This post contains email questions and my answers
A Malpighian body has two components- the glomerulus (a tuft of capillaries formed by the afferent arteriole) and the Bowman's capsule (a double-walled epithelial cup that encloses the glomerulus. Filtration occurs if the outward driving pressures exceed the inward reabsorption pressures. This balance is quantified by the Starling equation.
- Overview
- As mentioned, the rate of glomerular filtration is essentially governed by Starling Forces. However, because the glomerular capillaries are surrounded by the fluid in the Bowman's Capsule, the hydrostatic and oncotic pressure of Bowman's Space is used instead of those of the 'Interstitial Fluid'. Importantly, because no plasma proteins can cross the glomerular barrier during glomerular filtration, the oncotic pressure of fluid in Bowman's Space is essentially zero and is thus removed from the starling equation.
- Formally:
- GFR = Kf [(Pc-Pb)-(Πc)]
- GFR = Glomerular Filtration Rate (ml/min). Equivalent of Jv in Starling Forces
- Kf = Permeability Constant of glomerular capillaries
- Pc = Glomerular Capillary Hydrostatic Pressure
- Pb = Bowman's Space Hydrostatic Pressure
- Πc = Glomerular Capillary Oncotic Pressure
Physical determinants of the glomerular filtration rate
The Glomerular Filtration Rate (GFR) is a quantitation of the volume of fluid filtered through the glomerular barrier per unit time. The GFR is essentially determined by a special case of the starling equation and is given above. The primary physiological modulators of GFR are the afferent and efferent arteriolar resistances (RA and RE). As expected, increasing the afferent arteriolar resistance (RA) drops the pressure within the glomerulus and thus reduces GFR. The relationship between the efferent arteriolar resistance (RE) and GFR is more complicated. Initially, increasing RE boosts the pressure within the glomerulus and thus increases GFR. However, at higher values of RE the total blood flow through the glomerulus decreases and thus GFR drops.
What is the difference between homeostasis and adaptation?
I think you meant homeostasis instead of hemostasis. Homeostasis is the concept of animals maintaining a constant internal environment even when the external environment and/or stress factors or injury are present. Adaptation refers to how homeostasis is accomplished. Two examples:
1 Blood pressure is maintained within a narrow range of values even when there is a sudden change in gravity; e.g., when you rapidly stand up. The mechanisms that allow this adaptation are a baroreceptor reflex (rapid) and hormonal changes driven by renin produced in the kidneys (slow).
2 Arterial oxygen content is maintained at a normal value (20 mlO2/dL blood) even after you move from sea level to high altitude. The mechanisms that allow this adaptation are increased lung ventilation (rapid) and increased red blood cells driven by erythropoietin produced by the kidneys (slow).
Dr. Wood,
Hi Dr. Wood,
Could you please explain why there is oliguria in Nephritic syndrome?
Mechanisms of oliguria and acute kidney injury. Multiple mechanisms can potentially cause oliguria in the acutely injured kidney. Regional intrarenal differences in blood flow and redistribution; glomerular injury or altered intraglomerular hemodynamics; impaired tissue oxygenation causing preferential ischemia to the S 3 segment of the proximal convoluted tubule and the oxygen-avid thick ascending loop of Henle; loss of osmolar gradient, interstitial edema, or inflammation; and tubular or lower urinary tract obstruction can precipitate oliguria. CCD and MCD, cortical and medullary collecting ducts; Osm, osmolality; p t O 2 , tissue partial pressure of oxygen; Q B , renal blood flow; S 1 – S 3 , segments of the proximal convoluted tubule; TALH, thick ascending loop of Henle.
We are in MSK but I’ve come across a topic I’m lost in. I’m going over NSAID pharmacology and am struggling to understand the mechanism behind hyperkalemia associated with their use. From my understanding, the use of NSAIDs will block dilation of the renal afferent arteriole which would lead to a drop in GFR. I was under the impression that the kidney would sense this and would subsequently hype up the RAAS which would increase sodium and excrete potassium and H+ ions. However, this is clearly not the case as you see a Hyper- rather than Hypo- kalemia with certain NSAID use.
Do you happen to know the mechanism behind this?
]. The COX-2 isoform is constitutively present in the kidney, and, therefore, both nonselective NSAIDs and more selective COX-2 inhibitors reduce renal prostaglandins. (See "NSAIDs: Pharmacology and mechanism of action"
.)
]. Locally generated prostaglandins also may mediate part of the natriuretic effect of dopamine and of natriuretic peptides [6,7
].
]. These include hyperkalemia, hyponatremia, and edema. These complications are mediated in part by reductions in the secretion of renin and aldosterone and by increased activity of ADH [2,3,8
].
another good article is here
How does hypoxia cause constriction of pulmonary arteries?
In pulmonary arteries, hypoxia causes a triphasic response ending with a sustained phase of contraction52 and is termed “hypoxic pulmonary vasoconstriction”. This phenomenon is observed in isolated systemic or pulmonary arteries across many species including reptiles, birds and mammals53,54. Its physiological role is to adjust the ventilation/perfusion ratio by diverting blood to regions of the lung with adequate oxygen supply55. However sustained hypoxic constrictions may lead to pulmonary hypertension; the latter is a dramatic pathological situation still in search of an appropriate cure55,56. The acute phase of hypoxic constriction of pulmonary blood vessels is endothelium-dependent57,58, and ultimately results from the activation of Rho kinase leading to calcium sensitization in the vascular smooth muscle59. It is enhanced by inhibitors of NOS and phosphodiesterase V60. Metallothionein, a protein responsible for zinc homeostasis, may also be involved, since zinc chelation inhibits the contractile response in pulmonary arteries61. As regards the sustained phase of hypoxic constriction in the pulmonary circulation, cyclic adenosine diphosphateribose (cADPR), a molecule that modulates the activity of ryanodine receptors, appears to be responsible62. Indeed, hypoxia increases the production of cADPR, which facilitates calcium release from the sarcoplasmic reticulum63. Furthermore, the cADPR antagonist, 8-bromo-cADPR, abolishes the sustained phase of the hypoxic response64. These changes work in conjunction with calcium sensitization (also induced by hypoxia51) to produce hypoxic constriction.
1) If you’re sleeping and your heart rate drops to say, the 40’s, is the SA node still the starting point for depolarization or does the AV start to play a role? I would assume the drop in HR is due to a decrease in conduction velocity and that the SA node is still the primary depolarizer.
2) An athletic heart beats slower due to the increased stroke volume, which is due to strengthening of the left ventricle. At what point does LVH become pathologic? Are extreme athletes more prone to left heart problems?
Is the sum of partial pressures of gases in blood equal to total atmospheric pressure?
Not necessarily. This is true for alveolar gas pressures but not for blood. For practical purposes, liquids are incompressible and do not respond to changes in ambient pressure. Because of this, the sum of gas partial pressures in a liquid can be less than ambient pressure. Liquids such as blood and other body tissues will equilibrate only with the gas partial pressures to which they are exposed.
On the alveolar side of the alveolar membrane, the total partial pressures must equal ambient pressure. However, on the liquid side of the membrane, the total partial pressures can be less, and in some areas may be quite a bit less than ambient pressure. The partial pressure that a gas exerts in a liquid depends on the temperature, the solubility of the gas in the liquid and the amount of gas present. Thus, if the amount of gas present and the temperature remain constant, the partial pressure of the gas in a tissue is fixed. If one gas is removed from a tissue, the remaining gases do not expand to fill the partial pressure vacated by the gas that was removed. The figure below shows total partial pressures for air breathing at 1 ATA from inspired gas to venous blood. Because of the decline in PO2 from alveoli to arterial blood, the total gas partial pressure in arterial blood during air breathing at 1 ATA is 752 mmHg, less than ambient pressure (760 mmHg). If PaO2 is lower than 95 mmHg (assumed in this example), then the total partial pressure in arterial blood will be less.
Would the alveolar-arterial PO2 difference (A-a)PO2 be normal in a healthy person breathing 100% oxygen; i.e., would alveolar and arterial PO2 both increase by the same amount?
No, the (A-a)PO2 will be greatly increased in healthy lungs breathing 100% O2.
The figure below shows inspired to venous blood partial pressures during O2 breathing at 1 ATA (100% O2 at sea level). In this example, it is assumed that all nitrogen, argon and other trace gasses have been washed out of the system. During O2 breathing, the ventilation/perfusion inequalities in lung have a much greater impact on PaO2 than during air breathing. Under optimal conditions during O2 breathing at 1 ATA, PaO2 would be about 500 mmHg while alveolar PO2 is about 663 mm Hg. (PAO2 = (760 - 47) - 40/.8 = 663). As blood moves through tissue, the same 4.5 mL O2/dL blood is extracted, and PO2 falls to 57 mmHg in venous blood.
I understand that M3 receptors are located in MANY places in our body (especially smooth muscle)… including our endothelial cells (in which they activate NO synthesis -> diffusion into smooth muscle -> cGMP production -> relaxation.
However, how do circulating catecholamines (e.g. from a pheochromocytoma) circulating in our bloodstream ultimately get to exert their effect on smooth muscle adrenergic receptors? To my knowledge, there are no adrenergic receptors on our endothelial cells and from what I can remember, the only way smooth muscle contracts/relaxes in response to catecholamines is via neuronal synapses. I feel like I’m missing something here…
Beta-adrenoceptor agonists (β-agonists) bind to β-receptors on cardiac and smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) and kidneys (stimulate renin release). Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, β-agonists mimic the actions of sympathetic adrenergic stimulation acting through β-adrenoceptors. Overall, the effect of β-agonists is cardiac stimulation (increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation. Arterial pressure may increase, but not necessarily because the fall in systemic vascular resistance offsets the increase in cardiac output.
Blood vessels
Vascular smooth muscle has β2-adrenoceptors that have a high binding affinity for circulating epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic nerves.
These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by β2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).
Hi Dr. Wood,
Could you please explain why there is oliguria in Nephritic syndrome?
Mechanisms of oliguria and acute kidney injury. Multiple mechanisms can potentially cause oliguria in the acutely injured kidney. Regional intrarenal differences in blood flow and redistribution; glomerular injury or altered intraglomerular hemodynamics; impaired tissue oxygenation causing preferential ischemia to the S 3 segment of the proximal convoluted tubule and the oxygen-avid thick ascending loop of Henle; loss of osmolar gradient, interstitial edema, or inflammation; and tubular or lower urinary tract obstruction can precipitate oliguria. CCD and MCD, cortical and medullary collecting ducts; Osm, osmolality; p t O 2 , tissue partial pressure of oxygen; Q B , renal blood flow; S 1 – S 3 , segments of the proximal convoluted tubule; TALH, thick ascending loop of Henle.
We are in MSK but I’ve come across a topic I’m lost in. I’m going over NSAID pharmacology and am struggling to understand the mechanism behind hyperkalemia associated with their use. From my understanding, the use of NSAIDs will block dilation of the renal afferent arteriole which would lead to a drop in GFR. I was under the impression that the kidney would sense this and would subsequently hype up the RAAS which would increase sodium and excrete potassium and H+ ions. However, this is clearly not the case as you see a Hyper- rather than Hypo- kalemia with certain NSAID use.
Do you happen to know the mechanism behind this?
Here is what I found that makes pretty good sense. renal prostaglandins dilate both afferent and efferent arterioles (see nephron map
)
NSAIDs: Electrolyte complications
- Author:
- Richard H Sterns, MD
- Section Editor:
- Michael Emmett, MD
- Deputy Editor:
- John P Forman, MD, MSc
INTRODUCTION
Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed analgesics worldwide. These agents reduce pain, inflammation, and fever by inhibiting cyclooxygenase (COX), which results in decreased synthesis of prostaglandins. COX has two isoforms; inhibition of COX-1 is responsible for the gastrointestinal side effects of NSAIDs, while their desired antiinflammatory effects are due to inhibition of COX-2 [1
Renal vasodilatory prostaglandins promote the secretion of renin, impair sodium reabsorption in the loop of Henle and cortical collecting tubule, and partially antagonize the ability of antidiuretic hormone (ADH) to increase water reabsorption in the collecting tubules [2-5
These actions are not of major importance in normal subjects in whom basal renal prostaglandin production is relatively low. However, they may become clinically significant when prostaglandin synthesis is stimulated by underlying renal disease or by the vasoconstrictors angiotensin II or norepinephrine. Secretion of these vasoconstrictors is increased in states of effective volume depletion: true volume depletion due to gastrointestinal or renal losses (as with diuretic therapy) or reduced tissue perfusion due to heart failure or cirrhosis.
In the setting of effective volume depletion, NSAIDs, which inhibit prostaglandin synthesis, can produce a variety of complications related to renal dysfunction, each of which is reversible with discontinuation of therapy [2,3
In pulmonary arteries, hypoxia causes a triphasic response ending with a sustained phase of contraction52 and is termed “hypoxic pulmonary vasoconstriction”. This phenomenon is observed in isolated systemic or pulmonary arteries across many species including reptiles, birds and mammals53,54. Its physiological role is to adjust the ventilation/perfusion ratio by diverting blood to regions of the lung with adequate oxygen supply55. However sustained hypoxic constrictions may lead to pulmonary hypertension; the latter is a dramatic pathological situation still in search of an appropriate cure55,56. The acute phase of hypoxic constriction of pulmonary blood vessels is endothelium-dependent57,58, and ultimately results from the activation of Rho kinase leading to calcium sensitization in the vascular smooth muscle59. It is enhanced by inhibitors of NOS and phosphodiesterase V60. Metallothionein, a protein responsible for zinc homeostasis, may also be involved, since zinc chelation inhibits the contractile response in pulmonary arteries61. As regards the sustained phase of hypoxic constriction in the pulmonary circulation, cyclic adenosine diphosphateribose (cADPR), a molecule that modulates the activity of ryanodine receptors, appears to be responsible62. Indeed, hypoxia increases the production of cADPR, which facilitates calcium release from the sarcoplasmic reticulum63. Furthermore, the cADPR antagonist, 8-bromo-cADPR, abolishes the sustained phase of the hypoxic response64. These changes work in conjunction with calcium sensitization (also induced by hypoxia51) to produce hypoxic constriction.
1) If you’re sleeping and your heart rate drops to say, the 40’s, is the SA node still the starting point for depolarization or does the AV start to play a role? I would assume the drop in HR is due to a decrease in conduction velocity and that the SA node is still the primary depolarizer.
2) An athletic heart beats slower due to the increased stroke volume, which is due to strengthening of the left ventricle. At what point does LVH become pathologic? Are extreme athletes more prone to left heart problems?
A heart rate of 40 in a normal individual indicates sinus bradycardia due to lots of vagal tone lowering the slope of phase 4 of the node action potential. Lance Armstrong had a resting heart rate of 32! The bradycardia exists because of the larger stroke volume of enlarged hearts. The resting cardiac output is normal so heart rate has to decrease.
Athlete's heart is considered benign but is similar to hypertrophic cardiomyopathy where the LV is also enlarged. The difference is that halting training will lead to heart size returning toward normal in athletes. Also HCM involves thickening of the septum and outflow tract obstruction so the imaging studies are different.
Is the sum of partial pressures of gases in blood equal to total atmospheric pressure?
Not necessarily. This is true for alveolar gas pressures but not for blood. For practical purposes, liquids are incompressible and do not respond to changes in ambient pressure. Because of this, the sum of gas partial pressures in a liquid can be less than ambient pressure. Liquids such as blood and other body tissues will equilibrate only with the gas partial pressures to which they are exposed.
On the alveolar side of the alveolar membrane, the total partial pressures must equal ambient pressure. However, on the liquid side of the membrane, the total partial pressures can be less, and in some areas may be quite a bit less than ambient pressure. The partial pressure that a gas exerts in a liquid depends on the temperature, the solubility of the gas in the liquid and the amount of gas present. Thus, if the amount of gas present and the temperature remain constant, the partial pressure of the gas in a tissue is fixed. If one gas is removed from a tissue, the remaining gases do not expand to fill the partial pressure vacated by the gas that was removed. The figure below shows total partial pressures for air breathing at 1 ATA from inspired gas to venous blood. Because of the decline in PO2 from alveoli to arterial blood, the total gas partial pressure in arterial blood during air breathing at 1 ATA is 752 mmHg, less than ambient pressure (760 mmHg). If PaO2 is lower than 95 mmHg (assumed in this example), then the total partial pressure in arterial blood will be less.
Would the alveolar-arterial PO2 difference (A-a)PO2 be normal in a healthy person breathing 100% oxygen; i.e., would alveolar and arterial PO2 both increase by the same amount?
No, the (A-a)PO2 will be greatly increased in healthy lungs breathing 100% O2.
The figure below shows inspired to venous blood partial pressures during O2 breathing at 1 ATA (100% O2 at sea level). In this example, it is assumed that all nitrogen, argon and other trace gasses have been washed out of the system. During O2 breathing, the ventilation/perfusion inequalities in lung have a much greater impact on PaO2 than during air breathing. Under optimal conditions during O2 breathing at 1 ATA, PaO2 would be about 500 mmHg while alveolar PO2 is about 663 mm Hg. (PAO2 = (760 - 47) - 40/.8 = 663). As blood moves through tissue, the same 4.5 mL O2/dL blood is extracted, and PO2 falls to 57 mmHg in venous blood.
A look at the oxyhemoglobin dissociation curve helps explain why the (A-a)PO2 difference is so high. Because of the flat upper portion of the curve, a small drop in O2 content due to normal shunts and low V/Q cause a large drop in PO₂ (from PAO₂ = 663 to PaO₂ = 500 mm Hg.
