system. (MCQ)
o CL is an indicator of the effort required to expand the lungs to overcome recoil.
o Compliant lungs have low recoil, whereas stiff lungs have a large recoil force (MCQ)
Airway Resistance
o The rate of airflow for a given driving pressure depends on airway resistance:
o where
o V = flow rate (L/s)
o PA = alveolar pressure (mm Hg)
o R = airway resistance (R units)
o The more negative the intrapleural pressure (eg, during inspiration), the lower the airway
resistance. (MCQ)
o According to Poiseuille’s equation,
§ Where r = radius of the airway

o strong relationship exists between resistance and the radius of the airway.
o The following factors influence airway resistance:
o Stimulation of parasympathetic nerves produces bronchoconstriction. (MCQ)
o Stimulation of sympathetic nerves or circulating catecholamine produces bronchodilation.
(MCQ)
o Low lung volumes are associated with increased airway resistance(MCQ)
o High lung volumes are associated with decreased resistance. (MCQ)
o Breathing a high-density gas increases resistance to airflow
o Breathing a low-density gas decreases resistance to airflow .
o The first and second (ie, medium-sized) bronchi represent most of the airway resistance.
(MCQ)
o The pressure-volume curve
o not the same for inspiration and expiration
o this difference is called hysteresis, which is due primarily to the effects of airway
resistance

o Static compliance curves

o In fibrosis (lower curve) the lungs are stiff and less compliant and have increased
alveolar elastic recoil force
o Emphysema (upper curve) increases the compliance of the lungs and decreases alveolar
elastic recoil forces because the alveolar septal tissue that opposes lung expansion is
destroyed
Breathing cycle
• the breathing cycle is divided into phases: rest (the period between breaths), inspiration, and expiration.
• Transmural pressure
o transmural pressure is calculated as alveolar pressure minus intrapleural pressure.
o If transmural pressure is positive, it is an expanding pressure on the lung,
o if alveolar pressure is zero and intrapleural pressure is -5 cm H2O, there is an expanding
pressure on the lungs of +5 cm H2O (0 - [-5 cm H2O] = +5 cm H2O). (MCQ)
o If transmural pressure is negative, it is a collapsing pressure on the lung
o For all phases ofthe normal breathing cycle , despite changes in alveolar and intrapleural pressures,
transmural pressures across the lungs are such that they always remain open.

Volumes and pressures during the normal breathing cycle.
• Rest
o At rest, no air is moving into or out of the lungs.
o Alveolar pressure equals atmospheric pressure, and because lung pressures are always
referred to atmospheric pressure, alveolar pressure is said to be zero. (MCQ)
o There is no airflow at rest because there is no pressure difference between the
atmosphere (the mouth or nose) and the alveoli.
o At rest, intrapleural pressure is negative, or approximately -5 cm H2O. (MCQ)
o Why is the intrapleural pressure is negative (MCQ)
§ The opposing forces of the lungs trying to collapse and the chest wall trying to
expand create a negative pressure in the intrapleural space between them.
o The transmural pressure across the lungs at rest is+ 5 cm H2O (MCQ) (alveolar pressure
minus intrapleural pressure), which means that these structures will be open.
o The volume present in the lungs at rest is the equilibrium volume or FRC, which, by
definition, is the volume remaining in the lungs after a normal expiration. (MCQ)
• Inspiration
o During inspiration, the diaphragm contracts, causing the volume of the thorax to increase
o As lung volume increases, the pressure in the lungs must decrease. (Boyle’s law states
that P V is constant at a given temperature.)
o Halfway through inspiration
§ alveolar pressure falls below atmospheric pressure (-1 cm H2O).
§ The pressure gradient between the atmosphere and the alveoli drives airflow into
the lung.

o Air flows into the lungs until, at the end of inspiration
§ alveolar pressure is once again equal to atmospheric pressure
§ the pressure gradient between the atmosphere and the alveoli has dissipated
§ airflow into the lungs ceases
o The volume of air inspired in one breath is the tidal volume (VT), which is approximately 0.5
L (MCQ)
o the volume present in the lungs at the end of normal inspiration is the functional
residual capacity plus one tidal volume (FRC + VT). (MCQ)
o During inspiration, intrapleural pressure becomes even more negative than at rest. (MCQ)
o intrapleural pressure become more negative, or approximately -8 cm H2O at the end of
inspiration (MCQ)
§ Explanations : As lung volume increases
• the elastic recoil of the lungs also increases and pulls more forcefully
against the intrapleural space
• airway and alveolar pressures become negative.
o The extent to which intrapleural pressure changes during inspiration can be used to
estimate the dynamic compliance of the lungs.
• Expiration
o Normally, expiration is a passive process.
o Alveolar pressure becomes positive (higher than atmospheric pressure) because the elastic
forces of the lungs compress the greater volume of air in the alveoli.
o When alveolar pressure increases above atmospheric pressure air flows out of the lungs,
and the volume in the lungs returns to FRC.
o The volume expired is the tidal volume (MCQ)
o At the end of expiration , all volumes and pressures return to their values at rest and the
system is ready to begin the next breathing cycle.
• Forced Expiration
o In a forced expiration, a person deliberately and forcibly breathes out.
§ The expiratory muscles are used to make lung and airway pressures even more
positive than those seen in a normal, passive expiration.
§ In a person with normal lungs, the forced expiration makes the pressures in the lungs
and airways very positive.
§ Both airway and alveolar pressures are raised to much higher values than those
occurring during passive expiration.
o in forced expiration (MCQ)
§ airway pressure is +25 cm H2O
§ alveolar pressure is +35 cm H2O
§ intrapleural pressure-is +20 cm H2O
o Expiration will be rapid and forceful because the pressure gradient between the alveoli
(+35cmH2O) and the atmosphere (0) is much greater than normal whereas during a
normal passive expiration, alveolar pressure is +1 cm H2O
o Why the lungs and airways do not collapse under these conditions of positive intrapleural
pressure?
§ As long as the transmural pressure is positive, the airways and lungs will remain
open
§ During a normal forced expiration (MCQ)
•transmural pressure across the airways = airway pressure minus
intrapleural pressure is +5 cm H2O
o (+25 minus + 20] = +5 cm H2O
• transmural pressure across the lungs= alveolar pressure minus intrapleural
pressure is +15 cm H2O
o (+35 minus +20) = +15 cm H2O
• Therefore, both the airways and the alveoli will remain open because
transmural pressures are positive.
o Why forced expiration may cause the airways to collapse in a person with COPD. (MCQ)
o In COPD, lung compliance increases because of loss of elastic fibers
o During forced expiration,
§ intrapleural pressure is raised to the same value as in the normal person, +20 cm
H2O.
§ However, because the structures have diminished elastic recoil,alveolar pressure
and airway pressure are lower than in a normal person.
§ The transmural pressure gradient across the lungs remains a positive expanding
pressure, +5 cm H2O, and the alveoli remain open
§ However, the large airways collapse because the transmural pressure gradient
across them reverses, becoming a negative (collapsing) transmural pressure of -5 cm H2O.
o Obviously , if the large airways collapse , resistance to airflow increases and expiration is
more difficult.
o Persons with COPD learn to expire slowly with pursed lips, which raises airway
pressure, prevents the reversal of the transmural pressure gradient across the large
airways, and, thus, prevents their collapse.(MCQ)
Topic - Small intestine absorption
Intestinal Fluid and Electrolyte Transport
• Together, the small and large intestines absorb approximately 9 L of fluid daily (MCQ)

• What is the source of this large volume of fluid that is absorbed?

o there is slightly more than 9 L of fluid in the lumen of the gastrointestinal tract, volume of
liquid in the diet (2 L) (MCQ)
o combined volume of salivary , gastric, pancreatic, biliary , and intestinal secretions (7 L).
(MCQ)
o 100 to 200 mL is excreted in feces
• The tight junctions in the small intestine are “leaky” (have low resistance) and permit significant
paracellular movement (MCQ)
• tight junctions in the colon are “tight” (have a high resistance) and do not permit paracellular
movement. (MCQ)
Intestinal absorption
• Intestinal epithelial cells lining the villi absorb large volumes of fluid.
• The fluid absorbed is always isosmotic, (MCQ)

• Jejunum
o The jejunum is the major site for Na+ absorption in the small intestine).Na+ enters the
epithelial cells of the jejunum via several different Na+-dependent coupled transporters.
(MCQ)
o The apical membrane contains Na+- monosaccharide cotransporters (Na+-glucose and Na+-
galactose), Na+–amino acid cotransporters, and Na+-H+ exchange.
o After Na+ enters the cell on the coupled transporters, it is extruded across the basolateral
membrane via the Na+-K+ ATPase.
o Note that the source of H+ for Na+-H+ exchange is intracellular CO2 and H2O, which are
converted to H+ and HCO3 in the presence of carbonic anhydrase.
o The H+ is secreted into the lumen on the Na+-H+ exchanger, and the HCO3 is absorbed
into blood.
• Ileum

o The ileum contains the same transport mechanisms as the jejunum plus a Cl-HCO3 exchange
mechanism in the apical membrane and a Cl transporter, instead of an HCO3 transporter, in
the basolateral membrane (MCQ)
o Thus, when H+ and HCO3 are generated inside the epithelial cells in the ileum, the H+ is
secreted into the lumen via the Na+-H+ exchanger, and the HCO3 also is secreted into the
lumen via the Cl-HCO3 exchanger (rather than being absorbed into blood, as in the jejunum).
o The result of the combined Na+-H+ exchange and Cl-HCO3 exchange in the apical
membrane is net movement of NaCl into the cell, which then is absorbed.
o Thus, in the ileum, there is net absorption of NaCl , whereas in the jejunum there is net
absorption of NaHCO3. (MCQ)
• Colon
o The cellular mechanisms in the colon are similar to those in the principal cells of the late
distal tubule and collecting ducts of the kidney (MCQ)
o The apical membrane contains Na+ and K+ channels, which are responsible forNa+
absorption and K+ secretion. (MCQ)
o Like the renal principal cells, synthesis of the Na+ channels is induced by aldosterone, which
leads to increases in Na+ absorption and, secondarily, to increases in K+ secretion.

Topic - Smooth muscle contraction
Smooth Muscle
• Structure of Smooth Muscle

o Specialized contacts between individual smooth muscle cells have two functions: in
communication and as mechanical linkages.
§ Gap junctions (nexus) are areas of close opposition (~2 nm) between plasma
membranes of separate cells.
• Gap junctions serve as a low-resistance electrical coupling structure.
(MCQ)
§ Attachment plaques are characterized by a 10- to 30-nm gap between plasma
membranes of adjacent cells.
• These structures may serve as anchor points for thin filaments.
o Smooth muscle cells contain SR but in less abundant quantities compared to skeletal
muscle.
§ Like skeletal muscle SR, the smooth muscle counterpartaccumulates and releases
Ca2+.(MCQ)
§ Smooth muscle does not have a T-tubule system. (MCQ)
• Physiology of Smooth Muscle
o Smooth muscle is typically subdivided into two classes:
§ unitary, or visceral smooth muscle
§ multiunit smooth muscle.
o Both classes of smooth muscle share the following characteristics:
§ Smooth muscle is capable of contractions that are slow in onset but are sustained
for long periods of time with relatively little energy input required. (MCQ)
§ The motor innervation of smooth muscle is exclusively autonomic, either
parasympathetic or sympathetic. (MCQ)
§ All smooth muscle exhibits a certain degree of intrinsic tone , or basal resting
tension; contractions are superimposed on this tone.
o Visceral smooth muscle performs important functions in the vascular system, the airways ofthe
lung, the gastrointestinal tract, and the genitourinary tract.
§ Spontaneous activity is initiated in pacemaker areas and spreads throughout the
entire muscle. (MCQ)
§ Unlike pacemakers in cardiac muscle, smooth muscle pacemakers move around.
o Tension develops in response to stretch.
o Contractions are initiated by circulating hormones and are not typically initiated by motor
nerve impulses.
§ However, contractile activity may bemodified and regulated by motor nerve input.
o Spontaneous activity in visceral smooth muscle results from at least two types of
fluctuations in electrical activity:

§ Slow waves of depolarization are produced when the threshold is reached, as
occurs in longitudinal muscles of the intestines.
§ Spontaneous prepotentials, or spike potentials, produce an asynchronous discharge
resulting in irregular contractions such as occurs in the nonpregnant uterus.
• Calcium is the signal for contraction in smooth muscle.
o Smooth muscle does not contain troponin,
o Ca2+ binds to calmodulin and then the Ca2+-calmodulin complex activates the enzyme
myosin light chain kinase (MLCK). (MCQ)
o Ca2+-calmodulin-activated MLCK phosphorylates the heavy meromyosin component of
myosin and thereby consumes ATP. (MCQ)
o Phosphorylated myosin has a high affinity for actin, and crossbridges form between
myosin and actin. (MCQ)
• Relaxation of smooth muscle can occur through the following mechanism:
o Stimulation of Ca2+-pumping activity of either the plasma membrane or the SR reduces
the concentration of Ca2+ in the vicinity of the contractile elements. (MCQ)
o The activity of myosin light chain phosphatase can be increased.
o Phosphorylation of MLCK leads to decreased activity of this enzyme. (MCQ)
§ Multiunit smooth muscle

§ more similar to skeletal muscle than it is to visceral smooth muscle
§ much less abundant than visceral smooth muscle.
§ Examples of multiunit smooth muscle include ciliary muscle (the muscle
§ that focuses the eye), pilomotors (the muscles that cause hair erection(MCQ)
§ Multiunit smooth muscle does not contract spontaneously.
§ Multiunit smooth muscle is usually activated by motor nerve stimulation.
§ Multiunit smooth muscle is only minimally responsive to circulating hormones.
§ Multiunit smooth muscle does not respond to stretch by developing tension. (MCQ)
Topic - Thyroid
• Thyroid Hormones
o Formation of the Thyroid Hormones
§ The thyroid hormones are iodinated derivatives of tyrosine
§ Iodide is oxidized to iodine by thyroperoxidase.(MCQ)
§ Iodine is incorporated into tyrosine residues to form monoiodotyrosine (MIT) or
diiodotyrosine (DIT).
§ Two DITs are coupled to form Levothyroxine (T4).
§ One MIT and two DITs are coupled to form T3, or reverse T3 (rT3).
§ In the thyroid gland, most of the iodine is found in MIT and DIT.
§ Thyroxine (T4) is released in larger amounts than T3, the primary active hormone
§ rT3 is released but is inactive. (MCQ)
o Iodine Metabolism
§ Although several tissues take up iodide, only the thyroid gland significantly
incorporates iodine into protein.
§ The thyroid-to-serum ratio of iodide is normally 30:1. (MCQ)
§ Iodide is transported into the thyroid at the basal membrane of follicular
§ cells by an active process that may involveNa/K+-ATPase in the trapping
mechanism. (MCQ)
§ Iodide is oxidized to iodine in the follicular lumen.
• Iodine is incorporated into tyrosine residues (organification) to form MIT and
DIT.
• Coupling of MIT and DIT form T4 and T3
§ T4 and T3 are stored as parts of thyroglobulin residues (MCQ)
§ with TSH stimulation the residues are taken into the follicular cells by endocytosis.
§ In the cell, thyroglobulin residues are acted on by lysosomal and protease enzymes to
form T4 and T3, and to form MIT and DIT.
o Feedback Regulation of Thyroid Function
§ the primary negative feedback is at the pituitary (MCQ)
§ negative feedback regulation also occurs at the hypothalamus by blocking TRH
release.
§ T3 and T4 negatively feed back and inhibit TSH release from the anterior pituitary.
(MCQ)
§ Somatostatin and dopamine are inhibitory by blocking TSH secretion. (MCQ)
o Iodide and Thyroid Hormone Homeostasis
§ Iodide mediates thyroid hormone biosynthesis and release.
§ Decreased iodide in the diet decreases T4 and T3 secretions.
§ This increases TSH due to lack of feedback.
§ Increased TSH levels cause hypertrophy and hyperplasia of the thyroid (goiter).
§ With decreased iodine availability, the thyroid compensates, secreting more of the
active hormone, T3.
§ High iodide intake will decrease both thyroid hormone biosynthesis (Wolff-Chaikoff
effect) and release. (MCQ)
o Thyroid Hormone Transport
§ Thyroid-binding globulin (TBG)
• a glycoprotein produced by the liver
• binds approximately 70% of the T4 and approximately 80% of the T3 in
plasma. (MCQ)
§ Albumin
• has a much lower affinity for binding the thyroid hormones than does TGB
• the high concentration of albumin results in the binding of approximately 20%
of T4 and approximately 11% of T3.
§ During pregnancy, increased estrogen causes increased TBG production. (MCQ)
• Pregnant women do not become hyperthyroid, however, because free thyroid
hormone levels remain relatively constant. (MCQ)
§ Androgens and cirrhosis of the liver decrease TBG and decrease total thyroid
hormone, but individuals does not become hypothyroid, because the amount of free
hormone is adjusted to normal levels. (MCQ)

§ salicylates compete with T4 and T3 for binding sites on TBG, producing low total
thyroid hormone levels, but free hormone levels again remain relatively normal.
(MCQ)
o Physiologic Actions of Thyroid Hormones
§ T4 and T3 enter cells by passive diffusion
§ the biological effects of T4 are thought to be a result of its intracellular conversion to
T3.
§ The primary effect of the thyroid hormones is to increase O2 consumption
(calorigenic action) in all tissues of the body except brain, testes, and spleen.
§ Thyroid hormones increase oxygen consumption and basal metabolic rate (BMR).
§ Both respiration and cardiac output are increased in order to supply tissues with
increased O2.
§ In the heart, rate and force of myocardial contractions are increased.
§ If BMR increases, and adequate fuel (increased food intake) is not provided, catabolism
results and weight is lost.
• Hyperthyroid individuals often lose weight(MCQ)
• hypothyroid individuals often gain weight
§ The generalized muscle wasting in the presence of high concentrations of the
thyroid hormones is associated with muscle weakness and fatigability .
§ High levels of thyroid hormones also cause increased excretion of Ca2+ and
PO43−as well as decreased bone mass, and occasionally pathologic fractures, in
elderly women. (MCQ)
§ Thyroid hormones increase the BMR and stimulate heat production.
• Hyperthyroid individuals exhibit peripheral vasodilation and sweating.
• Hypothyroid individuals exhibit peripheral vasoconstriction and intolerance
to cold.
§ Thyroid hormones are necessary for normal growth and development.
• Individuals who are hypothyroid from birth are dwarfed and mentally
retarded. This condition is known as cretinism.
• If thyroid hormone replacement is not begun by the end of the first month
after birth, the neurologic defects causing mental retardation cannot be
reversed.
§ Many thyroid hormone actions are due to a synergistic interaction with the
sympathetic nervous system (MCQ)
• Thermogenesis
• Lipolysis
• Glycogenolysis
• gluconeogenesis).
§ Adrenergic blockade attenuates many of the cardiovascular and nervous system manifestations
(eg, tremor) of hyperthyroidism.
Topic - Respiration regulation

Brain stem control of breathing.
• Control of Breathing
o Breathing is controlled by centers in the brain stem with four components to control system:
§ chemoreceptors for O2 or CO2
§ mechanoreceptors in the lungs and joints
§ control centers for breathing in the brain stem (medulla and pons)
§ respiratory muscles, whose activity is directed by the brain stem centers
o Voluntary control can also be exerted by commands from the cerebral cortex (e.g.,breath-
holding or voluntary hyperventilation), which can temporarily override the brain stem.
• Brain stem control of breathing
o The frequency of normal, involuntary breathing is controlled by three groups of neurons or
brain stem centers
§ medullary respiratory center
§ the apneustic center
§ pneumotaxic center.
o Medullary Respiratory Center
§ located in the reticular formation
§ composed of two groups of neurons
• the inspiratory center (dorsal respiratory group) (MCQ)
• expiratory center (ventral respiratory group). (MCQ)
§ Inspiratory center
• controls the basic rhythm for breathing by setting the frequency of
inspiration. (MCQ)
• This group of neurons receives sensory input from
o peripheral chemoreceptors via the glossopharyngeal (CN IX) and
vagus (CN X) nerves (MCQ)

o mechanoreceptors in the lung via the vagus nerve. (MCQ)
• The inspiratory center sends its motor output to the diaphragm via the
phrenic nerve.
• The pattern of activity in the phrenic nerve includes a period of quiescence ,
followed by a burst of action potentials that increase in frequency for a few
seconds, and then a return to quiescence.
• Activity in the diaphragm follows this same pattern: Quiescence - action
potentials rising to a peak frequency (leading to contraction of the diaphragm)-
Quiescence.
• Inspiration can be shortened by inhibition of the inspiratory center via the
pneumotaxic center (MCQ)
§ Expiratory center.
• located in the ventral respiratory neurons (MCQ)
• responsible primarily for expiration
• Since expiration is normally a passive process, these neurons areinactive during
quiet breathing.
• During exercise when expiration becomes active, this center is activated.
o Apneustic Center
§ Apneusis is an abnormal breathing pattern with prolonged inspiratory gasps,
followed by brief expiratory movement
§ apneustic center is located in the lower pons (MCQ)
§ Stimulation of apneustic center apparently excites the inspiratory center in the
medulla(MCQ)
§ apneustic center prolongs the period of action potentials in the phrenic nerve (MCQ)
§ it prolongs the contraction ofthe diaphragm . (MCQ)
o Pneumotaxic Center
§ the pneumotaxic center is located in the upper pons (MCQ)
§ The pneumotaxic center turns off inspiration (MCQ)
§ It limits the burst of action potentials in the phrenic nerve (MCQ)
§ It limits the size of the tidal volume, and secondarily, it regulates the respiratory rate.
§ A normal breathing rhythm persists in the absence of this center.
• Cerebral cortex
o Commands from the cerebral cortex can temporarily override the automatic brain stem centers
o a person can voluntarily hyperventilate (i.e., increase breathing frequency and volume).
o The consequence of hyperventilation is a decrease in PaCO2, which causes arterial pH to
increase.
§ Hyperventilation is self-limiting, however, because the decrease in PaCO2 will
produce unconsciousness and the person will revert to a normal breathing pattern.
Although more difficult, a person may voluntarily hypoventilate (i.e., breath-holding).
§ Hypoventilation causes a decrease in PaO2 and an increase in PaCO2, both of which
are strong drives for ventilation
o A period of prior hyperventilation can prolong the duration of breath-holding.
§ Chemoreceptors
o Central Chemoreceptors
§ The central chemoreceptors, located in the brain stem, are the most important for the
minute-to-minute control of breathing.
§ These chemoreceptors are located on the ventral surface of the medulla, near the
point of exit of the glossopharyngeal (CN IX) and vagus (CN X) nerves and only a
short distance from the medullary inspiratory center. (MCQ)
§ Thus, central chemoreceptors communicate directly with the inspiratory center.
§ The brain stem chemoreceptors are exquisitely sensitive tochanges in the pH of
cerebrospinal fluid (CSF).
• Decreases in the pH of CSF produce hyperventilation(MCQ)
• increases in the pH of CSF produce hypoventilation
§ The medullary chemoreceptors respond directly to changes in the pH of CSF and
indirectly to changes in arterial PCO2
§ In the blood, CO2 combines reversibly with H2O to form H+ and HCO3- by the
familiar reactions.
§ Because the blood-brain barrier is relatively impermeable to H+ and HCO3-, theseions
are trapped in the vascular compartment and do not enter the brain.
• CO2, however, is quite permeable across the blood-brain barrier and enters the
extracellular fluid of the brain. (MCQ)
• CO2 also is permeable across the brain-CSF barrier and enters the CSF.
(MCQ)
§ In the CSF , CO2 is converted toH+ and HCO3- .
• Thus, increases in arterial PCO2 produce increases in the PCO2 of CSF , which
results in an increase in H+ concentration of CSF ( decrease in pH). (MCQ)
• The central chemoreceptors are in close proximity to CSF and detect the
decrease in pH. (MCQ)
• A decrease in pH then signals the inspiratory center to increase the breathing
rate (hyperventilation).
o Peripheral Chemoreceptors
§ There are peripheral chemoreceptors for O2, CO2, and H+ in the carotid bodies
located at the bifurcation of the common carotid arteries and in the aortic bodies above
and below the aortic arch
§ Information about arterial PO2, PCO2, and pH is relayed to the medullary inspiratory
center via CN IX and CN X, which orchestrates an appropriate change in breathing
rate. (MCQ)
§ Changes in arterial blood composition detected by peripheral chemoreceptors that
produces an increase in breathing rate:
§ Decreases in arterial PO2.
• peripheral chemoreceptors are relatively insensitive to changes in PO2
• They respond when PO2 decreases to less than 60 mm Hg
• Thus, if arterial PO2 is between 100 mm Hg and 60 mm Hg, the breathing
rate is virtually constant (MCQ)
• However, if arterial PO2 is less than 60 mm Hg, the breathing rate
increases in a very steep and linear fashion.

• In this range of PO2, chemoreceptors are exquisitely sensitive to O2; in fact,
they respond so rapidly that the firing rate of the sensory neurons may
change during a single breathing cycle. (MCQ)
§ Increases in arterial PCO2.
• The peripheral chemoreceptors also detect increases in PCO2 (MCQ)
• Increased PCO2 effect is less important than response to decrease in PO2.
• Detection of changes in PCO2 by the peripheral chemoreceptors also is less
important than detection of changes in PCO2 by the central
chemoreceptors.
§ Decreases in arterial pH.
• Decreases in arterial pH cause an increase in ventilation, mediated by
peripheral chemoreceptors for H+.
• This effect is independent of changes in the arterial PCO2
• mediated only by chemoreceptors in the carotid bodies (not by those in the
aortic bodies). (MCQ)
• Thus, in metabolic acidosis, in which there is decreased arterial pH, the
peripheral chemoreceptors are stimulated directly to increase the ventilation
rate (MCQ)
o Other receptors
§ In addition to chemoreceptors, several other types of receptors are involved in the
control of breathing, including lung stretch receptors, joint and muscle receptors,
irritant receptors, and juxtacapillary (J) receptors. (MCQ)
§ Lung stretch receptors.
• Mechanoreceptors
• present in the smooth muscle of the airways
• Hering-Breuer reflex(MCQ)
o When stimulated by distention of the lungs and airways,
mechanoreceptors initiate a reflex decrease in breathing rate called the
Hering-Breuer reflex.
o The reflex decreases breathing rate by prolonging expiratory time .
(MCQ)
§ Joint and muscle receptors.
• Mechanoreceptors located in the joints and muscles
• detect the movement of limbs
• instruct the inspiratory center to increase the breathing rate.
• Information from the joints and muscles is important in the early (anticipatory)
ventilatory response to exercise (MCQ)
§ Irritant receptors.
• Irritant receptors for noxious chemicals and particles
• located between epithelial cells lining the airways.
• Information from these receptors travels to the medulla via CN X (MCQ)
• causes a reflex constriction of bronchial smooth muscle
• causes an increase in breathing rate.
§ J receptors.
• Juxtacapillary (J) receptors are located in the alveolar walls are near the
capillaries. (MCQ)
• Engorgement ofpulmonary capillaries with blood and increases in interstitial fluid volume
may activate these receptors
• produce an increase in the breathing rate.
• For example, in left- sided heart failure, blood “backs up” in the pulmonary
circulation, and J receptors mediate a change in breathing pattern, including
rapid shallow breathing and dyspnea (difficulty in breathing). (MCQ)
Topic -Cardiac muscle contraction

• The cardiac muscle cell is composed of sarcomeres.

o The sarcomeres, which run from Z line to Z line (MCQ)
o composed of thick and thin filaments.
• The thick filaments are composed of myosin, whose globular heads have actin-binding sites and
ATPase activity.
• The thin filaments are composed of three proteins: actin, tropomyosin, and troponin
• Actin is a globular protein with a myosin- binding site(MCQ)
• Tropomyosin runs along the groove of the twisted actin strands and functions to block the myosin-
binding site.
• Troponin is a globular protein composed of a complex of three subunits; the troponin C subunit binds
Ca2+. (MCQ)
• When Ca2+ is bound to troponin C, a conformational change occurs, which removes the
tropomyosin inhibition of actin-myosin interaction.

• As in skeletal muscle, contraction occurs according to thesliding filament model, which states that
when cross-bridges form between myosin and actin and then break, the thick and thin filaments
move past each other.
• As a result of this crossbridge cycling, the muscle fiber produces tension.
• The transverse (T) tubules
o invaginate cardiac muscle cells at the Z lines(MCQ)
o continuous with the cell membranes
o function to carry action potentials to the cell interior.
o The T tubules form dyads with the sarcoplasmic reticulum, which is the site of storage and
release of Ca2+ for excitation-contraction coupling. (MCQ)
• Excitation-contraction coupling
o The cardiac action potential is initiated in the myocardial cell membrane, and the
depolarization spreads to the interior of the cell via the T tubules
o Recall that a unique feature of the cardiac action potential is its plateau (phase 2), which results
from an increase in gCa and an inward Ca2+ current in which Ca2+ flows through L-type
Ca2+ channels (dihydropyridine receptors) from extracellular fluid (ECF) to intracellular
fluid (ICF). (MCQ)
o Entry of Ca2+ into the myocardial cell produces an increase in intracellular Ca2+
concentration.
o This increase in intracellular Ca2+ concentration is not sufficient alone to initiate contraction,
but it triggers the release of more Ca2+ from stores in the sarcoplasmic reticulum
through Ca2+ release channels (ryanodine receptors). (MCQ)
§ This process is called Ca2+- induced Ca2+ release, and the Ca2+ that enters during
the plateau of the action potential is called the trigger Ca2+. (MCQ)
o Two factors determine how much Ca2+ is released from the sarcoplasmic reticulum in this
step:
§ the amount of Ca2+ previously stored
§ size of the inward Ca2+ current during the plateau of the action potential.
o Ca2+ release from the sarcoplasmic reticulum causes the intracellular Ca2+ concentration to
increase even further(MCQ)
o Ca2+ now binds to troponin C, tropomyosin is moved out ofthe way, and the interaction of actin and
myosin can occur. (MCQ)
o Actin and myosin bind, cross-bridges form and then break, the thin and thick filaments move
past each other, and tension is produced.
o Cross-bridge cycling continues as long as intracellular Ca2+ concentration is high enough to
occupy the Ca2+-binding sites on troponin C.
o A critically important concept is that the magnitude of the tension developed by myocardial
cells is proportional to the intracellular Ca2+ concentration. (Hence Digitalis can increase myocardial
contractility)
o Relaxation
§ occurs when Ca2+ is reaccumulated in the sarcoplasmic reticulum by the action of
the Ca2+ ATPase.
§ This reaccumulation causes the intracellular Ca2+ concentration to decrease to resting
levels.

§ In addition, Ca2+, which entered the cell during the plateau of the action potential, is
extruded from the cell by Ca2+ ATPase and Ca2+-Na+ exchange in the sarcolemmal
membrane.
§ These sarcolemmal transporters pump Ca2+ out of the cell against its electrochemical
gradient, with the
• Ca2+ ATPase using ATP directly (MCQ)
• Ca2+-Na+ exchanger using energy from the inward Na+ gradient.
• Contractility
o Sympathetic nervous system.
§ Stimulation of the sympathetic nervous system have a positive inotropic effect
§ positive inotropic effect has three important features:
• increased peak tension
• increased rate of tension development
• faster rate of relaxation.
§ Faster relaxation means that the contraction (twitch) is shorter, allowing more time
for refilling.
§ Mechanism of positive ionotropic effect (MCQ)
• mediated via activation of b1 receptors
• beta 1 receptors are coupled via a Gs protein to adenylyl cyclase
• Activation of adenylyl cyclase leads to the production of cAMP
• cAMP causes (MCQ)
o activation of protein kinases
o phosphorylation of proteins that produce the physiologic effect of
increased contractility.
• Two different proteins are phosphorylated to produce the increase in
contractility. these phosphorylated proteins then produce anincrease in
intracellular Ca2+ concentration.
o There is phosphorylation of the sarcolemmal Ca2+ channels that carry
inward Ca2+ current during the plateau of the action potential. (MCQ)
§ As a result, there is increased inward Ca2+ current during the
plateau and increased trigger Ca2+, which increases the
amount of Ca2+ released from the sarcoplasmic reticulum.
o There is phosphorylation of phospholamban (MCQ)
§ a protein that regulates Ca2+ ATPase in the sarcoplasmic
reticulum.
§ When phosphorylated, phospholamban stimulates the Ca2+
ATPase, resulting in greater uptake and storage of Ca2+ by the
sarcoplasmic reticulum.
o Parasympathetic nervous system.
o have a negative inotropic effect on the atria.
o This effect is mediated via muscarinic receptors, which are coupled via a Gi protein called GK
to adenylyl cyclase. (MCQ)
o Because the G protein in this case is inhibitory , contractility is decreased (opposite of the
effect of activation of beta1 receptors by catecholamines).

o Two factors are responsible for the decrease in atrial contractility caused by
parasympathetic stimulation. (MCQ)
§ ACh decreases inward Ca2+ current during the plateau of the action potential.
§ ACh increases IK-ACh, (constitutively active, acetylcholine-regulated K+-current
(IK,ACh) )thereby shortening the duration of action potential and, indirectly ,
decreasing the inward Ca2+ current (by shortening the plateau phase).
• Effect of Heart Rate on Contractility

o When the heart rate increases, contractility increases
o When the heart rate decreases, contractility decreases.
o Mechanism
§ When heart rate increases, there are more action potentials per unit time and an increase in the
total amount of trigger Ca2+ that enters the cell during the plateau phases of the
action potentials.
• if the increase in heart rate is caused by sympathetic stimulation or by
catecholamines, then the size of the inward Ca2+ current with each action
potential also is increased. (MCQ)
§ Because there is greater influx of Ca2+ into the cel l during the action potentials, the
sarcoplasmic reticulum accumulates more Ca2+ for subsequent release (i.e., increased
stored Ca2+).
• if the increase in heart rate is caused by sympathetic stimulation, then
phospholamban, which augments Ca2+ uptake by the sarcoplasmic
reticulum, will be phosphorylated, further increasing the uptake process.
o Two specific examples of the effect of heart rate on contractility, the positive staircase effect
and postextrasystolic potentiation,
§ Positive staircase effect. (MCQ)
• The positive staircase effect is also called the Bowditch staircase, or Treppe
(MCQ)
• When heart rate doubles, for example, the tension developed on each beat
increases in a stepwise fashion to a maximal value
• This increase in tension occurs because there are more action potentials per
unit time, more total Ca2+ entering the cell during the plateau phases, and
more Ca2+ for accumulation by the sarcoplasmic reticulum (i.e., more
stored Ca2+).
• Notice that the very first beat after the increase in heart rate shows no increase
in tension because extra Ca2+ has not yet accumulated
• On subsequent beats, the effect of the extra accumulation of Ca2+ by the sar-
coplasmic reticulum becomes evident.
• Tension rises stepwise, like a staircase
• With each beat, more Ca2+ is accumulated by the sarcoplasmic reticulum,
until a maximum storage level is achieved.
Topic -Cell membrane

• Plasma Membrane
o The lipid bilayer divides the cell into functional compartments.
o The fluid mosaic model is the accepted view of the molecular nature ofplasma membranes.(MCQ)
o proteins traverse the lipid bilayer and are incorporated within the lipids.
o Proteins and lipids can move freely in the plane ofthe membrane , producing the fluid nature of the
membrane.
o The plasma membrane is composed of phospholipids and proteins.
o Membrane lipids can be classified into three major classes: phospholipids,
o sphingolipids, and cholesterol.
o Phospholipids
§ most abundant membrane lipids. .(MCQ)
§ They have a bipolar (amphipathic) nature
§ contain a charged head group and two hydrophobic (water-insoluble, noncharged)
tails.
§ The hydrophobic tails face each other, forming a bilayer and exposing the polar head
group to the aqueous environment on either side of the membrane.
o Sphingolipids
§ have an amphipathic structure similar to phospholipids
§ allows them to insert into membranes.
§ These lipids can be modified by the addition of carbohydrate units at their polar end,
creating glycosphingolipids in brain cells.
§ Cholesterol
• predominant sterol in human cells
• it increases the fluidity of the membrane by inserting itself between
phospholipids, improving membrane stability.
o Membrane proteins
§ span the lipid bilayer are known as integral membrane proteins
§ The majority of integral membrane proteins span the bilayer through the formation of
Alpha-helices
§ Protein content of membranes varies from
• less than 20% for myelin,
• more than 60% in liver cells
Topic - Gastrointestinal hormones
• Gastrin
o secreted by G (gastrin) cells in the antrum of the stomach
o 2 Forms
§ a 17-amino acid straight chain peptide
• is called G17 or “little” gastrin
• the form of gastrin secreted in response to a meal (MCQ)
§ 34-amino acid form of gastrin
• is called G34 or “big” gastrin,
• is secreted during the interdigestive period (between meals) (MCQ)
• is secreted at low basal levels.

• each form of gastrin has its own biosynthetic pathway, beginning with its own
precursor, a progastrin molecule.
o The minimum fragment necessary for biologic activity of gastrin is the C-terminal
tetrapeptide
o Secretion of gastrin.
§ The physiologic stimuli that initiate gastrin secretion all are related to ingestion of
food.
• products of protein digestion (e.g., small peptides and amino acids),
• distention of the stomach by food
• vagal stimulation.
§ Among the products of protein digestion, the amino acids phenylalanine and
tryptophan are the most potent stimuli for gastrin secretion. (MCQ)
§ Local vagal reflexes also stimulate gastrin secretion.
§ In these local reflexes, the neurocrine released from vagal nerve endings onto the G
cells is gastrin-releasing peptide (GRP), or bombesin. (MCQ)
§ gastrin secretion is inhibited by a (MCQ)
• low pH of the gastric contents
• somatostatin.
o Actions of gastrin.
§ It stimulates H+ secretion by gastric parietal cells
§ it stimulates growth of the gastric mucosa, a trophic effect
• Cholecystokinin
o The functions of cholecystokinin (CCK) are coordinated to promote fat digestion and
absorption.
o CCK is a 33-amino acid peptide
§ a member of the “gastrin-CCK family”
§ CCK has some gastrin activity.
§ CCKA receptors are selective for CCK
§ CCKB receptors are equally sensitive to CCK and gastrin.
§ The minimum fragment of CCK necessary for its biologic activity is the C-terminal
heptapeptide (seven amino acids [CCK-7]).
o CCK is secreted by the I cells of the duodenal and jejunal mucosa (MCQ)
o two types of physiologic stimuli
§ monoglycerides and fatty acids (but not tri- glycerides
§ small peptides and amino acids.
o There are five major actions of CCK, (MCQ)
§ Contraction of the gallbladder with simultaneous relaxation of the sphincter of Oddi
• ejects bile from the gallbladder into the lumen of the small intestine.
• Bile is needed for emulsification and solubilization of dietary lipids.
§ Secretion of pancreatic enzymes.
§ Secretion of bicarbonate (HCO3-) from the pancreas.
§ Growth of the exocrine pancreas and gallbladder.
§ Inhibition of gastric emptying

• Secretin
o Secretin, a 27-amino acid peptide
o structurally homologous to glucagon (MCQ)
o a member of the secretin-glucagon family
o In contrast to gastrin and CCK, which have active fragments,all 27 amino acids of secretin
are required for its biologic activity.
o For activity, the entire secretin molecule must fold into its tertiary structure, an alpha helix.
o Secretin is secreted by the S cells (secretin cells) of the duodenum(MCQ)
o Produced in response to H+ and fatty acids in the lumen of the small intestine.
§ Thus, secretion of secretin is initiated when the acidic gastric contents (pH < 4.5)
arrive in the small intestine. (MCQ)
o The function of secretin
§ to promote the secretion of pancreatic and biliary HCO3-, which then neutra- lizes H+ in
the lumen of the small intestine.
• Neutralization of H+ is essential for fat digestion
• pancreatic lipases have pH optimums between 6 and 8,
• they are inactivated or denatured when the pH is less than 3. (MCQ)
§ Secretin also inhibits the effects of gastrin on the parietal cells (H+ secretion and
growth).
• Glucose-Dependent Insulinotropic Peptide (GIP),
o a 42-amino-acid peptide
o member of the secretin-glucagon family
o GIP produce most of the actions of secretin . (MCQ)
o GIP is secreted by K cells of the duodenal and jejunal mucosa.
o It is the only gastrointestinal hormone that is secreted in response to all three types of nutrients:
glucose, amino acids, and fatty acids.
o The major physiologic action of GIP is stimulation of insulin secretion by the pancreatic b
cells. (MCQ)
o The other action of GIP is inhibition of gastric H+ secretion.
• Candidate Hormones
o Motilin
§ a 22-amino acid peptide
§ secreted from the upper duodenum during fasting states. (MCQ)
§ Motilin initiates the interdigestive myoelectric complexes that occur at 90-minute
intervals.
o Pancreatic polypeptide
§ 36-amino acid peptide
§ secreted by the pancreas in response to ingestion of carbohydrates, proteins, or lipids .
inhibits pancreatic secretion of HCO3- and enzymes(MCQ)
o Enteroglucagon
§ released from intestinal cells
§ released in response to a decrease in blood glucose concentration.
§ It then directs the liver to increase glycogenolysis and gluconeogenesis. (MCQ)

§ Paracrines
o are synthesized in endocrine cells of the gastrointestinal tract.
o The paracrines do not enter the systemic circulation but act locally, reaching their target cells
by diffusing over short distances.
o Somatostatin
§ secreted by D cells (both endocrine and paracrine) of the gastrointestinal mucosa
(MCQ)
§ secreted in response to decreased luminal pH. (MCQ)
§ inhibits secretion of the other gastrointestinal hormones
§ inhibits gastric H+ secretion. (MCQ)
§ In addition to these paracrine functions in the gastrointestinal tract, somatostatin is
secreted by the hypothalamus and by the delta (d) cells of the endocrine pancreas.
(MCQ)
o Histamine
§ secreted by endocrine-type cells of the gastrointestinal mucosa, particularly in the H+-
secreting region of the stomach.
§ Histamine, along with gastrin and ACh, stimulates H+ secretion by the gastric
parietal cells. (MCQ)
§ NEUROCRINES
o Neurocrines are synthesized in cell bodies of gastrointestinal neurons

Topic - Co2 transport
Carbon Dioxide Transport in Blood
• Forms of co2 in blood

o CO2 is carried in the blood in three forms:
§ as dissolved CO2
§ as carbaminohemoglobin (CO2 bound to hemoglobin
§ as bicarbonate (HCO3-), which is a chemically modified form of CO2.
• HCO3- is quantitatively the most important of these forms.
• Dissolved CO2
o Henry’s law,
§ concentration of CO2 in blood is the partial pressure multiplied by the solubility of
CO2.
o The solubility of CO2 is 0.07 mL CO2/100 mL blood/mm Hg;
o concentration of dissolved CO2 in arterial blood, = 2.8 mL CO2/100 mL blood (40 mm Hg x
0.07 mL CO2/100 mL blood/mm Hg),
o it is approximately 5% of the total CO2 content of blood. (MCQ)
o because of the lower solubility of O2 , compared with CO2, dissolved O2 is only 2% of the
total O2 content of blood (MCQ)
• Carbaminohemoglobin
o CO2 binds to terminal amino groups on proteins (e.g., hemoglobin and plasma proteins such
as albumin).
o When CO2 is bound to hemoglobin, it is called carbaminohemoglobin, which accounts for
about 3% of the total CO2. (MCQ)
o CO2 binds to hemoglobin at a different site than O2 binds to hemoglobin.
o Bohr effect(MCQ)
§ CO2 binding to hemoglobin reduces its affinity for O2 and causes a right-shift of the
O2-hemoglobin dissociation curve (Bohr effect).
o Haldane effect(MCQ)
§ In turn, O2 bound to hemoglobin changes its affinity for CO2
§ when less O2 is bound, the affinity of hemoglobin for CO2 increases (the Haldane
effect).
• HCO3–
o Almost all of the CO2 carried in blood is in a chemically modified form, HCO3- accounts for
more than 90% of the total CO2 .
o The reactions that produce HCO3- from CO2
§ involves the combination of CO2 and H2O to form the weak acid H2CO3.
§ This reaction is catalyzed by the enzyme carbonic anhydrase(MCQ)
§ In turn, H2CO3 dissociates into H+ and HCO3-.
§ In the tissues,
• CO2 generated from aerobic metabolism is added to systemic capillary blood,
converted to HCO3-
• transported to the lungs
§ In the lungs, HCO3- is reconverted to CO2 and expired.
Topic - Muscle spindle
• Muscle Fibers
o Extrafusal fibers
§ innervated by a motoneurons (large cells in the ventral horn)
§ the most plentiful (MCQ)
§ provide the force for muscle contraction. (MCQ)
o Intrafusal fibers
§ innervated by Gamma motoneurons (MCQ)
§ are encapsulated in sheaths to form muscle spindles
§ are too small to generate force for muscle contraction.
§ Nuclear bag fibers (MCQ)
• intrafusal fibers innervated by group Ia afferents
• that detect the rate of change in muscle length
• have nuclei concentrated in a central bag-like region.
§ Nuclear chain fibers (MCQ)
• intrafusal fibers innervated by group II afferents
• detect static changes in muscle length
• have nuclei arranged in rows.
o Gamma motoneurons (MCQ)
§ adjust the sensitivity of the muscle spindle to provide appropriate responses during
muscle contraction.
• Function of Muscle Spindles
o Muscle spindles act as sensory receptors in skeletal muscle stretch reflexes.
§ They detect both static and dynamic changes in muscle length.
§ The finer the movement required, the more muscle spindles a muscle contains.
o Muscle spindle reflexes oppose increases in muscle stretching.
§ When muscle length is increased (stretched), the muscle spindle is stretched,
stimulating afferent groups Ia and II. (MCQ)
§ Group Ia afferents stimulate motoneurons in the spinal cord (MCQ)
• cause muscle contraction and shortening of the muscle.
o Both ends of the muscle spindle are connected in parallel with extrafusal fibers so that their
length and rate of change in length can be monitored.
• Muscle Reflexes
o The muscle stretch (myotatic) reflex
§ is a stereotyped muscle contraction in response to a stretch of that muscle.
§ This reflex is the primary mechanism for regulating muscle tone (tension is present in
all resting muscle).
§ Stretching of muscle spindles activates group Ia afferents that synapse with
motoneurons in the spinal cord, causing muscle contraction.
§ The best example is the knee-jerk reflex (MCQ)
• stimulated by tapping the patellar ligament
• that stretches the quadriceps muscle
• causing a sudden extension of the leg at the knee.
o The flexor withdrawal reflex (MCQ)
§ is a protective
§ a usually painful stimulus causes withdrawal of a stimulated limb.
§ This reflex may be accompanied by a crossed extension reflex, in which
§ the contralateral limb is extended to support the body.
§ Flexor reflex afferent groups II, III, and IV synapse polysynaptically onto
motoneurons in the spinal cord.
§ Because of the persistent neural activity in the polysynaptic circuits, an afterdischarge
occurs that prevents muscle relaxation.
o The inverse muscle stretch reflex
§ is associated with Golgi tendon organs arranged in series with extrafusal muscle
fibers that detect muscle tension. (MCQ)

§ Golgi tendon organs respond to increases in force or tension generated by muscle
contraction that increases the firing rate of group Ib afferent neurons. (MCQ)
§ Group Ib afferent neurons that innervate the Golgi tendon organs polysynaptically
also facilitate antagonists and inhibit agonist muscles. (MCQ)
§ Muscle tone and reflex activity are influenced bygammamotoneurons that directly
innervate muscle spindles and regulate their sensitivity to stretch.
§ Upper motoneurons innervate gamma motoneurons and influence the sensitivity of
muscle spindles to stretch (MCQ)


Nephron Anatomy and Physiology

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News4Medico.com onlinembbs.com anatomy2medicine.

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o PAH clearance can be used to measure renal plasma flow. (MCQ)

hydrostatic pressures (Pgc)

colloid osmotic pressure (gc)

o Variables that influence GFR include

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Consider the following example of a GFR calculation:

Urine flow = V = 2880 mL/24h = 2.0 mL/min

Pcr = 0.8 mg = 0.008 mg/mL

GFR = Ucr XV = (0.9 mg/mL X 2 mL/min) = 234 mL/min

Pcr 0.008 mg/mL

• Filtration fraction (FF) (MCQ)

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• Transport Mechanisms of Nephron Segments

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• K+ is filtered, reabsorbed, and secreted by the nephron. (MCQ)

• The glucose-filtered load is directly proportional to the plasma glucose concentration.

• Most of the filtered phosphate is reabsorbed in the proximal convoluted tubule

• Generation of a corticomedullary osmotic gradient

Hypoxemia and Hypoxia

• Hypoxemia is defined as a decrease in arterial PO2

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§ Carbon monoxide (CO) poisoning

§ The cardiovascular system consists of

Total peripheral resistance

§ Q = blood flow (L/min)

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o r4 = radius of the blood vessel to the fourth power.

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Topic - Lung Volumes and Capacities

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• inspiratory capacity (IC)

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§ VD = Physiologic dead space (mL)

§ VT =Tidal volume (mL)

§ PaCO2 = PCO2 of arterial blood (mm Hg)

§ PECO2 = PCO2 of mixed expired air (mm Hg)

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ALVEOLAR VENTILATION EQUATION

o if CO2 production is constant, then P ACO2 is determined by alveolar ventilation.

Topic - Oxygen dissociation curve

§ Saturation is the percentage of Hb-binding sites occupied by O2.

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§ Saturation versus partial pressure.

o Each saturation curve has a single P50

o which is the PO2 that gives 50% saturation

o Normal P50 = 26 mm Hg (MCQ)

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Changes in affinity of hemoglobin (Hb) for O2 (oxyhemoglobin dissociation curve).

Topic - Blood Pressure Cardiac out put

Cardiac Muscle and Cardiac Output

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