Medical Physiology Block 1 Week 2

Question 1

List the distribution of water in adult humans.

Answer 1

Total body water (60% of weight for males; 50% females); 60% of TBW is ICF; 40% ECF (75% interstitial, 20% intravascular (blood volume = (plasma volume)/1-hematocrit)), 5% transcellular)

Question 2

List the solute composition of key fluid compartments.

Answer 2

ICF: 15 mM Na, 120 mM K, 20 mM Cl, 4 mM of non-osmotic protein; interstitium: 145 mM Na, 4.5 mM K, 116 mM Cl; plasma: 142 mM Na, 4.4 mM K, 102 mM Cl, 1 mM non-osmotic protein (all compartments 290 mOsm)

Question 3

What is the formula for the Nernst equation?

Answer 3

Ex = (- (60 mv))/charge) log10 (Xinside/Xoutside)

Question 4

What is the formula for net driving force on an ion?

Answer 4

Net driving force= (Vm – Ex (nernst potential))

Question 5

Describe the key differences and similarities between pores, channels, and carriers

Answer 5

Pores - non-gated channel; channel- gated pore; carrier two gated channel (pores do not have saturation, channels and carriers abide by principles of Michaelis-Mentin)

Question 6

Explain the enzymatic cycle of the Na-K pump; how does ouabain block its function?

Answer 6

If E1 position is phosphorylated, the open gate of the carrier is facing the ICF; 3 Na bind and ATP hydrolysis sequesters Na in the carrier; due to ATP hydrolysis a conformation change allows Na to leave carrier; 2 K from ECF bind to sites in E2-P conformation; losing the P causes a conformation change to first sequester K then release it into ICF; New ATP restarts the process; (ouabain prevents K from entering the carrier)

Question 7

Distinguish between co-transporters and exchangers and give two examples of each.

Answer 7

Both use a ion with a high driving force to move another molecule against its electrochemical gradient (most of the time uses Na); co-transporters: Na/Glu & Na/Amino acid; exchangers: Na/Ca (NCX) & Na/H

Question 8

Describe regulation of intracellular calcium in typical non-excitable cells

Answer 8

When intracellular calcium in the cell rises, it binds to calmodulin and get shuttled out of the cell by an ATPase (Ca pump) or NCX exchanger

Question 9

Describe how various transporters (e.g. Na/H exchange, Cl/HCO2 exchange) contribute to the control of cytosolic pH

Answer 9

Acid extruders are secondary active transporters that are energized by the electrochemical Na + gradient across the cell membrane (without this more hydrogen ions would be present in the cell, in addition to less bicarbonate ion; result would be an acidic cell); Transport hydrogen ion out of cell and bicarbonate into cell (Na/H exchanger, Na/HCO3 cotransporter) (stimulated by decrease in pH)

Question 10

What would happen to the shape of the cell if the Na/K pump was inhibited?

Answer 10

The cell would swell and potentially burst

Question 11

Explain RVD and RVI and list the major transports that contribute to these regulatory volume changes; (how can cells adapt to long term osmotic pressure changes?)

Answer 11

RVD: In many types of cells, swelling activates Cl − or K + channels (KCl leaves the cell and water flows down its gradient out of the cell); RVI: In many types of cells, shrinkage activates the ubiquitous NHE1 isoform of the Na-H exchanger. In addition to mediating increased uptake of Na +, extrusion of H + alkalinizes the cell and consequently activates Cl-HCO 3 exchange. The net effect is thus the entry of Na + and Cl −. The resulting increase in intracellular osmoles then draws water into the cell to restore cell volume toward normal; (by synthesizing an osmolyte or secreting it into ECF

Question 12

What is the difference between paracellular and transcellular pathway?

Answer 12

A substance can bypass the cell entirely and cross the epithelium through the tight junctions and lateral intercellular spaces. This route is called the paracellular pathway; A substance can cross through the cell by sequentially passing across the apical and then the basolateral membranes, or vice versa. This route is called the transcellular pathway.

Question 13

Define a model for chloride secretion from an epithelial cell

Answer 13

adding Na/K/Cl transporter on basolateral surface allows influx of all three ions into cell (potassium shuttled out by channel; chloride leaves cell at luminal surface through channel and creates a negative luminal gradient allowing the passage of sodium paracellularly

Question 14

Define a model for sodium reabsorption from an epithelial cell

Answer 14

Na enters through channels on apical side and leaves through Na/K pump on basolateral side (creates a negative to positive gradient from lumen to basolateral surface, which allows chloride to enter into cell across its gradient paracellularly

Question 15

If an uncharged solute crosses the cell membrane by diffusion, then the flux of that solute will be related to?

Answer 15

directly proportional to the concentration gradient of the solute across the cell membrane; inversely proportional to the molecular weight of the solute; inversely proportional to the radius of the solute; inversely proportional to the thickness of the membrane; directly proportional to the partition coefficient of the solute (all derived from Fick’s law)

Question 16

Solutions A and B are separated by a membrane permeable to urea. Solution A is 10mM urea and solution B is 5 mM. If the concentration of urea in sol A is doubled, the flux of urea across the membrane will…?

Answer 16

the flux of urea across the membrane will be tripled (10-5 = 5; 20-5= 15)

Question 17

A subject (300 mOsm, 42 L) ingests 3L of water. Assuming no water loss from the body, the plasma osmolarity in mOsm/L after steady state has been attained will be?

Answer 17

C1V1 = C2V2 (C1 = 300 mOsm), V1 = 42 L, V2 = 45 L, solve for C2 (Ans: 280 mOsm; consider the body as one water compartment)

Question 18

What are the corrections that need to be made to calculate ion concentration in protein-free plasma when given the ion concentration in plasma?

Answer 18

Because of the albumins and other proteins, the ion concentration is 7% less; since the proteins are negatively charged, positively charged ion concentration is 5% less (- charged 5% more)

Question 19

What is the anion gap?

Answer 19

The sum of intravascular sodium is higher than the combination of anions (Cl and bicarbonate) (it is balanced out by negatively charged proteins in plasma); if the gap becomes to big, a patient has acidosis

Question 20

What is the largest glucose gradient that can be generated by secondary active transport via sodium electrochemical gradient with a stoichiometry of 1:1 or 1:2? How about calcium with 1:3 stoichiometry? What is the equation?

Answer 20

1:1 = 100; 1:2 = 10000; 1:3 = 10000 glu or calcium = (Na inside/Na outside) to the nth power x 10 to power of -Vm/60 (with glucose no charge, 2 sodiums makes - Vm/60 equate to 2; with 3 sodiums 1 calcium charges equate to 10 to the 1st power)

Question 21

When the net driving force is negative, cations will do what?

Answer 21

Move into cell (anions will do the opposite); current is the flow of positive charge

Question 22

Can ATPase function be reversed?

Answer 22

Yes

Question 23

hyperosmotic molecules v. hypertonic molecules

Answer 23

hyperosmotic solutions would diffuse across membrane without changing water flow; hypertonic solutions cause water to move towards the hypertonic solution

Question 24

Explain what happens when isotonic saline (saline and water), free water, or saline are added to ECF

Answer 24

Isotonic saline only increases ECF without adding an volume to ICF; free water dilutes the ECF causing water to move into cells and the osmolality of both compartments is lowered; adding saline will cause water to move out of cells increasing the osmolality of both compartments

Question 25

Explain what happens when urea is added to ECF

Answer 25

urea can cross the bilayer (lipophilic), then water will initially move out of cell; eventually urea will diffuse into the cell accompanied by water returning the cell to normal osmolality

Question 26

Relate the electrical description of a membrane (conductance, capacitance, batteries) to the underlying physical basis (ion channels, lipid bilayer, and ion gradients).

Answer 26

Lipid bilayer = capicitance; ion gradient = battery; ion channel = conductance

Question 27

Explain in words how ion channels, the bilayer, and ion gradients produce a voltage (the membrane potential) across the plasma membrane

Answer 27

The membrane potential can change with time primarily because of changes in the number and types of ions channels open (conductance of the circuit); Voltage of membrane = (conductance or chance a receptor is open to current) x reversal potential or Nernst potential of that ion (for all ions permeant to the membrane)

Question 28

Know (within a factor of 2-3) the normal ion concentrations (K+, Na+, Ca2+, and Cl-) inside and outside a skeletal muscle cell.

Answer 28

K inside: 155 mM (outside: 4.5 mM); Nai- 12 mM (145 mM outside); Ca: 10-4 mM inside (1 mM outside); Cl: 4.2 mM inside (116 mM outside)

Question 29

Explain the role of the Na+-K+ ATPase in setting the membrane potential. Compare that to the role of ion channels.

Answer 29

Immediate energy source of the membrane potential is not the active pumping of ions but rather the potential energy stored in the ion concentration gradients themselves. Of course, it is the ion pumps—and the secondary active transporters that derive their energy from these pumps—that are responsible for generating and maintaining these ion gradients (leaky channels?)

Question 30

Given conductance, how can you calculate the current going through a channel

Answer 30

I = conductance (G) x driving force of the ion; conductance does not change with voltage (V = I/G); total current equals n (# of channels open) x p (probability a channel is open) x i (current through a single channel)

Question 31

What is the difference between a voltage clamp and a patch clamp?

Answer 31

Voltage clamp is macroscopic (surveying the entire cell); patch clamp may be 2-3 channels at most

Question 32

For small depolarizations to voltages negative to threshold, an axon does not generate an action potential. Why?

Answer 32

the inward sodium current is smaller than the outward potassium current (in this situation the cell is not receiving enough current to create a positive feedback between opening of sodium channels and the flow of sodium channels into the cell causing further depolarization and open of more sodium channels)

Question 33

What is the effect of tetrodotoxin? What is the effect of TEA?

Answer 33

Blocks the outer entrance of sodium channels (at nanomolar concentrations); blocks outer entrance to potassium channels (at millimolar concentrations) (some channels are resistant to these drugs)

Question 34

During a 10 ms depolarization, potassium channels open and remain open, while sodium channels open and then inactivate. Why?

Answer 34

Potassium channels deactivate very slowly (an action potential may last 1-2 msec while these channels close at time scale of seconds); (sodium channels activate transiently upon depolarization (activate and then deactivate within ms into inactivated state; sodium channels return to activated state upon hyperpolarization (relative refractory period)).

Question 35

Explain the Hodgkin-Huxley model.

Answer 35

Potassium has four activation gates (eqaul, but independent) (a potassium channel is open if all 4 n gates are open (equation= n4)); sodium channel has 3 activation gates and one inactivation gate (a sodium channel is open if all 3 activation gates are open and 1 inactivation gate is open (equation= m3h); deactivation closes with depolarization; M gates have fast response to depolarization; n & h gates, slow

Question 36

What does it mean for a channel to be “voltage dependent”?

Answer 36

The probability that the channel is open depends on voltage.

Question 37

Explain how changes in membrane potential can cause a voltage-dependent channel to open, in terms of the effect of voltage on the rate constants for opening and closing.

Answer 37

Conformation changes change the energetic kinetics of a cell thus making it more favorable to open or close (in the case of Hodgkin Huxley model, the inactivation gate suggests that a channel can inactivate without opening)

Question 38

What does positive current mean?

Answer 38

current moving out of the cell

Question 39

When do h gate return to pre-action potential resting level?

Answer 39

at the end of repolarization