Physiology 5th Ed.

Frequently Asked Questions

The answers to frequently asked questions have been provided by the author, Professor Linda Costanzo. If you have a question that is not answered below then please email Dr. Costanzo atlcostanz@vcu.edu.

Cellular and Autonomic Physiology

What are the conventions for membrane potentials, currents, and the like?

What is a reversal potential?

What does Na+-K+ pump have to do with the resting membrane potential?

Why is Cl- said to be moving “uphill” on the Na+-K+-2Cl- cotransporter?

Why do we urinate/defecate in fight or flight?

Cardiovascular Physiology

Is the dihydropyridine (DHP) receptor an L-type Ca2+ channel?

RAP = EDV?

On ventricular pressure-volume loops, why doesn’t Point 2 go higher?

Why does increased preload or contractility shift the cardiac force-velocity curve upward?

What is transmural pressure?

Do cardiac output and venous return depend on RAP, or vice versa?

Why does the vascular function curve go in the opposite direction from the cardiac function curve?

In heterometric (Frank-Starling) compensation for decreased contractility, why is preload increased?

What is the effect of changes in TPR on RAP?

In capillaries, why do we use only protein osmotic pressure?

What’s the difference between automaticity and excitability?

Why does the vascular function curve have a negative slope?

What is the function of cardiopulmonary receptors vs. carotid sinus baroreceptors?

Why does the Valsalva maneuver decrease Pa?

In exercise, why is diastolic pressure decreased (or unchanged)?

In right heart failure, why does left heart cardiac output (CO) decrease?

Respiratory Physiology

Why does the chest wall want to “spring out”?

Can CO become perfusion limited?

Why is there hysteresis on the lung compliance curve?

What does pulse oximetry measure?

How do O2 and CO2 affect each other’s binding to hemoglobin?

Why is vital capacity decreased in both obstructive and restrictive disease?

Why does PO2 change much more than PCO2 (between mixed venous and systemic arterial blood)?

Why does decreased hemoglobin concentration (anemia) −› decreased DLCO?

Renal and Acid-Base Physiology

Why is there no hematocrit change in hyposmotic expansion and hyperosmotic contraction?

What’s the difference between secretion and excretion?

What’s the difference between RBF and RPF?

What are the units of clearance vs. reabsorption/secretion/excretion?

What’s the difference between clearance and excretion?

Why does clearance of PAH = RPF, but clearance of inulin = GFR?

What’s the difference between threshold and Tm?

Why does [TF/P]x/[TF/P]inulin = % of filtered x remaining in nephron?

How can I make sense of these TF/P ratios?

What is the role of brain osmolytes in disturbances of body fluid osmolarity?

Hyperventilation is a cause of respiratory alkalosis and a compensation for metabolic acidosis?

What’s the difference between compensation and correction of acid-base disorders?

What’s the difference between H excretion and urine pH?

Endocrine and Reproductive Physiology

Why does hypocalcemia cause muscle spasms?

Why are there urinary Ca2+ stones in primary hyperparathyroidism?

What is the effect of licorice on Type I mineralocorticoid receptors?

What is the dexamethasone suppression test?

Why are the diabetogenic hormones secreted in untreated diabetes mellitus?

Why is there no ketoacidosis in Type II diabetes mellitus?

Why is there muscle weakness in adrenocortical insufficiency?

What’s the difference between a primary and secondary endocrine disorder?

What’s the difference between hyperthyroid, hypothyroid, and euthyroid goiter?

FAQ Answers

Cellular and Autonomic Physiology

FAQ: What are the conventions for membrane potentials, currents, and the like?

Here are a few basic definitions and conventions that you may have forgotten or may never have known. Life will be vastly better once you get the terms down.

1.          Membrane potentials (Vm) are always expressed as intracellular relative to extracellular potential. Thus, if we say a membrane potential is −70 mV, that means inside negative. At rest, all excitable cells have negative Vm.

2.          Equilibrium potentials, calculated with the Nernst equation for a given ion, are always expressed as intracellular relative to extracellular. If we say an ion’s equilibrium potential is −90 mV, that means inside negative.

3.          Current flow (or current) in physiology is carried by ions. So, when your professor talks about physiologic experiments in which current is measured, that means flow of ions (e.g., Na+, K+, Cl-).

4.          Depolarization means the membrane potential becomes less negative, or positive.

5.          Hyperpolarization means the membrane potential becomes more negative.

6.          Repolarization means membrane potential is returning to its resting level, which for excitable cells means it is becoming more inside negative.

7.          Conductance = g = 1/resistance, or 1/R. To use conductance instead of resistance in Ohm’s law: V = I R make the substitution of g = 1/R V = I/g

FAQ: What is a reversal potential?

We calculate the equilibrium potential for an ion at a given concentration difference with the Nernst equation. The equilibrium potential says what potential difference would put the ion at electrochemical equilibrium at that concentration difference.

Reversal potential is measured in a voltage clamp experiment. In the experiment, there is a pre-set concentration difference across the membrane for the ion. Then, voltage (potential difference) across the membrane is held, or “clamped,” at a series of values. At each clamped voltage, current is measured (both direction and quantity of current flow). Let’s say, for illustration, that the membrane being clamped is highly permeable to K+ and no other ion. At each clamped voltage, therefore, the current measured is a K+ current. (Since no other ion is permeant, K+ is the only ion that can carry charge across the membrane.) The direction and magnitude of the current flow (measured in the experiment) depends on the electrochemical gradient for K+ across the membrane. When the clamped voltage is exactly equal to the K+ equilibrium potential, the direction of current flow “reverses” (e.g., from out to in) and, at that potential, there is zero current flow. (Perhaps a better name for reversal potential would be “zero current flow potential.”) In the previous scenario, the reversal potential = the potential at which there is no K+ current because K+ is perfectly happy = K+ equilibrium potential.

By comparing measured reversal potential for a membrane with calculated equilibrium potentials for various ions, we can determine which ions are permeable. If the measured reversal potential exactly equals the calculated K+equilibrium potential, the membrane is said to be K+-selective.

FAQ: What does Na+-K+ pump have to do with the resting membrane potential?

You may have been taught previously, or somehow arrived at the misimpression, that the Na+-K+ pump is responsible for the resting membrane potential or even the action potential. It’s not.

The Na+-K+ pump has little to do directly with membrane potential (either resting potential or action potential). Sure, the stoichiometry is 3 Na+ pumped out for 2 K+ pumped in (i.e., the pump is electrogenic), which makes the membrane potential inside negative. However, this electrogenic contribution to total resting membrane potential is small. The major role of the Na+-K+ pump in membrane potentials isindirect. It is responsible for establishing and maintaining the K+ and Na+ concentration gradients across the cell membrane that establish the diffusion potentials that determine membrane potential.

For example, resting membrane potential is determined primarily by K+. At rest, K+ conductance or permeability is high. K+ starts to diffuse from intracellular fluid (ICF) to extracellular fluid (ECF) down its concentration gradient (established by the pump), carrying a little positive charge across the membrane. At the membrane, inside the cell becomes negative, and outside the cell becomes positive (e.g., nerve resting potential is approximately −60 mV, inside negative). The Na+-K+ pump’s role is to establish the K+ concentration gradient that is responsible for the K+ diffusion potential that is responsible for the resting membrane potential. What little K+ diffuses out is pumped back into the cell via continued action of the Na+-K+ pump, maintaining the K+ concentration gradient.

We can apply similar thinking to the upstroke of action potential. Na+ channels open and Na+ conductance becomes briefly higher than K+ conductance. Now Na+ diffuses down its concentration gradient (outside to inside) that was established by the Na+-K+ pump. At the peak of the upstroke, membrane potential becomes inside positive due to this inward diffusion of a few Na+. What little Na+ diffuses in during the upstroke is pumped out by the Na+-K+pump to maintain the Na+ concentration gradient. The Na+-K+ pump’s role is to establish and maintain the Na+ concentration gradient that is responsible for the upstroke.

FAQ: Why is Cl- said to be moving “uphill” on the Na+-K+-2Cl- cotransporter?

This can be puzzling at first. The Cl- concentration is higher in ECF than ICF, so it seems that Cl- would be moving downhill (from ECF to ICF) on the Na+-K+-2Cl- cotransporter.

Cl- is moving down its concentration gradient, but when we deal with ions, we also must consider the electrical (potential) gradient in addition to the concentration gradient. Cells have an inside negative membrane potential. So, when Cl- moves into the cell on the Na+-K+-2Cl- cotransporter, it is moving down its concentration gradient, but against its electrical gradient. The chemical gradient for Cl- is usually a little less than the electrical gradient, so, overall, Cl- is moving uphill.

When dealing with ions, we always consider the electrochemical driving force on the ion (not just the chemical driving force) to determine whether it is moving uphill or downhill.

FAQ: Why do we urinate/defecate in fight or flight?

In case you’ve been wondering...,

Extreme fear massively activates the sympathetic nervous system, including the adrenal medulla. The effect of sympathetic activation is to relax the gut or bladder wall (Beta2 receptors), to constrict the sphincters (alpha1 receptors), and, overall, to decrease gut and bladder motility. Logically, this decreased motility allows the frightened person to put energy and attention elsewhere (e.g., running away).

However, from experience, we know that the first response to extreme stress may be defecation and/or urination, which is the opposite of the sympathetic effects you learned. So, what’s going on?

The reason for the initial defecation or urination is a fast, initial central nervous system (CNS) activation of the parasympathetics, targeted to gut and bladder as a prelude to fight or flight. The excitatory action of the parasympathetic nervous system in these tissues causes increased motility of gut and bladder wall and relaxation of sphincters-> defecation and urination. Then follows the classic sympathetic response of decreased motility.

It makes sense: The body first empties the gut and bladder and then stops them.

Cardiovascular Physiology

FAQ: Is the dihydropyridine (DHP) receptor an L-type Ca2+ channel?

Yes, but it doesn’t always function that way. Here are the basics of DHP receptors in skeletal and cardiac muscle. They function differently.

1.          DHP is a drug that binds dihydropyridine receptors.

2.          DHP receptor is one type of Ca2+ channel, the L-type Ca2+ channel (“L” stands for long-lasting).

3.          Skeletal muscle

o     DHP receptors are located on T tubules and function as voltage sensors.

o     Depolarization from action potential spreads to T tubules, causing a conformational change in DHP receptors.

o     A DHP receptor then communicates with the nearby sarcoplasmic reticulum (SR), causing release of Ca2+ through the SR Ca2+ channels (ryanodine receptors).

o     Technically, the DHP receptor is a Ca2+ channel.However, in skeletal muscle, it does not function as a Ca2+ channel (i.e., Ca2+ is not flowing through it as in cardiac muscle). The function in excitation-contraction coupling in skeletal muscle is as voltage sensor to tell the SR, “We’ve got an action potential; release Ca2+ for contraction.”

4.          Cardiac muscle

o     DHP receptors are located on sarcolemmal membrane (and T tubules).

o     DHP receptors do act as Ca2+ channels = L-type Ca2+ channels.

o     Open in response to depolarization −› responsible for plateau of action potential.

o     When open, Ca2+ enters the cardiac cell, which is called the trigger Ca2+.

o     Trigger Ca2+ causes release of more Ca2+ from the SR, or Ca2+-induced Ca2+ release.

o     Thus, in cardiac muscle, the DHP receptor functions as a Ca2+ channel −› Ca2+ enters the cell −› Ca2+-induced Ca2+ release = excitation-contraction coupling.

FAQ: RAP = EDV?

We use right atrial pressure (RAP) and left ventricular end-diastolic volume (EDV) interchangeably to represent preload. You may be confused as to how they can possibly be interchangeable. After all, pressure is not volume, atrium is not ventricle, and right is not left.

True, true, true. However, pressure is related to volume, and RAP is related to EDV. Blood flows from atrium to ventricle due to a pressure gradient. Right and left hearts are connected in series and must have equal venous returns and cardiac outputs in the steady state. So, RAP is correlated with left ventricular EDV by the following sequence:

1.          Venous return from the systemic circulation fills the right atrium. Central venous pressure is called “filling pressure” of the heart because it’s the pressure driving the venous return; RAP is only slightly less than central venous pressure, so it is also called “filling pressure” of the heart. Clinically, central venous pressure is measured as a close approximation of RAP.

2.          Blood flows from the right atrium to the right ventricle, driven by the small pressure difference between atrium and ventricle. The right ventricle fills to right end-diastolic volume.

3.          Therefore, end-diastolic volume of the right ventricle correlates with venous return to the right atrium and with RAP per previous explanation.

4.          Cardiac output of the right ventricle (to the lungs) correlates with right ventricular EDV (its preload) because of the Frank-Starling relationship as follows: Increased EDV −› increased overlap of thick and thin filaments −› increased cross-bridges −› increased tension −› increased stroke volume (SV) and cardiac output.

5.          Venous return from the lungs fills the left atrium, which then fills the left ventricle. All flows are equal on left and right in steady state. Thus, left ventricular EDV becomes the preload of the left ventricle, and it is correlated all the way back to RAP because of the series arrangement.

FAQ: On ventricular pressure-volume loops, why doesn’t Point 2 go higher?

Regarding the basic (control) ventricular pressure-volume loop, why doesn’t Point 2 go all the way up the systolic pressure volume curve? (It stops and makes a left, heading over to Point 3 for ejection, before it reaches the systolic pressure curve.)

You may have this question because you learned that the systolic pressure curve gives the maximum pressure that can be developed for a given end-diastolic volume (at a given contractility). So, if the ventricle can develop that pressure at that volume, why doesn’t it?

Point 2 on the control loop doesn’t go all the way up to the systolic pressure curve because it doesn’t have to! The ventricle begins contraction at Point 1. It develops pressure isovolumetrically (all valves closed) until it reaches aortic pressure at Point 2 (i.e., when it has matched the afterload, or aortic pressure). How far Point 2 goes is, therefore, determined by aortic pressure. The aortic valve opens, and the rest of the contraction is used for shortening—i.e., ejection of stroke volume through the open aortic valve (Point 2 −› Point 3).

A related point concerns the effect of increased afterload on the loop. If aortic pressure increases, the ventricle must develop more isovolumetric pressure to match the afterload and open the aortic valve: Point 2 must move up toward the systolic curve before shortening can begin. This will work as long as aortic pressure is less than the maximal systolic pressure for that volume (i.e., the ventricle can do it, although subsequent shortening will be reduced and, accordingly, stroke volume will be reduced).

Talking yourself around these loops is the best way to understand them!

FAQ: Why does increased preload or contractility shift the cardiac force-velocity curve upward?

The force-velocity curve for cardiac muscle says that initial velocity of shortening is highest at zero afterload (i.e., lift that feather super fast). As afterload increases, velocity decreases; at maximum afterload, velocity is zero (no shortening = isometric). By the way, initial velocity of shortening is analogous to initial velocity of ejection in cardiac muscle.

The force-velocity curve is shifted up and to the right by increased preload (length) and increased contractility. In other words, for a given afterload, initial velocity of shortening is higher with increased preload or contractility. Therefore, increased preload and increased contractility not only increase the volume of blood ejected (stroke volume) but also increase the speed at which blood is ejected. The FAQ addresses why this effect on velocity of ejection occurs.

Both increased preload and increased contractility increase the number of cross-bridges that cycle and the amount of ATP hydrolyzed. Increasing preload (length) increases the overlap of thick and thin filaments and the number of potential cross-bridges. Increased contractility increases the fraction of troponin C bound to Ca2+ and the fraction of potential cross-bridges that actually cycle. The more cross-bridges cycling −› the more shortening and faster shortening, which means faster ejection.

FAQ: What is transmural pressure?

The concept of transmural pressure is a recurring theme in physiology.

Rule: Transmural pressure across a structure = inside pressure − outside pressure (e.g., across large veins feeding the right atrium). If transmural pressure is positive, the structure is open; if transmural pressure is negative, the structure collapses. It’s the combination of inside and outside pressures (i.e., transmural pressure) that decides whether structures like veins or small airways are open.

Let’s play the transmural pressure game. Sorry that I can’t draw circles here, but you’ll get the idea. These are made-up numbers to illustrate various combinations of inside and outside pressure:

1.          Inside = 0, outside = −4, transmural = +4 = open (i.e., negative pressure outside holds a structure open)

2.          Inside = −2, outside = −4, trans = +2 = open (i.e., more negative outside than inside holds a structure open)

3.          Inside = +2, outside = +10, trans = −8 = closed (positive pressure outside can close a structure)

4.          Inside = −4, outside = −2 = closed (negative pressure inside can close a structure)

FAQ: Do cardiac output and venous return depend on RAP, or vice versa?

Do cardiac output (CO) and venous return (VR) depend on RAP, or does RAP depend on cardiac output and venous return? (Does it seem like each time you think you’re “getting it,” you hear something that seems opposite to your understanding?)

Cardiac output and venous return both depend on RAP; the relationships are shown, respectively, in the cardiac and vascular function curves. And RAP depends on cardiac output and venous return. In the closed CV system, there is no fixed dependent and independent variable. In the steady state, CO must equal VR, and the value of RAP at which that equality occurs (intersection of cardiac and vascular function curves) is the operating point of the system. There can be only small, transient inequality of CO and VR because the transient inequality produces a change in RAP that equalizes them again.

It’s all about getting cause and effect straight! Start at the beginning, and reason from there. If you’re told, “An increase in contractility occurs,” then that’s the beginning; reason step by step from there. If you’re told, “Blood loss occurs,” then that’s the beginning, and you reason step by step from there.

Here are a few examples that don’t require you to use the cardiac and vascular curves (although the curves give the same answers for new steady state). The first thing listed is the initiating event.

1.          Increased contractility −› increased SV and CO −› decreased RAP (more blood pumped out of the heart) −› increased VR (pressure gradient back to the heart is increased). New steady state: CO = VR, and higher than before.

2.          Increased blood volume −› increased VR −› increased RAP (more blood back to the heart) −› increased CO (Frank-Starling). New steady state: CO = VR, and higher than before.

3.          Venoconstriction −› increased VR (because the veins can hold less blood, called decreased unstressed volume) −› increased RAP (more blood back to the heart) −>increased CO (Frank-Starling). New steady state: CO = VR, and higher than before.

4.          Increased total peripheral resistance (TPR) −› two effects: (a) Increased afterload −› decreased CO −› increased RAP (more blood left in the heart). (b) Decreased VR (blood is “held” in the arteries, not allowed back to the heart) −› decreased RAP. Thus, the two effects on RAP approximately cancel, and RAP will be either slightly increased, slightly decreased, or unchanged. You would not be expected to predict RAP in this scenario, but do you see how the cause/effect works? New steady state: CO = VR, lower than before.

5.          Decreased contractility −› decreased SV and CO −› increased RAP (more blood left in the heart) −› decreased VR (decreased pressure gradient for blood flow back to the heart). New steady state: CO = VR, and lower than before.

FAQ: Why does the vascular function curve go in the opposite direction from the cardiac function curve?

The vascular function curve is determined experimentally as follows: The heart is stopped. Pressure everywhere in the system becomes the same = Pms = approximately 7 mm Hg. There is no flow because there’s no pressure difference anywhere. Then a pump is started up, which pumps blood out of the heart (simulating cardiac output). The pump is set at different rates. At each higher rate, RAP gets lower and lower. (Think about pulling blood out of the heart.) At each pump rate, cardiac output (which is equal to venous return) and RAP are measured. The higher the pump rate, the higher the CO and VR, the lower the RAP.

From this data, the vascular function curve is plotted, with CO/VR on y-axis and RAP on x-axis. Remember, the higher the CO/VR, the lower the RAP per the previous explanation. Why does venous return increase when RAP decreases? It does so because the lower the RAP, the bigger the pressure gradient between the systemic blood vessels and the right atrium.

Now, to the question! Cardiac and vascular function curves have an opposite relationship to RAP. In constructing the cardiac function curve, RAP is increased (from a reservoir). As RAP increases, CO increases (until CO levels off). But on the vascular function curve (see the previous explanation), as RAP increases, venous return decreases. How can this be true if CO and VR are always equal? This was the brilliance of Dr. Author Guyton. He plotted the two curves simultaneously, both as a function of RAP. Where they intersect, at that one value of RAP, they are equal, and that is the operating point of the CV system. That’s the RAP that satisfies both CO and VR relationships.

FAQ: In heterometric (Frank-Starling) compensation for decreased contractility, why is preload increased?

We can write the events in the order they occur:

1.          Decreased contractility = initial event

2.          Decreased stroke volume

3.          Less blood ejected, so more blood remains “behind” in the heart

4.          Increased EDV and RAP = increased preload

5.          Increased EDV (preload) −› increased stroke volume toward normal via the Frank-Starling mechanism. This is the compensation for the original decrease in stroke volume.

The initial decrease in stroke volume is compensated by increasing the length of the ventricular fibers for the next beat, thus the name heterometric compensation (literally, a compensation involving a change in length).

FAQ: What is the effect of changes in TPR on RAP?

Consider the effects of TPR on the vascular and cardiac function curves using the example of increased TPR:

1.          The vascular function curve rotates counterclockwise (arteriolar constriction means that less blood leaves the arteries −› decreased venous return).

2.          The cardiac function curve shifts downward (increased TPR “holds” blood in the arteries −› increased arterial pressure = increased afterload −› decreased cardiac output).

With increased TPR, venous return and cardiac output are always decreased.

The issue is this: What happens to RAP? The effect on cardiac function tends to increase RAP (blood left behind in the heart), but the effect on arterioles tends to decrease RAP (less blood returned to heart). Depending on the relative effects of increased TPR on the vascular and cardiac function curves, RAP can slightly increase, slightly decrease, or remain unchanged. That is, it is not predictable.

FAQ: In capillaries, why do we use only protein osmotic pressure?

When we talk about capillary Starling forces, we consider only the osmotic pressure due to protein (oncotic, or colloidosmotic, pressure). Sometimes students wonder: What happened to the other solutes in plasma and interstitial fluid? Don’t they contribute to the osmotic pressure? Why are we ignoring them?

Of course, the total osmotic pressure of plasma and interstitial fluid reflects the total concentration of solute particles (Na+, Cl-, K+, glucose, amino acids, protein). However, protein is the only solute with a significantly different concentration between plasma and interstitial fluid. (The other solutes have close to the same concentration in plasma and interstitial; the reflection coefficient for small solutes across capillary wall is zero.) Thus, protein is the only solute with a reflection coefficient of 1 across the capillary wall, the only solute that creates an effective osmotic pressure difference across the capillary wall, and the only solute that makes a difference Starling-wise.

FAQ: What’s the difference between automaticity and excitability?

It is important to separate these two concepts correctly in your mind!

Automaticity describes whether a myocardial cell can initiate its own action potential = ability to depolarize spontaneously = exhibits phase 4 (diastolic) depolarization. Automaticity is exhibited in the SA node, AV node, and His-purkinje system.

Excitability describes how easily a myocardial cell fires an action potential in response to inward, depolarizing current (e.g., current spread from a neighboring site that has fired an action potential). Excitability is described by the refractory periods! Always equate excitability with the concept of refractory periods and you will be in the right mindset! Let’s apply this to ventricle, where Na+ channels are used for upstroke. (For the SA node, we would talk about Ca2+ channels for upstroke.) In the absolute refractory period, Na+ channels are inactivated; no amount of stimulus can get the upstroke (and action potential) going. In the relative refractory period, the cell has started to repolarize, and Na+ channels are becoming available; if you give a larger-than-normal stimulus, you can get an upstroke. The effective refractory period is the first part of the relative refractory, where a larger stimulus can cause an action potential, but it is not sufficient to spread (be conducted) to next site (“effectively” useless).

FAQ: Why does the vascular function curve have a negative slope?

Intuitively, how does it make sense that the vascular function curve has a negative slope (i.e., venous return decreases as RAP increases)?

This is very important to clarify/visualize. What drives venous return? A pressure difference drives it (i.e., the pressure difference between the veins and the right atrium). Even though venous pressure is only slightly higher than right atrial pressure, there must be some pressure difference to drive blood flow back to the heart. The lower the RAP, the bigger the pressure difference driving venous return to the heart −› increased venous return; the higher the RAP, the smaller the pressure difference driving venous return −› decreased venous return.

FAQ: What is the function of cardiopulmonary receptors vs. carotid sinus baroreceptors?

Confusion arises because increased volume activates cardiopulmonary receptors, which then leads to tachycardia (increased heart rate). For example, in the Bainbridge reflex, increased venous blood volume −› increased heart rate. It seems opposite to what we would expect for the carotid sinus baroreceptors. Here’s the story:

The carotid sinus baroreceptors are on the arterial side; they detect changes in arterial pressure, and try to correct it.

The cardiopulmonary receptors (“low pressure” receptors) are on the venous side and detect changes in blood volume. The characteristics of cardiopulmonary receptors are as follows:

1.          They sense increased blood volume, which, logically, is detected in veins, not arteries (since that’s where most blood volume is).

2.          They work to get rid of volume (Na+ and water) by increasing urinary excretion.

3.          They do not regulate arterial pressure. They do not directly conflict with baroreceptor reflex (see the final comment).

4.          Actions of cardiopulmonary receptors, in response to increased volume are a. Increased heart rate, which is the odd thing. Increased vol −› afferent information from veins and atria −› nucleus tractus solitarius (NTS). Efferent information from NTS −› inhibits medullary vagal (cardioinhibitory) nucleus −› decreased parasympathetic to the SA node −› increased heart rate. b. Decreased sympathetic vasoconstriction in renal arterioles = renal vasodilation c. Combination of increased heart rate + renal vasodilation −› increased filtered Na+ and water −› increased Na+ and water excretion d. Increased ANF (ANP) −› renal vasodilation and decreased Na+ reabsorption −› increased Na+ and water excretion.

The increased heart rate seems flat-out wrong because we usually think: Increased venous volume −› increased venous return −› increased CO −› increased Pa, which should cause a reflex decrease in heart rate via carotid sinus baroreceptors. Yes, that’s a very important scenario. In that scenario, there would be a decreased heart rate, because the baroreceptor reflex, which regulates Pa, is more important and wins. However, pathophysiologically, there are situations with increased venous volume but normal or even decreased Pa (e.g., some etiologies of heart failure). The venous pressure receptors are designed to protect us in those situations by dumping Na+ and water in the urine.

Bottom line: If arterial carotid sinus baroreceptors and venous cardiopulmonary receptors disagree on what should happen to the heart rate, arterial baroreceptors win.

FAQ: Why does the Valsalva maneuver decrease Pa?

The Valsalva maneuver is forced expiration against closed glottis, which causes thoracic pressure to become positive.

1.          The veins that feed the right atrium, being thin-walled structures, are compressed or closed by this positive outside pressure −› decreased venous return to the right atrium −› decreased preload −› decreased cardiac output −› decreased Pa..

2.          The decrease in Pa is sensed by the carotid sinus baroreceptors, which then direct a decrease in parasympathetic output to the heart and an increase in sympathetic output to the heart and blood vessels. The most obvious effect of the decreased parasympathetic/increased sympathetic effects is an increase in heart rate. So, the valsalva can be used to test the integrity or sensitivity of the baroreceptor mechanism. That is, if the baroreceptor reflex is working, HR should increase appropriately during the valsalva.

3.          When the valsalva is stopped, there is a surge in venous return to the right atrium (pressure having built up behind the previously collapsed veins). There is increased venous return to the right atrium −› increased preload −› increased CO −› increased Pa −› inhibits baroreceptors −› increased parasympathetic/decreased sympathetic −› decreased HR.

FAQ: In exercise, why is diastolic pressure decreased (or unchanged)?

During exercise, diastolic pressure is decreased or is unchanged. Yet systolic pressure and pulse pressure are increased. Why doesn’t diastolic pressure increase?

The reason for decreased diastolic pressure is the decrease in TPR due to vasodilation in skeletal muscle (local metabolites −› active hyperemia). These local effects override sympathetic vasoconstrictor effects on skeletal muscle via alpha1 receptors. Because skeletal muscle mass is great, its arteriolar resistance makes a large contribution to TPR.

What about pulse pressure and systolic pressure? There is increased pulse pressure due to increased stroke volume (sympathetic Beta1). Because of the increased pulse pressure, systolic pressure increases.

What about mean arterial pressure (calculated as diastolic + 1/3 pulse)? Thanks to the decrease in diastolic pressure, it usually increases only slightly. Without the decrease in diastolic pressure, mean pressure would increase greatly, which would increase afterload on the left ventricle, which would decrease stroke volume. Think about it: In exercise, we need to pump more blood per time around the circuit. An increase in afterload on the left ventricle would work against that!) Consider the decrease in TPR as “permitting” the increase in cardiac output to occur.

Final, related thought: Dilation of skeletal muscle arterioles by local metabolites accomplishes two goals: It increases blood flow to the exercising muscle, and it decreases TPR and diastolic pressure to keep mean arterial pressure (afterload) from increasing as stroke volume and cardiac output increase.

FAQ: In right heart failure, why does left heart cardiac output (CO) decrease?

The issue is this: In the steady state, cardiac output of the right and left hearts must be equal. If the right heart CO decreases, then the left heart CO must also decrease. How does this happen? It may help to have the CV circuitry picture in front of you.

Right heart (where things started):

1.          Decreased CO of the right ventricle −› decreased blood flow to the pulmonary artery

2.          Blood “backs up” in and behind right heart

3.          Increased right atrial pressure

4.          Increased systemic venous volume and central venous pressure

Left heart (needs to decrease its CO to match right heart CO):

1.          Decreased blood flow (CO) in the pulmonary artery (see above)

2.          Decreased blood flow in the pulmonary vein = decreased venous return to the left heart

3.          Decreased left atrial pressure (preload)

4.          Decreased CO of the left ventricle (Frank-Starling mechanism) to match decreased CO of the right ventricle

Respiratory Physiology

FAQ: Why does the chest wall want to “spring out”?

This is sometimes hard to visualize. Think of the chest wall as analogous to a spring that you “contain,” or compress, between your fingers. The real chest wall is “contained” by our negative intrapleural pressure rather than by the force of your fingers. If you release the spring (or eliminate the negative intrapleural pressure), it springs out (i.e., expands). The analogy is imperfect, but it provides something more intuitive to visualize.

At equilibrium (FRC), the expanding force on the chest wall (how much it wants to spring out) = the collapsing force on the lungs (how much it wants to collapse).

When you inspire, the volume of the chest wall increases. The enlarged chest pulls more against the intrapleural space, making intrapleural pressure more negative, which increases the volume of the lungs (more negative pressure outside the lungs inflates them more). At the peak of inspiration, the combined system is not at equilibrium—the expanding force on the chest wall has decreased (the spring is less compressed), and the collapsing force on the lungs has increased (they have more volume in them); the two forces are not equal and opposite. The combined lung/chest system wants to collapse back to equilibrium where they will be equal and opposite (i.e., back to FRC).

FAQ: Can CO become perfusion limited?

If you wondered about this . . .

We consider CO a diffusion-limited gas as long as there are available binding sites on hemoglobin. In using CO to illustrate diffusion-limited exchange, we are assuming that there are plenty of binding sites on hemoglobin.

However, if all hemoglobin sites are occupied, then additional transfer of CO from alveolar gas to pulmonary capillary blood would raise the dissolved CO, raise the PCO, and eventually PaCO = PACO, which means perfusion limited.

Usually, for exam purposes, CO is considered to be diffusion limited.

FAQ: Why is there hysteresis on the lung compliance curve?

Regarding the lung compliance curve on an air-filled lung, the expiration curve is higher (steeper) than the inspiration curve. The difference in the curves is called hysteresis. Lung compliance, the slope, is higher during expiration than inspiration. Why? It’s the same lung, and compliance is an intrinsic property that depends on the amount of elastic tissue. Yes, that’s true, but surface tension also contributes to the inspiration curve (in addition to the role of the intrinsic compliance of the lung).

In the air-filled lung, there are different lung compliance curves, depending on whether we start from a deflated lung (inspiration curve) or from an inflated lung (expiration curve). However, if the inflation/deflation is done on a saline-filled lung, inspiration and expiration follow the same curve (no hysteresis); there is no hysteresis because there is no surface tension at the liquid-liquid interface. So, hysteresis is explained by surface tension at the air-liquid interface, which is further explained as follows:

Surface tension alters the inspiration limb on the air-filled lung. The starting point for the inspiration curve is low lung volume (low alveolar radius). Remember the strong intermolecular forces between liquid molecules that line alveoli that produce surface tension. When the alveolar radius is small (low long volume), it takes a lot of pressure to open the alveoli (Law of Laplace). Consequently, because of intermolecular forces between liquid molecules at the air-liquid interface, it is harder to inflate the lung than is expected based on the lung’s compliance alone, and the curve is flatter than expected. The expiration limb is determined by lung compliance only; starting at high volumes, there are no intermolecular forces to overcome as we deflate the lung. This is also why we consider the expiration limb to be the “true” lung compliance—it is not complicated by surface tension forces.

FAQ: What does pulse oximetry measure?

A pulse oximeter is a dual wavelength spectrophotometer. It measures absorbance at two wavelengths. Oxyhemoglobin and deoxyhemoglobin have different absorbances.

The machine calculates % O2 saturation (oxyhemoglobin) in arterial blood of the finger. The reason it detects arterial % O2 saturation is the “pulse” part. Background absorbances from venous and capillary blood are subtracted out (because they are steady [not pulsing] in the background). Arterial blood is “pulsing,” and the machine detects that previous background.

Note that pulse oximetry measures % O2 saturation of hemoglobin in arterial blood—it does not measure PO2. Knowing % saturation, we estimate PO2 from the O2-hemoglobin curve.

FAQ: How do O2 and CO2 affect each other’s binding to hemoglobin?

Both O2 and CO2 bind to hemoglobin. For O2, it’s a big deal: 98% of O2 is carried in blood bound to Hb. For CO2, a smaller component is bound to Hb.

Now to the point of the FAQ: O2 and CO2 bind at separate sites on hemoglobin, and the binding of each gas affects the affinity for the other in a way that makes sense.

1.          The binding of CO2 to hemoglobin reduces its affinity for O2. Thus, in the tissues, as CO2 is added to capillary blood and more CO2 is bound to hemoglobin, O2 is released more readily (right shift)—just when we need it! This is the Bohr effect.

2.          The release of O2 from hemoglobin increases its affinity for CO2. Again in the tissues, as O2 is being released from capillary blood to the tissues, CO2 binds to hemoglobin with higher affinity—just when we need it. This is the Haldane effect.

Once again, the body really knows what it’s doing!

FAQ: Why is vital capacity decreased in both obstructive and restrictive disease?

We learned an important distinguishing difference between obstructive and restrictive disease. FVC (vital capacity) decreases in both. However, in obstructive disease FEV1 decreases relatively more than FVC, while in restrictive disease FEV1 decreases relatively less than FVC. (This difference between the diseases is expressed in the ratio of FEV1/FVC: decreased in obstructive, increased in restrictive.)

We also learned the mechanism for the difference in FEV1/FVC. In obstructive disease, the problem is increased airway resistance, and expiration is the problem; since FEV1 describes the first second of forced expiration, and expiration is very sensitive to changes in airway resistance, it makes sense that FEV1/FVC would be decreased. In restrictive disease, elastic recoil of lungs is increased, expiration (which depends on elastic recoil) is relatively easy, and FEV1/FVC is increased.

This brings us to the FAQ: Why should vital capacity (FVC) be decreased in both diseases?

1.          Restrictive: Inspiration is the problem. The lungs are more elastic, less compliant, and all lung volumes, including vital capacity, are decreased because the person has trouble bringing air into the less compliant lungs.

2.          Obstructive: Expiration is the major problem. But why should impaired expiration cause a decrease in vital capacity? You must think sequentially here. Expiration is impaired, and air that should be expired (either in tidal breathing or in forced breathing) is not expired. This air remains in the lungs, increasing FRC and residual volume. The new equilibrium point for the lungs and chest wall occurs at higher FRC, and the person breathes at higher lung volumes. Now the higher FRC encroaches on the inspiratory lung volumes. Because the lungs are over-filled with air that should have been expired from previous breaths, there is less room for new, inspired air. Tidal volume, inspiratory reserve volume, inspiratory capacity, and vital capacity will all be decreased.

FAQ: Why does PO2 change much more than PCO2 (between mixed venous and systemic arterial blood)?

Issue: Why is the PO2 difference between systemic arterial (100 mm Hg) and mixed venous (40 mm Hg) so much greater than the PCO2 difference between systemic arterial (40 mm Hg) and mixed venous (46 mm Hg)?

Main points: (1) The O2 content of the blood depends on PO2 (via O2-Hb curve [i.e., % saturation]). (2) The CO2 content of blood depends on PCO2 (the CO2 content is mainly HCO3, which comes from CO2).

The body sets PO2 and PCO2 values for systemic arterial and mixed venous to give us the O2 and CO2 contents we need for metabolic demand of tissues. Here’s a summary of the systemic arterial and mixed venous content of O2 and CO2 (vol %) vs. PO2 and PCO2 (mm Hg).

O2 content

The O2 content is almost all O2-Hb.

Mixed venous = 15 vol % (PO2 = 40 mm Hg).

Systemic arterial = 20.4 vol % (PO2 = 100 mm Hg).

Mixed venous has approximately 5 vol % less than systemic arterial, which is the amount consumed by tissues.

Summary of O2: To decrease the O2 content by 5 vol % between systemic arterial and mixed venous requires a PO2 change from 100 mm Hg to 40 mm Hg −› % saturation on O2-Hb curve goes from 100% to 75%, which corresponds to 5 vol % in O2 content terms. This part of the O2-Hb curve is not very steep, so it requires a large change in PO2 to accomplish the required O2 content change.

CO2 content

The CO2 content is mostly HCO3-.

Mixed venous = 52 vol % (PCO2 = 46 mm Hg).

Systemic arterial = 48 vol % (PCO2 = 40 mm Hg).

Mixed venous has 4 vol % more CO2 than does systemic arterial, which was added by the tissues.

Summary of CO2. To increase the CO2 content of mixed venous by 4 vol % requires a very small change in PCO2 from 40 to 46 mm Hg. That’s because the CO2 content vs. PCO2 is steep and linear (whereas, the O2-Hb curve in the relevant range is not steep and not linear because of saturability).

Also note: 4 vol % CO2 added in tissues/5 vol % O2 consumed = 0.8 = 4/5 = 40/50 = R.Q. = R.

FAQ: Why does decreased hemoglobin concentration (anemia) −› decreased DLCO?

The answer is not physiology but how the DLCO measurement is made.

Decreased Hb concentration −› decreased DLCO, which produces the “huh?” Decreased Hb concentration doesn’t truly decrease DL—the true DL reflects the diffusion properties of the alveolar/pulmonary capillary barrier. However, what you should know is that Hb concentration alters measured DL in the single-breath CO method (the way we measure DL). The measurement involves disappearance of CO from alveolar gas, and part of that disappearance includes the binding of CO to Hb. Lower Hb concentration −› less of this binding component. It’s useful to know, because persons with decreased Hb (i.e., anemia) show a decrease in the measured DLCO that does not reflect a true change in permeability of the barrier.

Renal and Acid-Base Physiology

FAQ: Why is there no hematocrit change in hyposmotic expansion and hyperosmotic contraction?

Hematocrit (Hct) is the fractional volume occupied by red blood cells. In many situations, if ECF volume is increased (and, consequently, plasma volume is increased), Hct decreases (the same number of RBCs is “dissolved” in a larger plasma volume); for convenience, call that a decrease in RBC “concentration.” Conversely, in many situations, if ECF and plasma volume are decreased, Hct increases (the same number of RBCs is “dissolved” in a smaller plasma volume); for convenience call that an increase in RBC “concentration.”

With excessive water drinking or SIADH (hyposmotic expansion), it seems that Hct should decrease; as ECF and plasma volume increase, there would be dilution of RBC concentration. But we see that Hct is unchanged with gain of water. Why? This occurs because there’s a shift of water into cells (we always equalize ECF and ICF osmolarities). RBCs are cells, and water shifts into them along with all other cells. This water shift causes RBC volume to increase, which would tend to increase Hct (since Hct is fractional volume). The two effects offset each other—dilution of RBC concentration by the increased ECF volume (decreased Hct) and swelling of RBCs (increased Hct)—and the result is no change in Hct. However, plasma protein concentration does decrease because of the dilutional effect of increased ECF volume.

Similarly, in water loss (hyperosmotic contraction, dehydration), there’s no change in Hct, although we think it should increase. Same idea: The decrease in ECF volume would, by itself, cause an increase in Hct. But there is a shift of water out of cells (to equalize ECF and ICF osmolarities) and the RBCs shrink like all other cells. The shrinkage of RBCs decreases their volume, which by itself would decrease Hct. The two effects offset, and the result is no change in Hct, although plasma protein concentration increases because of decreased ECF volume.

FAQ: What’s the difference between secretion and excretion?

Excretion = excretion rate = the amount of any substance excreted/time in the urine. Excretion is the net result, or sum, of the three processes involved in making urine: filtration, reabsorption, and secretion.

Secretion has a very specific meaning. It is the movement, or transport, of a substance from peritubular capillary blood (this is “postglomerular” blood) into the lumen of the nephron (i.e., into the urine). Secretion is the second way a substance can end up in the urine (the first way is filtration). Secreted substances include organic acids like PAH, organic bases like morphine, NH3, and K+.

FAQ: What’s the difference between RBF and RPF?

Renal plasma flow (RPF) is to renal blood flow (RBF) as plasma is to whole blood. It’s as simple as that. Plasma is the “watery” part of blood, the rest of blood is the cells. Plasma is 93% water (called plasma water) and 7% plasma proteins. Fractional volume occupied by RBCs = Hct; fractional volume occupied by plasma = 1 − Hct.

Why would we want to know renal plasma flow? After all, it’s whole blood that flows into the renal artery, not just plasma. The reason we want to know RPF is that’s the parameter we can measure with PAH. PAH (the marker for RPF) is dissolved only in plasma, not in RBCs. So we measure RPF with PAH, and we calculate the RBF from the RPF, by knowing the hematocrit. If we could put a flowmeter on the renal artery, we could measure RBF directly. But we can’t, so we use the PAH method.

FAQ: What are the units of clearance vs. reabsorption/secretion/excretion?

It is essential to be clear about units. Unless things have changed since my day, a basic survival strategy in chemistry and physics classes was this: Make the units cancel. At the very least, it is a great way to check your work. The same goes for physiology problems. But for this strategy to work, you must know what the final units should be!

Clearance: Units are volume/time (e.g., mL/min, L/hour, L/day, L/year, L/century). Renal clearance means volume of plasma cleared of a given substance by the kidneys per unit time. Clearance of inulin happens to be GFR because inulin is cleared from plasma only by filtration. Clearance of PAH happens to be effective RPF because PAH is cleared from plasma by a combination of filtration and secretion.

Filtered load, reabsorption rate, secretion rate, excretion rate: All of these have units of amount/time (e.g., mg/min, mmol/min, mmol/hr, mEq/hr). When calculating these, we multiply a flow rate X concentration to get units of amount/time. For example, filtered load = GFR (a flow rate) X plasma concentration of a substance. For another example, excretion rate = urine flow rate X urine concentration of a substance.

FAQ: What’’s the difference between clearance and excretion?

Clearance is volume of plasma cleared of a substance per unit time. Excretion rate is, literally, the amount of the substance excreted in urine per unit time.

Clearance and excretion are generally related. You may have noticed that the numerator of the clearance equation is excretion rate:

C = UV/P, where UV = excretion rate

Usually, the higher the excretion rate, the higher the renal clearance—makes sense, since substances are cleared from the plasma by excreting them in urine.

FAQ: Why does clearance of PAH = RPF, but clearance of inulin = GFR?

Why is the clearance of PAH the RPF (technically, effective RPF), while the clearance of inulin is the GFR?

First, renal clearances are different for different substances based on how the substance is handled in the kidney. A substance that is filtered only will have a midrange clearance and be called a glomerular marker; a substance that is filtered and reabsorbed will have much lower clearance; a substance that is filtered and secreted will have a much higher clearance. Clearance is mL/min of plasma cleared, or ridded, of that substance.

To illustrate the difference between what is measured by the clearances of PAH and inulin, let’s put some PAH and inulin into the plasma and have that plasma flow into the renal artery and then into the afferent arterioles. About 20% of that RPF containing inulin and PAH is filtered across glomerular capillaries; whatever inulin and PAH is in that 20% of the RPF will be excreted (i.e., that plasma is cleared of its inulin and its PAH). The remainder of the RPF (80%) is not filtered and flows into the efferent arterioles and then into peritubular capillaries. The PAH (but not the inulin) in that portion of the RPF is secreted and then excreted; that portion of the RPF is cleared of its PAH but not of its inulin.

Bottom lines: The entire (effective) RPF is cleared of its PAH by a combination of filtration and secretion; that is why the renal vein PAH is nearly zero (almost all the PAH was removed from the plasma and excreted in the urine). Only 20% of the RPF is cleared of its inulin; that 20% is the GFR.

In further support of this: Clearance of inulin = GFR = approximately 120 mL/min. Clearance of PAH = effective RPF = approximately 600 mL/min. Filtration fraction = 120/600 = 20%; that’s the 20% that is filtered. It works!

FAQ: What’s the difference between threshold and Tm?

The terms threshold and Tm are often used in reference to glucose. The terms refer to different things, have specific definitions, and are expressed in different units. Threshold is the plasma concentration at which glucose first appears in the urine (i.e., its units are mg/dL). The glucose threshold is about 200 mg/dL. That is, glucose is first excreted in urine when the plasma concentration is 200 mg/dL.

Tm is the maximum rate of glucose reabsorption, the rate at which the glucose transporters are fully saturated; its units are a rate, mg/min. Tm for glucose is about 375 mg/min.

We can compare threshold and Tm, but not directly. To compare them, we must describe them in the same terms. For example, we could describe the plasma glucose concentration at which reabsorption is saturated (the plasma concentration at which Tm occurs). That plasma glucose concentration is about 350 mg/dL. (The fact that the plasma concentration at which Tm first occurs has a similar absolute value to the Tm itself is one reason we get confused. They are so close, 350 and 375.)

The threshold for glucose (plasma glucose of 200 mg/dL) is much lower than the plasma concentration at which Tm occurs (plasma glucose of 350 mg/dL). This difference is the splay, which is accounted for by (1) heterogeneity among nephrons (different nephrons spill glucose in the urine at different plasma concentrations) and (2) low affinity of the Na+-glucose cotransporter.

A common error is to call Tm a concentration, in order to force a comparison of threshold and Tm in the same units. The danger in doing this (other than that it’s not correct) is that it sounds so plausible, we may forget that Tm is not a concentration but a rate of reabsorption.

FAQ: Why does [TF/P]x/[TF/P]inulin = % of filtered x remaining in nephron?

We have learned that [TF/P]x/[TF/P]inulin (the so-called double ratio) equals the % of filtered load of x remaining in nephron. But where does that come from?

SNGFR = single nephron GFR

in = inulin

V = urine flow rate

1.          % of filtered load remaining = excretion rate of x at any point in nephron divided by filtered load of x in nephron

2.          Excretion rate at any point in nephron = [TF]x X V

3.          Filtered load of nephron = SNGFR X Px = [TF]in X V/[P]in X Px

4.          Substituting and canceling out V: % of filtered load remaining = [TF/P]x/[TF/P]in

FAQ: How can I make sense of these TF/P ratios?

The best way to understand the T/P ratios is to think about specific examples that make them more real.

First, a clarification: The P in the denominator of TF/P refers to systemic plasma concentration of a substance and is assumed to be constant. Of course, P can vary, but for TF/P analysis, we call it constant. It follows that all variations in TF/P are due to changes in TF concentration of the substance along the nephron.

TF is tubular fluid, which is analogous to urine.

Now let’s look at specific examples that make this less theoretical and, we hope, more useful. Again, TF/P is simply comparing, by use of a ratio, the concentration of a substance in tubular fluid to its concentration in systemic plasma (assuming that plasma in the denominator does not change).

1.          In Bowman’s space, TF/P for all freely filtered substances is 1.0 because the concentration in TF is identical to the plasma it came from. Nothing has happened so far in the nephron to change it.

2.          In proximal tubule, [TF/P]Na+ and [TF/P]osmolarity = 1.0 because Na+ and solute (osmoles) are reabsorbed in exact proportion to water. The effect of the proportionality is that the concentrations of Na+ and osmolarity in TF don’t change even though lots of both have been reabsorbed.

3.          In the proximal tubule, [TF/P]glucose and [TF/P]amino acids are ‹1.0 and actually fall all the way to 0. This is because glucose (and amino acids) is reabsorbed relatively much more than water and Na+, so the TF concentration falls.

4.          In TALH, [TF/P]Na+ and [TF/P]osmolarity are ‹1.0 because both Na+ and total solute are reabsorbed more than water. (Water is not reabsorbed because TALH is impermeable to it.) TALH is called the diluting segment because this process “dilutes” TF.

5.          Regarding inulin: Once filtered, inulin is inert in the nephron (i.e., it is neither reabsorbed nor secreted). So, changes in [TF]inulin depend only on the amount of water in tubular fluid. As water is reabsorbed (i.e., removed from tubular fluid), the [TF]inulin concentration rises. Each nephron segment in which water is reabsorbed causes the [TF]inulin concentration to rise further. Thus, [TF/P]inulin is 1.0 in Bowman’s space (like all freely filtered substances) and rises from that number. For example, [TF/P]inulin at the end of the proximal is about 3.0 because 2/3 of the water has been reabsorbed at that point.

FAQ: What is the role of brain osmolytes in disturbances of body fluid osmolarity?

Main points: o Change in ECF osmolarity −› fluid shifts between ICF and ECF. o Brain cells do NOT like fluid shifts in and out. Swelling of brain cells in a fixed structure (the skull) causes seizure; shrinking of brain cells causes myelinolysis (death). o If a change in ECF osmolarity occurs slowly (is chronic), the brain has an adaptive mechanism to protect itself from swelling or shrinking of its cells. o The brain synthesizes osmolytes, which are osmotically active organic solutes such as sorbitol. o In the brain, osmolytes work in two different ways in two different scenarios:

1.          If ECF osmolarity is increased, brain osmolytes are synthesized and remain inside the brain cells. In this way, brain ICF osmolarity is increased by these osmolytes to match the ECF osmolarity. In the rest of the body cells, water shifts from ICF to ECF (to make ICF/ECF osmolarity equal in steady state), but in the brain, no water shift is needed because osmolarities are already matched and equal. So, in chronic dehydration, thanks to osmolytes, brain cells don’t shrink. Dehydration (water loss) is treated by giving water, but it must be done very slowly. That’s because brain cells have increased ICF osmolarity with all those osmolytes. If you dilute ECF osmolarity too fast, water rushes into brain cells, causing seizure. So you give water (as 5% glucose) slowly, allowing brain cells time to get rid of the osmolytes that it no longer needs.

2.          If ECF osmolarity is decreased, the brain synthesizes osmolytes but now exports them to the brain ECF. In this way, brain ECF osmolarity doesn’t decrease as in the rest of the body. (Without the osmolytes, brain ECF osmolarity would be low as in the rest of body.) This maneuver keeps brain ECF and ICF osmolarity equal, so no water shifts into brain cells (as happens in rest of the cells in the body). Low osmolarity is treated by giving Na+(saline), but it must be given slowly. The brain ECF needs time to get rid of the osmolytes it no longer needs; if you increase brain ECF osmolarity too fast, water will shift from brain ICF −› brain ECF −› shrink brain cells = central pontine myelinolysis and death.

FAQ: Hyperventilation is a cause of respiratory alkalosis and a compensation for metabolic acidosis?

A person can hyperventilate as compensation for metabolic acidosis. Or a person can hyperventilate as the cause of respiratory alkalosis. How do we tell the difference?

The difference is cause and effect. The answer is that pH is different in the two disorders, and that’s why we always begin acid-base analyses with the pH. Decreased pH means some kind of acidosis. Increased pH means some kind of alkalosis. If no pH is given, you must calculate it, and then proceed!

A person with metabolic acidosis will have decreased HCO3 and consequently decreased pH. He or she will hyperventilate and decrease the PCO2 as compensation, tending to return pH toward normal. But the pH will still be acidic!

A person with respiratory alkalosis will be hyperventilating and have decreased PCO2. The decrease in PCO2 will cause increased pH. Mass action (acute) and renal compensation (chronic) will decrease the HCO3 and tend to return pH toward normal. But the pH will still be alkaline!

FAQ: What’s the difference between compensation and correction of acid-base disorders?

Compensation means compensating, or trying to normalize, the blood pH while the person has an acid-base disorder. Compensation for metabolic disorders is respiratory (via change in breathing −› change in PCO2). Compensation for respiratory disorders is renal (via change in HCO3 reabsorption −› change in blood HCO3). The person still has the acid-base disorder! The compensatory mechanisms try to keep the blood pH as close to normal as possible so the person can live.

Correction means restoring normal acid-base balance, or correcting what initially caused the acid-base disorder. You can call it “restoration” or “correction.” After correction, the person no longer has an acid-base disorder and all blood values are normal. Correction of metabolic disorders is achieved by restoring the HCO3 concentration to normal. Correction of respiratory disorders means that breathing returns to normal and PCO2 is restored to normal; some respiratory disorders are not correctable (e.g., chronic respiratory acidosis due to COPD, in which the person will live forever with chronic respiratory acidosis, with renal compensation).

FAQ: What’s the difference between H excretion and urine pH?

H excretion = total amount of H excreted in the urine per minute. H excretion is determined by the amount of urinary buffer (since we can excrete only small amounts of free H). The reason that only small amounts of free H are permitted in the urine (min urine pH = 4.4) is that H ATPase can pump H against a certain free H gradient (1000-fold); if free H concentration in the urine becomes more than 1000-fold the blood H concentration, H ATPase cannot pump any more H into the urine. So to keep H excretion going, we titrate the secreted H by urinary buffers such as HPO4-2, thus preventing free H concentration from rising too much. When we run out of urinary HPO4-2, we find NH3 to buffer the secreted H. When we’ve titrated all the urinary buffers, the next secreted H will raise the free H concentration (i.e., drop the urine pH to 4.4). (Sure, if we added more A- of a buffer with appropriate pK at this point, we could keep H excretion going further, but that’s hypothetical.)

Urine pH is simply another way of expressing free H concentration. Generally, urine pH will correlate with the amount of H excreted, but they are not the same thing. Type IV RTA is one case where the urine pH can be very low, but the total H excretion is decreased (due to deficient urinary buffer [NH3]).

Endocrine and Reproductive Physiology

FAQ: Why does hypocalcemia cause muscle spasms?

This is among the all-time top ten physiology FAQs! We know that increased Ca2+ causes increased muscle contraction, not the other way around, and therein lies the confusion.

The Ca2+ that increases contraction (initiates cross-bridge cycling by binding troponin C) is intracellular Ca2+. When we talk about hypocalcemia causing muscle spasms, we mean extracellular Ca2+.

Hypocalcemia (decreased extracellular Ca2+) causes increased excitability of excitable cells, including sensory and motor nerves and muscle. This is because low extracellular Ca2+ lowers (makes more negative) the threshold potential, and less inward current is required to depolarize to threshold and fire action potentials. Thus, hypocalcemia produces tingling and numbness (effects on sensory nerves) and spontaneous muscle twitches (effects on motoneurons and the muscle itself).

FAQ: Why are there urinary Ca2+ stones in primary hyperparathyroidism?

You may have learned about “stones, bones, and groans” as a mnemonic for primary hyperparathyroidism. “Stones” refers to the urinary Ca2+ stones that result from increased urinary Ca2+ excretion. But initially, this doesn’t make sense, because the direct action of PTH on the kidney is to increase Ca2+ reabsorption, which should lower urinary Ca2+. Urinary Ca2+ is increased in primary hyperparathyroidism because the serum Ca2+, and consequently the filtered load of Ca2+, is elevated. Even though high levels of PTH continue to cause increased renal Ca2+ reabsorption, it is overwhelmed by the high filtered Ca2+load. In this situation, both reabsorption of Ca2+ and excretion of Ca2+ are increased.

FAQ: What is the effect of licorice on Type I mineralocorticoid receptors?

Regarding Type I mineralocorticoid receptors in the kidney (i.e., the receptors for aldosterone):

1.          Type I receptors are supposed to be activated by aldosterone and other mineralocorticoids.

2.          But Type I receptors bind cortisol and aldosterone with equal affinity.

3.          Circulating levels of cortisol are typically much higher than circulating levels of aldosterone. Thus, without a clever solution, these Type I receptors would be swamped with cortisol and never “see” the changes in aldosterone that are supposed to control them (e.g., to cause changes in Na+ reabsorption).

4.          Clever solution: The kidney has 11Beta-hydroxysteroid dehydrogenase that locally converts cortisol to cortisone. Cortisone has a much lower affinity for the Type I receptors. This removes cortisol from the picture so that it doesn’t swamp the Type I receptors; now the Type Is are available to bind and react to changes in circulating aldosterone.

5.          Licorice inhibits 11Beta-hydroxysteroid dehydrogenase, preventing renal “inactivation” of cortisol to cortisone. Now the Type Is see huge levels of cortisol and are activated by them, as if they are seeing high levels of mineralocorticoid −› hypertension and hypokalemia.

FAQ: What is the dexamethasone suppression test?

Dexamethasone is a potent synthetic glucocorticoid. It has all the actions of the natural glucocorticoid (cortisol), including feedback inhibition of ACTH secretion.

Dexamethasone is used in a test of adrenal disorders called the dexamethasone suppression test. Dexamethasone is administered in either low dose or high dose. It should inhibit ACTH secretion, which then causes a decrease in cortisol secretion. In the test, cortisol levels are measured.

The dexamethasone suppression test is used to determine the etiology of hypercortisolism. In other words, in a person with symptoms of hypercortisolism and elevated serum cortisol, what is the cause? Is an adrenal tumor secreting too much cortisol? Or is an ACTH-secreting tumor driving the adrenal cortex to secrete too much cortisol (Cushing’s disease)? The results are interpreted as follows:

1.          In normal persons, low-dose dexamethasone inhibits ACTH secretion, which inhibits cortisol secretion, which is measured in the test.

2.          In Cushing’s syndrome caused by adrenal tumor secreting too much cortisol, neither low-dose nor high-dose dexamethasone inhibits cortisol secretion. The adrenal tumor secretes its cortisol autonomously and is not under ACTH control; it doesn’t care that ACTH secretion is completely inhibited.

3.          In Cushing’s disease (ACTH-secreting tumor secreting too much ACTH and driving too much cortisol secretion), low-dose dexamethasone does not inhibit ACTH/cortisol secretion because the tumor is less sensitive to feedback inhibition by glucocorticoids than is normal anterior pituitary tissue. However, high-dose dexamethasone does inhibit ACTH/cortisol secretion.

FAQ: Why are the diabetogenic hormones secreted in untreated diabetes mellitus?

In severe untreated diabetes mellitus, there is increased secretion of diabetogenic hormones (i.e., growth hormone, cortisol, epinephrine, glucagon). We would expect secretion of these hormones to be inhibited secondary to hyperglycemia. Apparently, these hormones are secreted secondary to stress.

The point (in case you were wondering) is that the diabetogenic hormones are turned on and worsen the hyperglycemia (not a good thing!). And in the case of Type I diabetes mellitus, this increase in glucagon contributes to development of ketoacidosis as explained in the FAQ on why there is no ketoacidosis in Type II diabetes mellitis.

FAQ: Why is there no ketoacidosis in Type II diabetes mellitus?

Ketoacidosis can be an acute complication of Type I (insulin-dependent) diabetes mellitus but usually is not a complication of Type II diabetes mellitus. The reason for the difference is not completely understood but includes the following:

In Type I diabetes mellitus, without insulin there is overproduction of ketoacids, resulting in ketoacidosis, because (1) insulin deficiency increases lipolysis in adipose, increases plasma-free fatty acids (FFAs), and increases hepatic FFAs and (2) increased glucagon (secondary to decreased insulin, see later) increases hepatic production of ketoacids from the increased FFAs supplied from adipose.

In Type II diabetes mellitus, ketoacidosis typically does not occur because there is (1) some insulin present so FFAs don’t increase as much and (2) hepatic resistance to glucagon.

Interestingly, persons with Type II are more likely to have hyperosmolar coma as an acute complication than are persons with Type I. The hyperosmolar coma is a result of severe hyperglycemia (higher than in Type I) and severe volume depletion due to osmotic diuresis (due to glucosuria). Persons with Type I who develop ketoacidosis get earlier medical treatment because of the symptoms (e.g., vomiting), whereas persons with Type II don’t have ketoacidosis or the symptoms that would bring them to the doctor; thus, their hyperglycemia and volume depletion is “allowed” to worsen.

It seems wrong that glucagon would increase in untreated diabetes mellitus (reasoning that hyperglycemia should shut off glucagon). But it’s true. In severe, untreated diabetes that is heading toward ketoacidosis, the diabetogenic hormones, including glucagon, are secreted secondary to stress. The increased level of glucagon is detrimental because it worsens hyperglycemia and it facilitates production of ketoacids from fatty acids.

FAQ: Why is there muscle weakness in adrenocortical insufficiency?

Addison’s disease (primary adrenal cortical insufficiency) is associated with muscle weakness and fatigue. Why?

Remember, Addison’s involves destruction of all zones of the adrenal cortex, including zona glomerulosa, which normally secretes aldosterone. Without aldosterone, there is decreased K+ secretion −› increased blood K+(hyperkalemia). Per the Nernst equation, this causes depolarization of the resting membrane potential in skeletal muscle −› closure of Na+ channels required for upstroke of the action potential. In order to fire another action potential, recall that membrane potential must repolarize to make the Na+ channels “available” again. If Na+ channels are inactivated and remain inactivated (due to steady depolarization secondary to hyperkalemia), it’s harder to fire action potentials in muscle −› muscle weakness.

FAQ: What’s the difference between a primary and secondary endocrine disorder?

In conventional usage, primary disorder means that the final gland in the hormonal system is hypersecreting or hyposecreting its hormone. Examples of “final” gland in the system are adrenal cortex, thyroid, parathyroid, and gonads. So primary disorders are primary adrenal hyperplasia (Cushing’s syndrome), primary adrenal failure (Addison’s), destruction of the thyroid, destruction of the parathyroids, primary aldosteronism due to an aldosterone-secreting tumor, central diabetes insipidus, primary failure of the testes. The problem originates in the “final” gland.

Secondary disorder means there’s a defect in the system prior to the final gland that drives the gland to hyper- or hyposecrete its hormone. Some examples of secondary disorder are (1) hypocalcemia −› secondary hyperparathyroidism,(2) low ACTH −› secondary hypoadrenalism, (3) ACTH-secreting tumor −› secondary hyperadrenalism (Cushing’s disease), (4) TRH or TSH deficiency −› secondary hypothyroidism, and (5) decreased arterial pressure −› secondary hyperaldosteronism.

Sometimes, the designation of primary or secondary is not necessary. What’s important is to know the causative mechanism and the subsequent chain of events. For example, Graves’ disease is not usually called primary or secondary. It’s just Graves’, and you need to understand what causes it (antibodies to TSH receptors on thyroid, which causes hyperthyroidism, which then leads to decreased TSH).

FAQ: What’s the difference between hyperthyroid, hypothyroid, and euthyroid goiter?

Goiters (enlarged thyroid) can be present with hyperthyroidism (what you expected), hypothyroidism (what you didn’t expect), and euthyroidism (wasn’t even on your radar screen).

Bottom line: TSH and things that act like TSH (e.g., thyroid-stimulating immunoglobulins that circulate in Graves’ disease) have a trophic effect on the thyroid (cause it to enlarge).

Important background: The terms hyperthyroid, hypothyroid, and euthyroid describe the clinical states of excess thyroid hormone, deficient thyroid hormone, and normal thyroid hormone respectively—not the size of the thyroid, but blood levels of thyroid hormone. You understand whether goiter will be present by analyzing each etiology of thyroid disease.

Graves’ = most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulins, like TSH, drive the thyroid to secrete excess T4 and T3. Trophic effect on thyroid gland causes goiter. TSH levels are decreased by negative feedback, and it’s the immunoglobulin that causes goiter in this case.

TSH-secreting tumor = uncommon cause of hyperthyroidism. Increased TSH drives the thyroid to secrete excess T4 and T3. Trophic effect causes goiter.

Ingestion of T4 = factitious hyperthyroidism. Increased levels of thyroid hormone (from the ingestion) cause decreased TSH by negative feedback. NO goiter, in fact thyroid will shrink with time.

Autoimmune thyroiditis = common cause of hypothyroidism. Thyroid hormone synthesis is impaired by antibodies to peroxidase, leading to decreased thyroid hormone secretion. TSH levels are increased by negative feedback, and the trophic effect of high TSH causes goiter. Yes, the gland enlarges even though it is not effectively synthesizing thyroid hormones.

TSH deficiency (anterior pituitary failure) = uncommon cause of hypothyroidism. Thyroid hormone secretion decreases because of decreased TSH. NO goiter because TSH levels are low.

I--deficiency leads transiently to decreased synthesis of thyroid hormone, which increases TSH secretion by negative feedback. Increased TSH has a trophic effect on the gland, causing goiter. The enlarged gland (which is otherwise normal) can often maintain normal blood levels of thyroid hormone, and the person is clinically euthyroid (asymptomatic). If the gland can’t quite maintain normal blood levels of thyroid hormone, the person is symptomatically hypothyroid.


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