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Jan Kirchhof

Physiology

UMF Targu Mures

Physiology Topics UMF Targu Mures 2012


Topic 1
Cell membrane structure, types of membrane proteins Organization: fluid mosaic lipid-protein model (1972 Singer, Nicolson) fits on TD stability o Semi permeable lipid bilayer (hydrophilic heads outside, lipophilic tails inside) in which membrane proteins are inserted Chemical composition: 30% H2O, 70% organic substances (proteins + lipids barrier: more lipids; metabolism: more proteins) Membrane proteins: o Ensure functionality: Transporter (e.g. maintaining of ion conc.) carrier proteins, channel proteins Enzyme (protein synthesis) adenylate cyclase guanilate cyclase phospholipase C protein kinases A, C Cell surface receptor (signal transmission, reaction with ligands inducing special reactions inside the cell) Adrenergic (react to symphatic neurotransmitter noradrenalin) o Alpha 1 receptors contraction of smooth muscles of vessels and bronchioles o Alpha 2 receptors contraction of smooth muscles of digestive sphincters o Beta 1 receptors stimulating effects on heart o Beta 2 receptors relaxation of smooth muscles of vessels and bronchioles Cholinergic (react especially to acetylcholine) o Nicotinic receptors stimulated by acetylcholine and nicotine present at ganglionic synapses, neuromuscular junctions blocked by curare o Muscarinic receptors stimulated by acetylcholine and muscarine (Pilzgift) present in end-organs (ACh released by postganglionic neurons/parasympathetic) blocked by atropine Cell adhesion (interacting/identifying between cells cell identity marker role in immune response) Attachment to cytoskeleton o Intrinsic (peripheral) proteins outside of bilayer (on outer or inner surface, often to integral proteins attached) o Extrinsic (integral) proteins inside of bilayer (can be completely through membrane transmembrane proteins)

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 2
Mechanism of transport through cell membrane Passive transport (no energy consumption, transport with/ down the conc. gradient) o Simple diffusion Uncharged particles flow from higher to lower concentrations (speed depends on: permeability, lipid solubility) lipophilic particles through lipid bilayer, hydrophilic ones through aquaporins o Facilitated diffusion by carrier proteins High speeded transport for too large particles (e.g. glucose) Transmembrane protein transporter/ carrier protein (specific for certain particle) Can be coupled with other transport (e.g. sodium) cotransport o Diffusion using channel proteins Integral membrane proteins (bidirectional) Ion channels (sodium, potassium, calcium channels) o Valtage-gated opening depends on electrical gradient Aquaporins (water channels) Active transport (energy consumption (ATP), transport against conc. gradient, optimal at 37C) Primary active transport (direct use of energy (ATP hydrolysis)) Sodium potassium pump (maintains resting potential): o ATP-ase (membrane protein) + intracellular face: binds 3 Na to ATP pumped out + extracellular face: binds 2 K to ATP pumped in + secondary active transport (use of stored energy in Na conc. gradient) made by carriers (integral membrane proteins) uniport transport: single substance in certain direction cotransport: transport of a substance is coupled with transport of another substance o symporters: 2 substrates in same direction (e.g. sodium glucose transporter) o antiporters: 2 substrates in different direction, using conc. gradient of one to drive the other Vesicular transport (transport of macromolecules): Exocytosis: releasing proteins Endocytosis: importing proteins by enclosing them in membrane Phagocytosis (cell eating): immersion of solid substances pinocytosis (cell drinking): immersion of liquid substances

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 3
Membrane potential resting potential: o selective permeability of cell membrane: inside (neg.): potassium ions, organic anions (macromolecules, cannot pass membrane) outside (pos.): sodium ions, chloride ions o ions are asymmetrically distributed causes membrane potential of -70 mV o many blablablablabla hier muss noch weitergemacht werden (s.28) Action potential: o Cell is in resting state and receives a signal (voltage variation) + Membrane permeability changes voltage gated Na channels open sodium flows inward inside becomes positive If a certain threshold is reached action potential (all or nothing, amplitudes same value, strengthen by frequency) o Depolarization phase (strong depolarization until +30 mV) + All Na channels open + + Na channels start closing, K channels start opening o Overshoot (amplitude is reached) o Repolarization phase: + K channels opened potassium flows out inside gets back to resting potential Sodium potassium pump restarts and renews resting potential o Hyperpolarization (-90 mV): 2+ + 2+ at depolarization Ca gets into cell gets out at repolarization and keeps K channels open until Ca level is low Sodium potassium pump renews resting potential o Resting potential is reached (process lasts 1-2 ms) Potentials can be measured by intracellular microelectrodes (recorded on oscilloscope)

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 4
Water content of the body and organs, water compartments, control of water intake Water content: o Age: fetus 100% baby at birth 80% adult 70% elderly person 50% o organs: brain 85% heart 77% lungs 80% teeth 10% liver 73% bones 22% kidneys 80% muscle 73% skin 71% blood 79% o total body water (compartments): intracellular 30-40% Extracellular 16-20% (plasma 4%, interstitial 16%) lymph, fluid around brain, plasma, joint fluid, fluid in stomach + intestines, blood solid matter 40% tissue, bone daily water requirements: 30-40ml/kg/day o sources (2500ml/day) water drinking, food, metabolic water o losses (2500ml/day) urine, feces, respiration, skin o pathological losses bleeding, vomiting, diarrhea control of water intake: neuro hormonal mechanisms and sensation of thirst o osmoreceptors thirst center in hypothalamus involved hormones: ADH (antidiuretic hormone) reduces water elimination by kidney (at night for not peeing in your pants) Atrial natriuretic peptide enhances renal elimination of sodium, sec. of water Renin-angiotensin aldosterone system reduces renal elimination of sodium and water Renin from kidney ANG1 ANG2 thirst, production of aldosterone (reduce elimination)

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 5
Osmosis and osmotic pressure, causes of edema Movement of H2O through semi permeable membrane to higher concentrated solution (influenced only by particles number) Isotonic solution: equal concentration of solutes (isotonic physiologic solution: 9gNaCl/l) Hypertonic solution: higher concentration of solutes cells become wrinkled (H2O out of cell) Hypotonic solution: lower concentration of solutes cells swell, membrane ruptures (H2O into cell) Osmotic pressure: o Generated by water movement from low to high conc. the higher the conc. the higher the osmotic pressure o Physiologic solution: 5500 mmHg, 6.7 atm, 300 mOsm o Movement of water across capillary wall: More permeable than cell membrane, impermeable for proteins depends on balance between hydrostatic pressure and oncotic pressure (osmotic pressure of proteins) gradient edema: o accumulation (Anhufung) of fluids in interstitium (swelling of parts of the body, usually legs gravity) o causes: reduced concentration of plasma proteins (loss, reduced synthesis (kidney, liver disorders), diet deficiency) increased capillary permeability (inflammation) increased venous pressure no balance between pressure gradients (heart failure, standing still) blocked lymphatics (filarial worms (Fadenwrmer), removal of lymph vessels)

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 6
Blood pH, buffers, acidosis, alkalosis blood: fluid tissue (cells and plasma) o primary functions: transportation, exchange o secondary functions: immunity, thermoregulation, fluid volume balance, pH balance + pH: negative decadal logarithm of the amount of basic or acidic character due to the concentration of H in a solution of water o pH scale: 0-14 pH = 7 neutral + pH < 7 acidic (high conc. of H ) + pH > 7 basic (low conc. of H ) o blood plasma and body fluids pH: 7.38 (7.35-7.4) mechanisms to maintain the acid/base balance: lungs expel CO2 kidneys eliminate acids in urine skin secrets excess acids plasma contains buffer that neutralize the pH buffer systems are a mixture of a weak acid and a conjugated base or vice versa that have a buffer capacity o blood buffer (total amount: 48 mEq/l): bicarbonate/carbon dioxide buffer system (most important plasma buffer system 75%) HCO3 controlled (independent) in kidneys CO2 controlled (independent) in lungs Plasma bicarbonate: 22-26 mEq/l (at 40 mmHg pCO2) Hb and OxiHb buffer (25%), phosphate buffer (<1%) Acidosis (low blood pH, disorder of 0.2pH can lead to serious health consequences) o Respiratory acidosis (CO2 too high too much CO2 production, too less CO2 excretion) Caused by: airway obstruction, pulmonary disease, thoracic or muscular disorder, CNS lesion, paralyzing agent o Metabolic acidosis (HCO3 too low) Caused by: diarrhea, renal failure; diabetic, alcoholic keto acidosis; extreme exercise lactic acid; cardiac arrest Leads to: tremor (Zittern), lethargy (Schlfrigkeit), coma, tachycardia (Herzrasen), arrythhmia Alkalosis (high blood pH, disorder of 0.2pH can lead to serious health consequences) o Respiratory alkalosis (CO2 too low) Caused by: hyperventilation, anxiety, fever, hypotension, high altitude (Hhe), heat stress 2+ + Leads to: low conc. of HCO3 and Ca (HCO3 + H H2CO3 CO2 + H2O) o Metabolic alkalosis (HCO3 too high) Caused by: vomiting (loss of HCl), loss of acids in urine (diuretics), aldosterism, cushing syndrome Leads to: confusion, seizures, nausea, arrhythmia, angina

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 7
Blood volume, hematocrit, control of blood volume Blood volume: 2 o 5-6 liter (depends on body volume and gender 76 ml/kg, 2.6 liter/m ) o Composition: Plasma (55%) Cells (45%) White blood cells and platelets (<1%) Red blood cells (45%) Hematocrit (ratio between blood cells and plasma hematokrit = red cells / total): o Males: 42-50% o Females: 39-48% Control of blood volume: o Body functions controlled by vegetative nervous system and endocrine glands o Physiological blood volume control mechanisms: Control of fluids and electrolytes by kidneys Control of cardiac output by heart Control of arterial blood pressure by vessels Control of erythropoiesis by kidneys Control of protein synthesis by liver o Increased blood volume leads to: Reduces secretion of ADH and aldosterone renal elimination of water and sodium is increased Increases blood pressure high hydrostatic pressure forces H2O to interstitium increases glomerular filtration Stimulates secretion of atrial natriuretic peptide (ANP/Herzvorhof-Faktor) increases elimination of water and sodium Causes dilatation of blood vessels (because reduced sympathetic activity)

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 8
Plasma electrolytes, their roles, anion gap Content of plasma (90% H2O): o Amino acids o Proteins (albumins, globulins, fibrinogen) o Gases o Nitrogenous waste o Electrolytes (1 g/dl, 300 mmol/liter) Cations (150 mmol) + Na 143 mmol + K 5 mmol 2+ Ca 2.5 mmol Anions (150 mmol) HCO3 27 mmol Cl 103 mmol Proteins Role of electrocytes: o General: important for function of muscle and nerve cells, maintenance of water balance (osmotic pressure gradient, blood pH) + o Na + Cl maintain osmotic pressure o HCO3 maintains blood pH (component of major buffer system) 2+ o Ca role in: o neuro-muscular excitability (Erregbarkeit) o muscular contraction o blood coagulation o bone metabolism together with phosphates 2+ o activation of enzymes together with Mg 2+ 2+ o Fe + Cu role in erythropoesis o I component of thyroid hormones Balance of electrolytes o Maintaining balance with food + intestinal absorption and elimination, regulated by hormones (ADH, aldosteron, etc.) o Controlling concentration by active transport not really sure Plasma anion gap: o Important for diagnosis of metabolic acidosis + + o Calculation: AG = ([Na ]+[K ])-([Cl ]+[HCO3 ]) o VN(AG) = 12 (higher values if loss of HCO3- and no equalization by Cl )

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 9
Plasma proteins: classification, roles Plasma proteins (6-8 g/dl blood; synthesis of 15 g/day in liver): albumin, globulin (alpha, beta, gamma), fibrinogen, hormones, enzymes o Seperation by electrophoresis (alkaline solution proteins become neg. charged go to pos. pole (in order mentioned above)) Albumin: o Molecular mass: 67 kDa o Most abundant (hufigestes) >55% o Produced in liver o Maintains oncotic pressure o Transports: hormones, fatty acids, bilirubin, drugs 2+ o Binds Ca o Buffers pH Globulins: o Molecular mass: 90-1300 kDa o Produced in liver and immune system o Isolated by electrophoresis in: alpha 1, alpha 2, beta 1, beta 2, gamma o Transport substances o Enzymatic active o Defensive role (immunoglobulins) Classification due to carried substances o Metalloproteins (carrying metals): transferin (Fe), ceruloplasmin (Cu) o Glycoproteins (carrying carbohydrates): immunoglobulins (IgA, IgG, IgM,IgE) o Lipoproteins (carrying lipids): chylomicrons, VLDL, IDLP, LDL, HDL (due to density) Roles of plasma proteins: o Maintenance of oncotic pressure (albumin) o Maintenance of pH (albumin) o Transport (espec. by globulins: ions, carbohydrates, lipids, hormones, drugs) o Defence (globulins: immunoglobulins, complement, properdin, reactive C protein) o Maintenance erythrocyte sedimentation rate o Enzymes (activation and inhibition of proteolysis (Proteinabbau), blood coagulation, fibrinolysis (Gerinnselauflsung))

Nonprotein nitrogenous compounds in plasma Urea/Harnstoff (20-40 mg/dl; 3.3-6.6 mM) o Final product of protein metabolism o High value hepatic insufficiency o Low value ureamia in acute nephritis, renal insufficiency, can cause coma Creatinine, creatine o Product of muscular metabolism o Synthesized in liver, kidney, pancreas Uric acid/Harnsure (3-6 mg/dl) o Final product of nucleoprotein metabolism o High value in gout/Gicht (disease affecting small articulation urate crystals are deposited) Bilirubin (0.2-0.8 mg /dl) o Final product of Hb metabolism o High values in hepatis, excessive hemolysis, obstacles in biliary tract cause jaundice/icterus (test only on blood test, after normal blood values skin is 4 more days yellow)

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 10
Blood sugars Glucose (main blood sugar) o VN (glycaemia): 80-100 mg/dl; 4.4-5.5 mM/liter o Source: food, glycogen (glycogenolysis), amino acids + lactic acid + fats (neoglucogenesis) o Liver is mainly involved in glucose production o Hyperglucaemiant (increase glycaemia) : Food Glucagon (alpha-pancreas) Growth hormone ACTH (Adrenocorticotropin hormone) stimulates synthesis of glucocorticoids Thyroid hormones o Hypoglucaemiant (decrease glycaemia): insulin (beta-pancreas) (normal glycaemia after 2h) o Diabetes Mellitus (fasting glycaemia >126 mg/dl; daily glycaemia >200 mg/dl) failure in forming or utilizing (nutzen) insulin leads to hyperglycaemia) diabetes, obesity, arterial hypertension risk factor for cardiovascular disease complications: macroangiopathy (arteriosclerosis stroke, cardiac infarction) microangiopathy (kidney nephro-; eyes retino-; nerves neuropathy; high cholesterol + keton bodies) type 1 DM (IDDM) insulin dependent DM autoimmune disease antibodies result beta cell destruction (only 5% survive) failure of producing insulin type 2 DM insulin independent DM obesity, diet, physical activity are important factors beta cells produce enough insulin, but not enough relative to body mass and glycaemia o no absolute but rather deficiency beta cells get tired, tissue desensitizes to insulin, does not take up glucose properly insulin resistence gestational diabetes sometimes at women in pregnancy

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 11
Blood fats triglycerides, phospholipids, fatty acids, cholesterol VN (blood fats/lipids): 700-800 mg/dl High levels of blood lipids are a risk factor for cardiovascular disease ( amount of cholesterol is considered as an index of risk) Cholesterol is important for body functions, but when too much deposits on vascular walls atherosclerosis o VN (chol.): 100-220 mg/dl; 2.6-5.7 mmol (but differences in age, sex, diet, country) Lipoproteins are transporter for blood fats o Made of lipids bound to proteins (especially globulins) forming globular micelle particles o Present a hydrophil surface: phospholipids, apolipoproteins (transports hydrophob lipids), cholesterol o Present a hydrophob core: triglycerides, cholesterol esters o Classification: Alpha, beta globulins (by electrophoresis) Due to density (by ultracentrifugation) in this order quantity of fat decreases, quantity of protein increases Chylomicrons Very low density LP (VLDL) Intermediate density LP (IDL) Low density (LDL) (bad cholesterol, carries cholesterol from liver to the cells) High density (HDL) (good cholesterol, collects cholesterol from tissue, bringing it to liver) 2 2 Body mass index (BMI = weight [kg] / height [m ]) o Underweight < 18.5 o Normal weight 18.5 24.9 o Overweight 25 29.9 o Obesity > 30 Waist circumference should be: o men < 90 o women < 80

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 12
Erythropoiesis, erythropoietin, role of iron erythrocytes (red blood cells) o formed in the red bone marrow erythropoiesis controlled by erythropoietin (EPO)(hormone) synthesized by kidney (,liver) when too less O2 in blood (altitude training) 1. Kidney senses hypoxia (anemia) increases endogenous EPO production 2. EPO acts on E-progenitor (Vorlufer) cells in bone marrow production of new erythrocytes 3. Kidney senses increased tissue oxygenation decreases EPO production Erythropoiesis: o Hemocytoblast (stem cell) at division remains one stem cell, the other becomes the precursor cell o Proerythroblast (committed cell/Vorluferzelle) o Early erythroblast phase 1: ribosome synthesis o Late erythroblast phase 2: hemoglobin accumulation(Anhufung) o Normoblast phase 3: ejection of nucleus o Reticulucyte (youthful erythrocytes) o Erythrocyte Role of iron in the body: o Necessary for energy production of cells, cellular growth, proliferation o Erythrocytes contain iron in form of Hb oxygen carrier o 3-4 g iron in the body 10-20 mg/day intake (diet) 1 mg/day (absorption in duodenum and upper jejunum) 3+ 2+ Entering duodenal membrane: Fe Fe (ferri reductase) In duodenal membrane: passing membrane or binding to ferritin to be stored 2+ 3+ Exiting duodenal membrane: Fe Fe (ferri oxidase), binding to transferrin for transport transport in blood by transferrin (globulin) 75% bound to Hb, 10-20% stored in liver and heart bound to ferritin, no physiological excretion o VN (iron in serum): Men: 65 175 g/dl Women : 50 170 g/dl Children: 50 120 g/dl o Symptoms of iron deficiency: Lethargy, weakness, fatigue (Mdigkeit), depression, headache Angina, shortness of breath, cardiorespiratory disturbance Impaired cognition (beeintrchtigte Wahrnehmung) Impaired immune system Endocrine, metabolic disorders Gastrointestinal disturbance Other nutrients important for erythropoiesis: o Vitamin B12 (size and function of erythrocytes) o Folate (vitamin B9) o Copper

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 13
Characteristics of erythrocytes: dimension, number, composition, lifespan Dimension: o Disc diameter: 7 m o Thickness: 2 m 3 o Volume: 85 m 2 o Surface: 125 m 2 o Total surface: 3000 m Number of erythrocytes: 12 o 4-6*10 /liter (physiological variations due to age (greater in newborn), sex (greater in males), altitude Reduced number: characteristic of anemia Increased number: poliglugolia Different size and shape: category of anemia Anisocytosis size: <7 m or >10 m Poikilocytosis shape Modifications can be observed with microscopes Properties: o Highly deformable visco elastic property of membrane important for circulation in small vessels Composition: o H2O: 57% -12 o Hb: 33% (30 pg or 30*10 g) o Lipids: 7% o Sugar: 3% Enzymes playing a role in erythrocytes metabolic activity: o Carbonic anhydrase CO2 transport o 2,3-Diphosphoglycerate binds to tensed form of Hb lowers O2 affinity (O2 is emitted at higher partial pressures of CO2) Lifespan: o 120 days (youthful erythrocytes called: reticulocytes (0.5 1.5 %)) o 1% destroyed per day by agglutination and hemolysis 80% in spleen

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 14
Blood groups: AB0 system, Rhesus system AB0 system (by Landsteiner): o 4 main blood groups: 0, A, B, AB o Erythrocyte surfaces present antigenic determinants antigens o Blood plasma presents opposite antibodies of blood group o Erythrocytes agglutinate if antigen and corresponding antibody come together (A with alpha, B with beta) o Group 0 (45%): no antigen antibody alpha and beta no agglutination o Group A (40%): antigen A antibody beta agglutination with group 0 and B o Group B (11%): antigen B antibody alpha agglutination with 0 and A o Group AB (4%): antigen A and B no antibody agglutination with 0, A, and B Rhesus system: o 85% (white people, 96% black) are Rh+ (have system) o 15% are Rho Rh antigen has many components: C, c, D, d, E, e most powerful: D Presence of antigen D (or D + another) Rh+ Presence of other antigens Rho 2 cases of risks:: Second transfusion with Rh+ blood to Rh- patient Rh- mother with Rh+ fetus (at second pregnancy) risk of erythroblastosis fetalis Rh- persons develop antibodies (anti D) at first time anti D reacts with Rh+ blood at second time destruction Prevent sensitization at pregnancy: give mother 72h after birth Rh immune globuline o destroys Rh+ erythrocytes, before she produces antibodies blood transfusions only permitted with Rh and AB0 compatibility (some blood group and Rhesus factor)

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 15
Hemoglobin: quantity, structure, disorders Hb is red colored protein, made by heme (synthesized in mitochondria) and globin (synthesized in ribosomes) o Globin: 4 polypeptide chains (alpha, beta, gamma, delta) 3 types of Hb due to the polypeptide chains: A1 2 alpha + 2 beta dominant Hb at age of one year A2 2 alpha + 2 delta F 2 alpha + 2 gamma fetal Hb o Heme (4): tetrapyloric structure, porphyrine ring, contains iron, can bind one O2 molecule 8 Each erythrocyte contains 3*10 Hb molecules (88% of erythrocyte) Total amount of Hb in blood: o Men 13.5 16.5 g/dl o Women 12 15 g/dl o Children 11 16 g/dl o Pregnant women 11 12 g/dl (some amount of Hb, but more volume) o 1 g Hb can combine with 1.34 ml O2 1 liter blood can carry 2 dl O2 (5 liter blood = 1 liter O2) Hemoglobin disorders (modification of structure, shape, capacity to carry oxygen) hemoglobinopaties: o Thalasemia (recessive hereditary disease): Deficiency in globin chain production: no or less production of beta chains no HbA1, instead HbA2, HbF instability of erythrocytes quick destruction inefficient erythropoiesis chronic anemia especially in mediterranean zone o Sickle cell disease: Abnormal structure of globin chain (beta6 glutamine is exchanged with valine) forming HbS (sickle) erythrocytes are sickle shaped, have reduced resistance more hemolysis (excreted in urine red color) multiple organ infarcts (thrombosis) Red blood cell destruction (in spleen, liver, bone marrow rupturing of cell membrane): o Hb is degraded to: Globin recycled Heme is degraded to: Iron recycled Biliverdin is reduced to: o Bilirubin is bound to albumin o forming complex albumin-unconjugated/indirect bilirubin o goes to liver where complex is broken o bilirubin is recombined with glucoronic acid o forming conjugated/direct bilirubin o excreted in bile going to small intestine, transformed to: Stercobilinogen and stercobilin partially excreted (color of stool) partially reabsorbed (excreted by kidney) Urobilinogen and urobiln (color of urine) o Total amount of bilirubin in blood: 0.8 mg/dl o VN (bilirubin in blood) = 0.2 1.0 mg/dl > 2 mg/dl icterus/jaundice (yellow colored skin and conjunctiva (Bindehaut)) excessive hemolysis (increased bilirubin production over livers capacity) prehepatic hepatic disease (decreased bilirubin uptake by the liver) hepatic obstacles on bilary truct (white stool operate quick) posthepatic

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 16
Compounds of hemoglobin oxyhemoglobin O2Hb o labile combination Hb and oxygen major form of oxygen transport in arterial blood o each Hb can bind 4 O2 molecules reduced Hemoglobin HHb + o deoxyHb: O2Hb HHb + O2 + K o present in venous blood (3 g/dl, if amount increases to 4-5 g/dl cyanosis (bluish lips and fingers)) carbaminohemoglobin CO2Hb o labile combination Hb and carbondioxide form of CO2 transport in the blood carboxyhemoglobin COHb o stable combination of Hb and CO (great affinity of Hb to CO) o VN (COHb/Hb) < 1% (levels of city people and smokers are higher, appr. 5%) 10% impaired judgement 50% unconsciousness (risk of death) CO poisoning: reddish skin o Withdraw CO from Hb with high partial pressure of O2 (increases O2 affinity) methemoglobin MetHb 2+ 3+ o Fe Fe (oxidation): cannot bind to oxygen o VN (MetHb/Hb) = 0 3% higher values lead to cyanosis (can be caused by nitrates from water) dangerous for babies, they do not have MetHb reductase sulfhemoglobin SHb o stable combination of Hb and sulfur o no carriage of oxygen o occurs when Hb is exposed to some drugs (phenacetin, sulfonamides) relationship of Hb binding O2 o arterial blood: ca. 20 ml O2 / 100 ml blood (98% saturation, because some venous blood) o factors increasing Hb affinity binding O2 (at lungs): low temperature (in lungs) weak basic pH, low pCO2 Bohr effect o factors decreasing Hb affinity binding O2 (in tissues): high temperature (in tissues) weak acidic pH, high pCO2 Bohr effect 2,3 DPG (tensed state of Hb takes 2,3 DPG stabilizes T form, O2 emission)

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 17
Leucocytes: number, classification, leucocytic formula Leucocytes (white blood cells): o Nucleated blood cells, role in defense mechanisms 3 o VN = 6000 8000 / mm o leucopoieses (formation) in bone marrow: hemocytoblast (stem cell) monoblast (committed cell) monocyte myeloblast (committed cell) promyelocyte/granulocyte neutrophil, eosinophil, basophil lymphoblast (committed cell) lymphocyte stimulated by several growth factors/colony stimulating factors (CSF) cytokines/interleukins (IL) Classification: o Form of nucleus (morphologic): Polymorphonuclear cells (PMN) (neutrophils, eosinophils (like acids), basophils (like basics)) Mononuclear cells (monocytes, lymphocytes) o Presence of granulations (morphologic): Granulocytes (neutrophils, eosinophils, basophils) Agranulocytes (monocytes, lymphocytes) o Functions: Phagocytes (neutrophils, eosinophils, basophils, monocytes) Immunocytes (lymphocytes) Neutrophils (60% of leucos, proliferation by IL1): o Staining: cytoplasmic lysosomal granules are stained by acidic and basic mildy o Nuclei: elongated, pinched in several lobes (metamyelocyte, non-segmented, segmented neutrophil) o 12 m cell diameter o Role: destroy foreign invaders (bacteria) by enzymes of lysosomal granules, inflammation process Eosinophils (3% of leucos, proliferation by IL5) o Staining: cytoplasmic lysosomal granules are stained acidic red (eosin) o Nuclei: large, two connected lobes o 12-14 m cell diameter o Role: involved in allergies, number increased at parasitic worm infection Basophils (1% of leucos) o Staining: cytoplasmic lysosomal granules are stained basic blue o Nuclei: large, irregular, sometimes 3 lobes o 11-13 m cell diameter o Role: production of heparin (anticoagulant), inflammation process, involved in allergies (bronchial asthma by histamin) Monocytes (6% of leucos) o Nuclei: large, unlobed, kidney-bean shape o 20 m cell diameter (largest leucocyte) o Role: Interact with lymphocytes recognize and destroy foreign bodies Stimulus: transformed to macrophages (200 m) Production of substances for immune response (ILs, interferons, growth factors, toxic radicals) Present antigens to lymphocytes and have MHC (major histocompatibility complex) Lymphocytes (30% of leucos) o Nuclei: round, surrounded by thin rim of cytoplasm o 7-8 m diameter (small) o Role: crucial (entscheidende) role in immune response

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 18
Lymphocytes B and T, classification, roles Both types are produced in bone marrow, distinguishable by specific markers (CD) T-cells (matured in thymus (T), recognize antigens in antigen presenting cells): o T helper/inducer cells (CD4 marker) stimulate activity of B-cells, cytotoxic T-cells, suppressor cells o T amplifier (verstrken) cells (CD4 marker) stimulate activity of cytotoxic T-cells, natural killer T-cells o T suppressor (unterdrcken) cells (CD5 marker) reduce activity of killer T-cells o T cytotoxic/killer cells (CD8 marker) can kill all foreign recognized cells (cancer, virus infected, transplanted) secrete: perforins, tumor necrose factor, interferons o T natural killer cells front line soldier kill directly any non-self cell without B-/T-cell action B-cells (matured in bone marrow (B)) o Stimulus: transformed in plasmocytes they secrete antibodies/immunoglobins react with specific antigens

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 19
Substances involved in the nonspecific body defense non specific body defense belongs to the second line immediate response involving: o phagocytes (neutrophils, eosinophils, basophils, monocytes-macrophages (big eaters) o proteins: interferons (alpha, beta, gamma) produced when cell is infected by virus protect other cells around resistance is short termed (one week) complement proteins (have to be activated) produced by liver coat surface of microbe (opsonization) facilitate identifying + engulfing (verschlingen) for macrophage membrane attack complex (MAC) form holes in microbes cell membrane death of microbe properidin act with activated complement proteins on microbes, fungi destroying them lisozyme present in saliva and tears destroys cell membrane of bacteria reactive C protein (globulin) activates complement proteins facilitates opsonization and phagocytosis

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 20
Phagocytosis and inflammatory response Phagocytosis (part of non-specific defense system) o engulfing pathogens (bacteria, fungi, viruses) by leucocytes o steps: 1. Adherence of microbe to phagocyte 2. Ingestion of microbe in phagocyte 3. Formation of phagosome (phagocytic vesicle) 4. Fusion of phagosome with lysosome (contains digestive enzymes) forming phagolysosome 5. Digestion of ingested microbe by enzymes 6. Formation of residual body containing indigestible material 7. Phagocyte discharges waste material Inflammatory response (major part of non-specific defense system) o Activated by tissue damage (microbes, insects bites, physical agents) o Effector-cells secrete mediators (involved in defense processes) Mast cells histamine, leukotrien C4, prostaglandine E2, tryptase Eosinophils leukotrien, prostaglandin E2, ECP,EDN, TGF-beta, IL 5, IL 4 T-cells IL 4, IL 5, IL 10, IL 13 Basophils histamine, IL 4, IL 13 o Steps: 1. Pathogens enter wound 2. Platelets release blood-clotting proteins at wound 3. Mast cells secrete factors mediate vasodilation + vascular constriction more blood, plasma, cells at wound 4. Neutrophils secrete factors kill and degrade pathogens 5. Neutrophils and macrophages remove pathogens phagocytosis 6. Macrophages secrete cytokines (hormone) attract immune system cells to wound, activate tissue repair cells 7. Inflammatory response lasts until foreign material is eliminated, wound is repaired o Inflammatory signs: Heat Redness Pain Swelling

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Jan Kirchhof

Physiology

UMF Targu Mures

Topic 21
Types of immunity, MHC MHC (major histocompatibility complex): o Present in all body cells o MHC proteins belong to HLA (human leucocyte antigen) system unique for an individual o MHC proteins present antigens (from pathogens) to B- and T-cells Antigen presentation: 1. Antigen (from pathogen) enters dendritic cell 2. antigen is breaken down 3. these pieces bind to MHC protein in ER 4. MHC-complex is transported to cell surface by golgi apparatus 5. MHC protein presents antigen in cell surface o Class I MHC (intracellular): Presents antigens found inside of infected cell to cytotoxic T-cells (CD8) Cytotoxic T-cells identify these infected cells and eliminate them cellular immune response o Class II MHC (extracellular): Presents antigens found outside the cell to helper T-cell (CD4) Helper T-cell produces specific antibodies and stimulates activity of certain phagocytes o Phagocytes inactivate the extracellular pathogens and eliminate them humoral immune response Immunity: o Introduction: System that defends the body against pathogens (bacteria, viruses, fungi, protozoa, prions) Immune tolerance: B-, T-cells ignore own tissue considered as own tissue Antigen recognized by immune system as foreign induce formation of antibodies Antibodies (gamma globulins immunoglobulins) produced by plasma at stimulus from B-cells Vaccines (contain killed microbes antigens) induce immune response forming own antibodies long term Serums (contains antibodies) act immediately short term protection o Two types: Innate (angeborene) immunity (non specific) Natural resistence Acts like barrier Use process of inflammatory response Adaptive/acquired (erworbene) immunity Natural: passive (maternal), active (infection) Artificial: passive (antibody transfer serum), active (immunization vaccine)

21

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 22
The humoral immune response and cellular immune response Humoral immune response (extracellular): o Based on production of antibodies by plasma cells (due to stimulus of B-cells) Antibodies destroy antigens (activate complement proteins) o Humoral response in allergies: Allergies are exaggerated responses at second meeting with an antigen After first meeting: antibodies (IgE) are produced in high quantity bind to effector cells (mastocytes, basophils) o secrete histamine, leucotrienes act especially on smooth muscles examples: urticaria (Nesselausschlag), allergic rhinitis (hay fever), bronchial asthma, anaphylaxis Cellular immune response (intracellular): o Based on action of T-cells (due to stimulus after contact with antigen presenting cell) o Autoimmunity: lymphocytes recognize own body cells as foreign/non-self destruction of own cells o AIDS (acquired immune deficiency syndrome) HIV (human immunodeficiency virus) destroys helper T-cells depressed immune system

22

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 23
Thrombocytes/Platelets: number, morphological characteristics, functions, disorders Thrombocytes (platelets): o anucleated (kernlos) o disc shaped fragements, 2 3 m diameter 3 o VN = 150000 300000 / mm o Lifespan: 8 10 days o thrombopoiesis (formation) in bone marrow hemocytoblast (stem cell) megakaryoblast promegakaryocyte megakaryocyte platelets (approximately 8000 per megakaryocyte) o components: canalicular system alpha granule (contain Willebrand Factor (vWF), thrombin, thrombospondin, growth factors) microtubules glycogen mitochondria 2+ dense body (contain ADP, Ca , serotonin) microfilaments surface glycoproteins (receptors for collagen, ADP, serotonin, vWF) o function: scanning vascular system, respond to endothelial damage bind to injuries (in seconds) component of clotting system platelet activation (when binding to injuries): o Exocytosis of dense granules and alpha granules o Activation of phospholipase A2 (membrane enzyme) formation of thromboxane A2 (TXA2) o Shape change (projecting fingers) reversible o Adhesion between platelets and collagen under endothelium forming platelet plug (white clot) Supported by receptors (vWF, fibrinogen) Fibrin strengthens structure platelet aggregation (thrombus formation, growth) irreversible o Coagulation reaction is promoted platelet activation + coagulation red clot o Disorders: Atherosclerosis 2+ Building up of deposits (fatty substances, cholesterol, waste, Ca , etc.) in inner lining of artery o Creates plaque o Reduces blood flow Activated platelets are involved at damage of endothelial lining and atherosclerotic lesion o interacting with monocytes, lymphocytes o Influence plaque progression blood clots blockade heart, brain damage Causes of arterial wall damage: high cholesterol, smoking, hypertony, DM, obesity, inactivity Antiplatelet agents can prevent arterial wall damage Disorder of platelet quantity or quality spontaneous bleedings Thrombocytopenia (reduced quantity) blood seeps in tissue purpura (purple blotches (blaue Flecken)) Glanzmanns thrombasthenia (hereditary): poor quality, disorder in GP IIb/IIIa (receptor) production o excessive bleeding

23

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 24
Hemostasis: phases, disorders hemostasis is the process that stops bleeding o primary/cellular hemostasis 1. vascular constriction induced by pain (caused by injury) and vasoconstrictive substances (serotonin) by platelets 2. intervention of platelets adhesion, activation, aggregation o secondary/plasmatic hemostasis 3. formation of fibrin mesh coagulation of blood fibrinogen is transformed to fibrin forms a mesh over blood cells (red thrombus) 4. dissolution of the clot Fibrinolysis destruction of fibrin filaments with the action of plasmin (protease) o Fibrin degradation products are E, D, X, Y fibrinopeptides medical practice o Not physiological fibrinolysis (dissolve intravascular clots): Streptokinase (produced by streptococcus bacteria) activates plasminogen to plasmin activates fibrinolysis o Not physiological inhibiting of fibrinolysis (prevention of excessive blood loss during operation) Aprotinin (trasylol) (from bovine (Rinder) lungs) Hemostatic and fibrinolytic system are balanced due to cooperation of activating and suppressing enzymes Disorders: o Hemorrhage (risk for bleeding) Hemophilia (inherited disorder): deficiency of any clotting factors (most F VIII) excessive bleeding DIC (disseminated intravascular coagulation): Caused by: massive tissue damage, sepsis, pregnancy complications, snake bites, cancer, liver disease Overwhelmed action of anticoagulant and fibrinolytic systems o microthrombi, tissue ischemia (Minderdurchblutung), consumption of platelets and coagulation factors and anticoagulants severe bleeding o Clotting (risk for thrombosis) Arterial/venous thrombosis: Can lead to obstruction or mobilization of thrombi in blood vessels (embolism) Medical treatment: deobstruct vessels a) dissolve clot, b) mechanical removal (angioplasty (balloon, stent))

24

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 25
Coagulation of blood, clotting factors, anticoagulants Coagulation: o Enzymatic process: fibrinogen is transformed in fibrin that forms a mesh entrapping the blood cells (red thrombus) Controlled by intervention of clotting factors: o Factor I fibrinogen o Factor II prothrombin o Factor III tissue thromboplsatin o Factor IV calcium ions o Factor V labile factor o Factor VII stable factor o Factor VIII antihemophilic factor o Factor IX Christmas factor/plasma thromboplastin component (PTC) o Factor X Stuart-Prower factor o Factor XI plasma thromboplastin antecedent (PTA) o Factor XII Hageman factor o Factor XIII fibrin stabilizing factor Most of them are glycoproteins (globulins) formed in liver Factor II, VII, IX, X need vitamin K for synthesis o Coagulation cascade: Initiated by 2 pathways: Contact activation pathway /small endothelial damage (intrinsic) Tissue factor pathway / tissue damage (extrinsic) both activate final common pathway of factor X, thrombin (most imp. subst. of cascade feedback mech.), fibrin pathways are series of reactins where enzymes + cofactors are activated and catalyze next reaction learn picture of the book 2 pages after clotting factors o anticoagulants (inhibit coagulation) natural anticoagulants: heparin o produced in liver and lung (from basophils and mastocytes) o inhibits activity of thrombin o acts fast but not long for acute problem antithrombin III o inhibits activated II, IX, X, XI, XII, kallicrein, plasmin, VII o heparin amplifies action Protein C + S o Produced in liver with VitK o Inhibits activated V, VIII o Facilitates intravasacular clot lysis Extrinsic anticoagulants: Coumadin (inhibits vitK no synthesis of II, VII, IX, X) 2+ Citrates (binds Ca ) Hirudin (blocking thrombin)

25

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 26
Kidney anatomy, component of the nephron Kidney: o Primary organ of homeostasis (Aufrechterhaltung des Gleichgewichts) of: Volume of body fluids Composition of body fluids Excretion of metabolic waste in the urine o Anatomy: Large, bean shaped organ, situated at dorsal side of visceral cavity, protected by renal capsule (tough fibrous coat) Urinary system (way of urine): kidney ureter urinary bladder urethra outside Components (longitudinal section): Cortex (low b) surrounds pyramids (darker, triangular structures) Medulla (high b) made by pyramids Renal pelvis (inner part of kidney) collects urine from calyces drains in ureter 6 Nephron: basic functional unit of kidney (approximately 10 in kidney, 90% have to work for proper function) o Glomerulus + Bowmans capsule form renal corpuscle (situated in cortex continued by) o Proximal convoluted tubule (situated in cortex continued by) o Loop of Henle (u-shaped) (sit. in cortex or medulla, depends on length continued by) loop in medulla: juxtamedullary nephron (15%) loop in cortex: cortical nephron o Distal convoluted tubule (situated in cortex continued by) o Collecting tubule (goes in medulla continued by ureter)

26

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 27
Renal blood flow, pressures Blood supply: o Renal artery Receive approximately 20% of cardiac output (ca. 4 ml/min/g) one of highest blood flow values o Renal veins drain blood of kidney in vena cava inferior o Pressures: (values are inaccurate; HP in mmHg (hydrostatic pressure); b in mmHg (oncotic pressure)) Arteria renalis HP 100 b 30 Afferent arteriole HP 100-60 b 30 Glomerular capillary HP 60 b 30-35 Efferent arteriole HP 60-25 b 35 meeting point of two curves Peritubular capillary HP 25 b 35-30 Infrarenal vein HP 25-10 b 30 Vena renalis HP 10-5 b 30 Afferent + efferent arterioles are major resistence sites major sites for RBF (renal blood flow) control If HP > b filtration (glomerular capillaries) If b > HP reabsorbtion (peritubular capillaries)

27

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 28
Mechanisms of urine formation mechanisms: o Glomerular filtration (blood plasma) at glomerulus from vessels to renal interstitial fluid (primary urine) o Tubular reabsorbtion of water and solutes at prox. conv. tubules from renal interstitial fluid to vessels o Tubular secretion at distal conv. tubules from vessels to interstitial fluids Nephrons receive blood by afferent arterioles entering glomerulus Blood leaves glomerulus by efferent arterioles o High vascular resistance low pressure in peritubular capillaries reabsorbtion (H2O and solutes from renal interstitial fluid) o 90 95% of postglomerular RBF: perfuses renal cortex o 5 10% of postglomerular RBF: perfuses renal medulla vasa recta o 1% of postglomerular RBF: perfuses inner medulla that serves medullary osmolar gradient

28

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 29
Glomerular filtration, concept of clearance Glomerulus is surrounded by Bowmans capsule presents capillaries inside (podocytes around cytoplasmic extension for filtration Capillaries are very permeable to plasma large portion filtered from blood o Proteins are not filtered, too big (>10m), if: damage, proteinuria, glomerulopathy Amount of filtered plasma depends on: Capillary hydrostatic pressure 55 mmHg Blood oncotic/ colloid osmotic pressure -30 mm Hg Capsular hydrostatic pressure -15 mmHg Capsular oncotic/ colloid osmotic pressure 0 mmHg o +10mmHg towards outside RBF (renal blood flow): 1250 ml/min RPF (renal plasma flow): 650 ml/min GFR (Glomerular filtration rate): 125 ml/min (10/55 * 650 ml) Resistance of afferent and efferent arterioles important for RBF, RPF, GFR o Constriction of afferent arteriole high afferent resistance lower pressure in glomerular capillaries (lower filtration pressure) o lower GFR o Constriction of efferent arteriole opposite effects RBF/GFR regulation (autoregulation, nervous regulation, humoral regulation) o Autoregulation: Can maintains RBF, GFR in blood pressures between 80 200 mmHg (in absence of neural/humoral factors) Starts through myogenic response Outside of 80 200 mmHg more pressure dependent less than 40 mmHg severely reduced GFR o Sympathetic nerves: Acts on afferent and efferent arterioles effects RBF/GFR Cardiovascular baroreceptors effects RBF/GFR o Humoral regulation: Hormones for vasoconstriction: noradrenalin, adrenalin, angiotensin, ADH, serotonin Hormones for vasodilation: prostaglandins, bradykinin, dopamine (!), natriuretic peptide, papaverine)

29

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 30
Juxtoglomerular apparatus (JGA) structure and function JGA is situated near glomerulus and distal tubule (with macula densa) Equilibrium between GFR and tubular function tubular function is adapted to maintain GFR constant o tubularglomerular feedback mechanism (TGF) JGA regulates RBF/GFR through TGF If GFR changes (e.g. high GFR high tubular fluid flow rate high Cl delivery) o tubular fluid flow rate changes (through prox. tubule, loop of Henle, dist. tubule (macula densa)) Cl delivery and reabsorbtion rate at macula densa changes JGA determines vascular volume change by change of: o Arterial pressure (direct + arterial barareceptors) o Venous volume (indirect through atrial receptors (Vorhof) sympathetic nerv. sign.; catecholamine (hormons)) o Fluid delivery to macula densa (direct) JGA response: o Renin release changes rate of excretion: H2O + salt; changes peripheral resistance o GFR change changes rate of excretion: H2O + salt o Peritubular capillary pressure change (HP and ) changes rate of excretion: H2O + salt

30

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 31
Function of renal tubules Filtration o Large portion of plasma is filtered from blood into renal tubules glomerular filtrate o Needed substances are put back into blood reabsorbtion o Rest is left and excreted by urine Reabsorbtion o Movement of H2O (passive) + solute (active or passive due to substance and tubular segment) from tubular lumen into peritubular capillary network Secretion o solute (mostly active) from blood into tubular lumen proximal renal tubules constitution: o inner surface: luminal surface of epithelium brush border of microvilli (increases surface) role of epithelium: reabsorb ions, nutrients, H2O transport it to capillaries o outer surface: basal/lateral cell membrane infoldings, contact with interstitial fluid and blood vessels + major function: Na reabsorbtion (60 70% of filtrate) o at basolateral membrane: + + primary engine: prim. active transport (ATP-ase: Na out, K in) creates strong conc. gradient (neg. in cell) o at luminal surface: + passive transport of Na (conc. gradient) 2+ 2+ + sec. act. transport (conc. gradient) symport (cotrans.): glucose, aminoacids, electrolytes (Ca , Mg , K , Cl , HCO3 ) + o e.g. sodium glucose transport: 2 Na + 1 glucose into cell, gluc. out cell by independent mechanism 90% of glucose, aminoacid, HCO3 of filtrate is reabsorbed H2O (60 70% of filtrate) is reabsorbed by osmosis, rest filtrate remains isotonic Bicarbonate reabsorbtion: + o At lumen: HCO3 (filtered) + H (secreted) CO2 + H2O + o Inside cell: hydration of CO2 (CO2 + H2O) H (goes to lumen) + HCO3 (transported to ISF by (1)Na-(3)HCO3 cotransporter) o reabsorbtion of HCO3 (1 disappears from tubular fluid and appears at ISF) Chloride reabsorbtion: o At luminal surface: Cl-base(HCO3, HCO2 formate, oxalate) antiport o At basolateral membrane: Cl channel + K -Cl symport Some weak organic acids (uric acid, PAH, penicillin), bases (acetylcholine, atropine, morphine) actively secreted in prox. tubule Some substances (e.g. urea) reabsorbed or secreted by prox. tubule

31

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 32
Role of loop of Henle (in medulla) Continuation of proximal renal tubule, presents 3 regions: o Thin walled descending limb Highly permeable to H2O, almost completely impermeable to solutes H2O from filtrate to surrounding medium by osmosis o increases up to 1200 mOsm/l (at hairpin turn) filtrate reaches isotonic state there o Thin walled lower part ascending limb + Highly permeable to Na , Cl , little perm. to urea, almost completely impermeable to H2O + Passive diffusion of Na , Cl from filtrate to surrounding medium o Thick walled upper part ascending limb + Active diffusion of Na , Cl from filtrate to surrounding medium (needs energy, maintains osm. conc. grad. in medulla) Reabsorbtion of H2O + solutes (flowed in medulla) by vasa recta (capillary network around loop of Henle in medulla) 75% of original glomerular filtrate reabsorbed by prox. tubule 25% reaches loop of Henle + o 15 20% of original Na conc. reabsorbed by loop of Henle Tubular fluid (filtrate) leaves loop of Henle: slightly hypotonic (200 250 mOsm/l) to blood, contains mainly urea + wastes Interstitial fluid of medulla is hypertonic

32

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 33
Role of distal tubule Reabsorbtion of electrolytes and H2O (quantity due to hormonal control by aldosterone and ADH) Distal tubule can be divided (anatomically + functionally) in 2 parts: o Cortical collecting tubule (action of aldosterone), 2 cell types P(principal) cells + Secrete K + Reabsorb Na + aldosterone released at low Na conc. in blood, at dehydration + + + + o stimulates Na -K ATP-ase, high number of Na -, K -channels) o Renin angiotensin aldosterone system (active at hypovolemia, hypotension) I(interrelated) cells + + + + Acid-base regulation (by K -H ATP-ase pump secr. of K , reabs. of H ) o Medullary collecting tubule (action of ADH) H2O leaves from filtrate to hypertonic medullary interstitium (H2O conservation, reduced diuresis (renal elimination)) ADH mechanism: ADH attaches to V2 receptor o Starts cascade (Gs protein adenylate cyclase, cAMP, protein kinase A) forces insertion of aquaporin2 at laminal surface/apical membrane H2O moves (due to osmotic pressure) in cells, leaves at basolateral membrane by aquaporin3/4 Kidney is able to maintain osmolality of body fluids constant wide range of osmolar conc. (50 1200 mOsm/l) excretion

33

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 34
Urinary concentration and dilution (bad topic) due to osmolar gradient between corticomedullary junction and tip of papilla + + o reabsorbtion at thick ascending limb (l.o.H.) Na , K , Cl o events (transport-, permeability-related) at distal tubule and collecting duct explanation of osmolar gradient in medulla: countercurrent (Gegenstrom) multiplication theory o depends on countercurrent flow (example of an oven) energy (heat) transferred from outgoing- to ingoing-air no loss of energy at inner medulla: high urea concentration o loop of Henle at thin descending limb l.o.H.: H2O is reabsorbed NaCl conc. of tubular fluid increases at thin ascending limb l.o.H.: NaCl is reabsorbed (passive diffusion, impermeability for H2O) o vasa recta (passive exchange) going down towards papilla: taking urea from ISF conc. increases going up from papilla: loss of urea into ISF conc. decreases

34

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 35
Role of kidney in acid base balance acid-base balance in various body fluids maintained by a constant H conc. o dynamic process, regulated mainly by lungs and kidney o blood buffers react to acids and bases (products of metabolism) lungs: control independently CO2 excretion rate + kidneys: control independently concentration of HCO3 excr. of acids (NH4 )/bases (H2PO4 ,HCO3 ) in urine VN: pH = 7.4; [HCO3 ] = 24 mmol/l; Pco2 = 40 mmHg Kidney: 2 ways maintaining acid-base balance o Retaining filtered HCO3 + + + + Reabsorbtion of HCO3 by H secretion (Na -H antiport, H ATPase electrogenic process) o At proximal tubule (80 90%) with carbonic anhydrase (sit. at brush border) o At distal tubule (10 20%) with carbonic anhydras (sit. inside tubular cells) + CO2 + H2O (with carb. anhydrase) H2CO3 (dissociates) H + HCO3 caused by plasma concentration, extracellular fluid volume o Excreting acid (regarding to non-volatile/fixed acid 50 100mmol/day) Made by: Formation and excretion of titratable acid (ca. 50% of excreted acid) o Amount of measurable excreted acid in urine (determine amount of base (OH ) bringing pH to 7.4) o Production is accomplished by phosphate buffer (HPO 4Na2/H2PO4Na) leads to generate new HCO3 (renews consumpted buffer base of fixed acid) Secretion of ammonium NH4 (ca. 50% of excreted acid) o NH3 (ammonia) produced in tubular cells (end product of amino acid metabolism) Glutamine (major precursor) deaminated to glutamate (+GDH (glutamate dehydrogenase)) NH3 + PDG (phosphate dependent glutaminase) NH3 Alinine,glutamine can be transformed to glutamate o NH3 can easily diffuse into tubular lumen and plasma (secretion) Big portion secreted at prox. tubule reabsorbed as NH4 at asc. limb l.o.H. Most excreted NH4 is secreted at collecting duct + o Nonionic diffusion of NH3 excretion of NH4 loss of H generation of new HCO3 o Disorders in acid-base balance acidosis/alkalosis (can be compensated with HCO3 , but not as fast as in lung CO2) + Resp. acidosis: increased secretion of H increased production of HCO3 Resp. alkalosis: decreased reabsorbtion + production of HCO3 Met. acidosis: accumulation of acid products (lactic acid, urea, etc.) reabsorbtion of all filt. HCO3 increased production of HCO3 and NH3 Met. alkalosis: chloride depletion (Schwund), vomiting, diaretics increased filtration + excretion of HCO3
+

35

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 36
Dieresis, diuretics, composition of urine Tubular fluid goes along nephron enters ureter enters bladder Diuresis (production of urine): approx. 1ml/min (1.5liter/day) o Excessive accumulation of body fluids in some diseases (e.g. hypertension, heart failure, pulmonary and systemic edema) Use of diuretics (water pills) increase urinary salt + H2O excretion Diuretics (present several classes for specific sites of action in nephron) + + o Loop diuretics: inhibit Na , K , Cl transport at thick asc. tubule l.o.H. o Thiazide diuretics (chlorothiazide, metalazone): inhibit NaCl transport at distal tubule (do not use in renal problems) + o K sparing (sparen) diuretics: spironolacetone: autogonize (works against) aldosterone + amiloride: inhibits Na channels o Carbonic anhydrase inhibitors (acetazolamide): inhibit transport of HCO3 out of prox. tubule o Osmotic diuretics (manitol): is filtered, not reabsorbed remains in lumen creates osmotic pressure pulls H2O from cell into lumen Urine composition (variable proportion of dissolved substances): o H2O 95% o Urea 2% 25.5g o Cl 0.6% 6.6g + o Na 0.1% 4.1g + o K 0.6% 3.2g o Creatinine 0.1% 2.7g o HCO3 1.2g o Uric acid 0.03% 0.6g o NH3 0.05% o Sulphate 0.18% o Phosphate 0.12% 2+ o Mg 0.01% 2+ o Ca 0.015%

36

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 37
Renal failure, artificial kidney Renal function disturbance (can lead to renal failure) due to: o Intrinsic conditions: infectious process, obstructive lesions, disturbance of blood supply o Extrinsic conditions: shock, hemorrhage (Blutung), toxic materials, transfusion reactions Renal failure leads to temporary or permanent kidney damage o loss of normal function can be substituted by artificial kidney renal dialysis substance transfer by semipermeable membrane (diffusion (small particles), osmosis) one side: blood (velocity: 300ml/min) other side: dialyzing solution (always fresh, 500ml/min) requires good artery and vein, lasts 4 5h, 3 times a week 2 types of renal failure o Acute renal failure: abrupt onset, potentially reversible o Chronic renal failure: progress slowly over 3 month, can lead to permanent renal failure

37

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 38
Micturition (Urinieren) urine is accumulated in vesica urinaria (capacity of approx. 400ml) o urine comes from ureter no reflux because valvular flaps at uretral-vesical junction initial accumulation slightly increase in pressure (10 20cm , 0.01 0.02bar) later accumulation pressure increases slightly until capacity is reached at 200ml afferent (to CNS) impulses in pelvic nerves sensation of distension (Spannung) wish to urinate voluntary (freiwillig) control of micturition until 400ml o over 400ml pressure can increase to 100cm/0.1bar involuntary micturition initiation of micturition: voluntary act willful relaxation of external sphincter by inhibition of pudendal nerves (somatic) micturition reflex is autonomic: o activation of parasympathetic fibres stimulation of detrusor muscle increase in intravesical pressure (up to 25 50cm) o sympathetic hypogastric fibres action not entirely clear (int. sphincter)

38

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 39
The role of the kidney as endocrine organ kidney produces some hormones, involved in endocrine regulation of body functions renin: o proteolytic (protein break down) enzyme o produced at level of JGA o induces activation of ANG1 forms ANG2 releases aldosterone EPO: o Controls erythropoiesis (look topic 12) Prostaglandins (PGE2, PGI2, PGF1A, PGF2) and leukotriens: o Control RBF o PGs: induce vasodilatation, increase dieresis Important role in 1.25-(OH)2VitD3) production o Sunlight + 7-dehydrocholesterol cholecalciterol (VitD3) (in small amount via diet fish, meat) Liver 25-dihydroxyvitamin D3 o Kidney 1.25-dihydroxyvitamin D3 2+ o maintains Ca balance in body (by action of PTH (parathyroid hormone) 2+ increased Ca absorption (small intestine) 2+ increased Ca reabsorption (kidney) increased bone mineralization

39

Jan Kirchhof

Physiology

UMF Targu Mures

Topic 40
The neuro-humoral control of renal function neural control of renal activity is limited (even normal function of transplanted kidney): o adrenergic stimulation (by sympathetic splachnic nerves) + vasoconstriction (especially at afferent arteriole reduced GFR, increased Na reabsorption at prox. tubule) Humoral control of renal activity by several hormones: o ANG2 Via AT1 receptors (ANG2 receptor type 1) vasoconstriction with reduced diuresis Via AT2 receptors (ANG2 receptor type 2) vasodilatation with enhanced diuresis and natriuresis o Aldosterone + Enhances Na reabsorption o ADH Induces massive reabsorption of H2O o PTH 2+ 2+ Reduces loss of Ca , Mg + + Increase elimination of Na , K , HCO3 o Kalicrein-bradykinin system Induces vasodilatation Opposing action of renin-ANG system o Renal prostaglandins (PGE2, PGF1A, PGF2) Induce vasodilatation with diuresis and natriuresis o Thyroid hormones Increase GFR o Insulin Influences glucose transport o ACTH and glucocorticoids + Increase glucose, Na reabsorption

40

Jan Kirchhof

Physiology

UMF Targu Mures

Clearance: volume of plasma, cleared from a given substance per time unit o The effect of increasing plasma conc. of a substance according to the clearance depends on handling the substance by tubules Handling: filtered clearance is constant Handling: filtered + reabsorbed clearance increases Handling: filtered + secreted clearance decreases o With clearance you can determine GFR Inulin (fructose polymer) it is only filtered GFR = (U*V)/P (U: conc. urin, P: conc. plasma, V: volume urin) Creatinine (endogenous substance) filtered + 10% secreted (prox. tubules) o With clearance you can determine RPF PAH (p-aminohippuric acid (weak acid)) filtered + secreted (renal venous conc. ca. 0) Renal extraction of PAH ca. 90% represents volume of RPF o Glucose clearance: Glycaemia <250 mg/dl 100% of filtrate is reabsorbed Glycaemia 250 375 mg/dl reabsorbtion decreases Glycaemia >375 mg/dl 0% of filtrate is reabsorbed Glycaemia >250 mg /dl excretion in urine starts Clearance: 0 (glyc. 0 250 mg/dl), like inulin (glyc. > 250 mg/dl)

41