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Compartmentalization of Fluids 1.

Describe the major subdivisions of the body fluids and the approximate percentage of total body water, sodium and potassium in each compartment. TBW (total body water) = Body weight x .6 ECF = 2/3 TBW ICF = 1/3 TBW

Isotonic saline = 0.9% = 0.9 gms NaCl/100 ml

=

9 gms NaCl/liter

(9 gms NaCl/L) ÷ (58 gms/mole NaCl) = 0.155 M NaCl 155 mM NaCl 1M NaCl dissociates into 1.87 Osm (not into 2 Osm because a small fraction is undissociated in solution as NaCl) 155 mM x 1.87 is ~ 290 mOsm 2. Be able to use the normal concentrations of Na+, K+, Cl-, and HCO3- in extracellular and intracellular fluids to interpret electrolyte disorders. -Hyponeutremia: lots of water, not any food -Cholera:

3. Explain why fixed negative charges on plasma proteins leads to a difference in the concentrations of anions in plasma water vs interstitial fluid. - Because Plasma proteins are very negative (average 14 meq/L), but can’t cross capillary epithelium, they force cations

4. Explain why a change in total amount of NaCl in the body primarily affects the extracellular fluid volume rather than extracellular osmolality when water/drinking is not limiting. - Water follows ions and will maintain osmolality across the membrane. So a sodium pump deficiency (i.e. dysfunctional CFTR) results in deficiency. 5. Explain why a change in concentration of NaCl in extracellular fluids reflects a disorder in water intake or output rather than sodium intake or output. If there is elevated NaCl intake, thirst will accompany and the [NaCl] will normalize. Someone would have to drink lots of fluids without salt/food fluids to lower [NaCl] - this happens with alcoholics who don't eat food/salt sometimes. Since water movement will equilibrate osmolality between ICF and ECF elevated or depressed [NaCl] indicates either not enough (person in the desert question) or too much fluid (beer). Finally, I didn't give you enough info to address the "why" but basically it pertains to the thirst response or access to water.

6. Demonstrate the ability to predict how infusions of: isotonic saline, water, hypotonic and hypertonic fluid affect ICF and ECF volume and osmolality. - See problem set

Cinitial x Vinitial (+/-) Cchange X Vchange = Cfinal X Vfinal

Ionic Equilibria and Membrane Potential
1. Distinguish between net flux and unidirectional flux

JAB or JBA are unidirectional fluxes Net flux: Sum of unidirectional flux Unidirectional fluxes exist when Net Flux is zero 2. Define: electrochemical potential, electrochemical equilibrium, equilibrium potential difference, membrane potential, conductance Electrochemical Potential: Chemical potential (dependent on concentration) + Electrical potential (dependent on charge of electrical field) Electrochemical Equilibrium: When the net forces of concentration differences and voltage differences are of equal magnitude, but of opposite direction Equilibrium Potential: The voltage difference that prevents the movement of an ion down a concentration gradient

- Ion specific - Nernst Equation

RT/ F = 25 for ln, 60 for log Membrane Potential: Weighted average of the equilibrium potential of all the ions across a membrane - Chord Conductance equation

Conductance: The rate of travel of an ion across a membrane The total conductance (g) of the membrane for any ion is equal to the number of channels (N) times the single channel conductance (γ), times the probability that the channel is open (Po): g = γNPo 3. Describe how voltage differences across membranes are generated by ion fluxes - Ions moving at different rates cause voltage differences

4.Write the Nernst equation and the chord conductance equation, and use each equation appropriately to calculate equilibrium potentials for Na+, K+, and Cl-, and membrane potentials 5. List the major clinical symptoms of cystic fibrosis: - Mechanism: defect in CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Sweat: Salty Sweat Pancreas: Decrease Pancreatic Enzymes Lungs: Thick, dehydrated mucosal lining  Pseudimonas Aeruginosa infection

6. Describe the mechanism of sweat production in sweat glands - Primary sweat is secreted by Acinar cells in secretory coil of duct (bottom of sweat gland) - ion reabsorption in epithelial cells of resportive duct  reduces osmolality of sweat  Cl- absorbed through CFTR  pulls NA+ through channels (to maintain electrical equilibrium. 7. Explain the relationship between elevated sweat NaCl in cystic fibrosis and altered chloride permeability

- CFTR deficiency reduces chloride permeability in the membrane.

Membrane Transport Mechanisms
1. Categorize the following as either active transport or passive carrier-mediated transport: ion pumps: Active ion channels: passive-carrier mediated facilitated diffusion transporters: passive-carrier mediated sodium-solute cotransporters: Active 2. Define: CFTR: Cystice Fibrosis Transmembrane Conductance Regulator: Cl passive ligand-gated transport protein channel Gating: mechanism for controlling activation of channel in membrane (ligand vs voltage gating) cardiac glycosides: ouabain and digitalis: stabilizes E2-P transition state of NA,K-ATPase  end result is Ca buildup in cytoplasm  increased muscle contraction symport: Na transport down gradient coupled to brings molecule into cell  Na, glucose symporter Antiport: Na transport down gradient coupled to extruding molecule from cell (ex/ Na, H antiporter on apical face of epithelium) Electrogenic: contributes to the membrane potential  Ex/ Na,K ATPase Isotonic Hypertonic Hypotonic transcellular pathway: Passes through cell, through apical and basolateral membranes paracellular pathway: Passes through tight junction apical basolateral brush border: microvilli coated surface  apical membrane of intestines amiloride: Sodium channel inhibitor (also Na/antiporter)  CF treatment Furosemide: inhibits Na,K,2Cl-symporter DIDS: Inhibits Cl,HCO3- antiporter 3. What is the most common mutation in CFTR and what are the consequences of that mutation for CFTR function? - delta508 – loss of phenylalanine

AA deletion causes CFTR to get stuck in ER, never reaches membrane

4. Explain how the activity of Na,K-ATPase can generate a membrane potential. - The difference in stoichiometry of Na/K transport (3 + out, 2+ in) contributes to a negative membrane potential inside the cell 5. List two mechanisms whereby transport of small molecules or ions is regulated in animal cells. •1) Modification of transcription and translation rates •2) Posttranslational modification: phosphorylation Ex/ CFTR •3) Insertion into and removal from the plasma membrane - Recruitment of GLUT4 (glucose channel) to membrane due to insulin •4) Reversible binding of regulatory molecules Ex/ Lingand gated 6. Describe three mechanisms that are used by animal cells to maintain a constant intracellular volume in response to changes in extracellular osmolarity. 1) Hypotonic medium: Cell activates K channels (Cl follows) which move down their gradient -Bring water with them, shrinking cell 2) Hypertonic medium: Cell activates Na channels (Cl follows) which moves into the cell - Water follows and cell swells 3) Na,K-ATPase 7. Explain the mechanism whereby Vibrio cholerae causes symptoms of cholera and how oral rehydration therapy for cholera works. In this disease the bacterium Vibrio cholerae invades the GI tract and secretes a protein toxin called cholera toxin. The toxin inhibits the Na/H antiporter in intestinal villus cells and activates chloride efflux through chloride channels in the crypt cells. The net reduction of NaCl absorption and increase in Cl- secretion leads to diarrhea and loss of fluids and electrolytes. Oral Rehydration therapy: Uses a sugar, salt solution to create a glucose chemical gradient that pulls sodium into the cell through the Na,Glucose-symporter. It gives the body time to fight the infection

8. Describe the mechanism of electrolyte and water secretion by secretory epithelia and explain how mutations in CFTR affect this mechanism to cause symptoms of cystic fibrosis. - See answer in Ionic Equilibria

Acid Base Homeostasis: Maintaining Homeostasis + Acid-Base Balance
I. Maintaining Homeostasis Objectives 1. Use the normal value range of the constituents in Table 1 in interpretation of simple clinical scenarios

a. b. Simple clinical scenarios (see question 3) 2. Define feedback regulation and its importance in homeostasis a. Feedback regulation= controller. Aka, a mechanism that uses the results of a process to regulate the rate at which the process occurs i. InputPlantOutput Controller ii. Input example: brain senses thirst, vasopressin released iii. Plant: kidneys, where vasopressin acts (In general, a plant accepts an input and makes it an output) iv. Output: low volume high osmolality urine produced NOTE: For this lecture, ECF constituents= output v. Controller: kidneys, which no longer stimulated NOTE: For this lecture, nervous and hormonal systems that act on a plant to regain homeostasis b. Importance to homeostasis: feedback control is responsible for specific normal ranges of ions, amongst other important functions in the body that keep us alive 3. Define the main organ systems responsible for rapid and for long term homeostatic regulation of each of the following: plasma sodium/volume, plasma potassium, plasma pH, plasma osmolality (For efficacy, I have combined objective 1 in here, regarding simple clinical scenarios) a. Rapid response in homeostasis (this fuses with the next lecture on acids and bases) i. ECF buffering: bicarbonate, proteins, etc. (fastest) ii. IF buffering: bone, protein, organic and inorganic phosphates (2nd fastest) b. Long term homeostasis i. Respiratory compensation (in minutes, not seconds, so it’s not really long term, but it’s not the mere seconds of the previous two) ii. Renal adjustment: takes days to reach full efficacy

Molecule &  in ECF Na+ 

Which organ systems at work Cardiovascular system (to sense changes), renal, brain (thirst response) Cardiovascular system (to sense changes), renal, brain (thirst response)

Homeostatic Regulation Pathway

Atria stretch receptors release atrial natriuretic peptide inhibit renal Na+ and volume reabsorption increased output (slow)

What Clinical Scenario is this?/ Range Hypernatremia >146 mM

OR

Na+ 

Dietary Na+ sensed in GI tract factors releasedincrease urine Na+ excretion (fast) Cardiovascular stretch receptors and baroreceptors sense decreased Na+
Nervous signals simulated, increasing Na+ retaining hormones angiotensin II and aldosterone (fast) Increased sympathetic nervous system outflow to increase Na+ and volume reabsorption by kidney

Hyponatremia <138 mM

Brain stimulates thirst to restore volume (fast)

(slow) K+  Muscle and renal Increased insulin increases Na+ pump activity in muscle and fat K+ pumped into ICF (fast) OR Increased K+ secreted into urine via K+ channels and increased aldosterone (which increases K+ channel activity) (unsure) Increased renal K+ reabsorption and transfer of K+ out of muscle ICF into the ECF (slow) ECF buffering decreases CO2 (hyperventilate) (slow) OR Kidneys increase net acid output and increase reabsorption of HCO3 for further ECF buffering (slow) ECF buffer increases CO2 (hypoventilate) (slow) OR Decrease renal acid output and decrease renal HCO3 reabsorption (slow) Osmoreceptors release vasopressin from pituitary produce low volume high osmolality urine (slow) Osmoreceptors also stimulate thirst (fast) Lack of vasopressin production of high volume dilute urine (unsure) Hyperkalemia >5 mM

K+  H+ 

Muscle and renal Lungs/respiratory and renal

Hypokalemia <3.8 mM Acidemia <7.3 pH

H+ 

Lungs/respiratory and renal

Alkalemia >7.4 pH

Osmolality 

Brain and renal

Osmolality

Brain and renal

Dehydration, profound sweating <280 mOsm/kg Too much water or beer, >290 mOsm/kg

Acid-Base Balance Objectives
1. Learn the various buffers in the body that are important in responding to acid-base changes, and learn the relative speed of each group of buffers a. Fastest (seconds): ECF buffers i. HCO3-, via HCL+ NaHCO3 NaCl + H2CO3 H2O + CO2 ii. Plasma proteins iii. Inorganic phosphate iv. Amino acids, etc. b. 2nd fastest (seconds to minutes): ICF buffers i. bone- up to 40% of the acid load ii. proteins iii. organic and inorganic phosphates c. 3rd fastest (minutes to hours): Respiration rate i. controlled by nerves that sense pH and CO2 d. 4th fastest (hours to days): Renal adjustment i. started in minutes but full effectiveness is not until several days ii. due to renal gene expression change 2. Write the Henderson-Hasselbach equation:

there it is.

3. Explain the unique role of the CO2- HCO3- system in regulating body fluid pH a. CO2 + H2O H2CO3 HCO3- + H+ b. why is this is a good buffer
i. [HCO3-] is in great quantity ii. CO2 and HCO3- are well regulated by respiration and renal systems iii. CO2 is volatile, so it readily leaves the body iv. HCO3- is easily removed via renal system or absorbed back c. Conclusion: pH can be quickly and easily be regulated using the above buffer system 4. Learn the changes in blood pH, [HCO3-], and Pco2 that occur in the following uncompensated acid-base disturbances: metabolic acidosis, metabolic alkalosis, respiratory acidosis, respiratory alkalosis a. Acidosis and alkalosis: interplay of respiratory and renal (metabolic) regulation of CO2 and HCO3b. This is different from acidemia and alkalemia, which is the term describing the pH in blood and does not describe whether respiration or metabolism resulted in the academia or alkalemia

Disorder metabolic acidosis metabolic alkalosis respiratory acidosis respiratory alkalosis

pH    

[H+]    

primary disturbance plasma[HCO3-] plasma[HCO3-]  PCO2  PCO2

compensatory response  PCO2,  respiratory  PCO2,  respiratory  [HCO3-], renal production  [HCO3-], renal loss

d. Patterns to help remember this stuff i. metabolic acidosis/alkalosis is compensated via respiration regulation, and vice versa ii. if [HCO3-] is disturbed, it is compensated by PCO2, and vice versa 5. Explain how the kidney compensates for acid-base disturbances induced by the respiratory system, and how the respiratory system compensates for metabolic disturbances a. Respiratory acidosis- caused by hypoventilation or lung diseases that decrease respiration rate i. Kidneys secrete and excrete H+ b. Respiratory alkalosis-caused by hyperventilation, hypoxia, pain, or hysteria i. Kidney will attempt to hold onto HCO3 c. Metabolic acidosis- caused by diarrhea, diabetes, renal failure i. Lungs will reduce pCO2  breath faster d. Metabolic alkalosis- caused by ingestion of strong base or loss of acid (vomiting) i. Reduced breathing

c.