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Slide 20 -
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Biology 319/519, Endocrinology
Fall 2008 Blood Pressure Controls:
Vasopressin,
Atrial Natriuretic Peptides
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The Renin-Angiotensin- Aldosterone Axis Blood pressure is primarily maintained in vertebrates by the balanced function of three systems:
Vasopressin (VP, Anti-diuretic Hormone, ADH) which controls water balance by regulating the loss and elimination of water into urine,
The Renin-Angiotensin-Aldosterone (RAA) cycle which regulates the amount of sodium ion (Na+) lost and eliminated in urine,
And, the production of Atrial Natriuretic Peptides (ANF, ANP) that counter the actions of VP and the RAA system. Physical Chemistry States that for a fluid-filled rigid system there is a reciprocal relationship between pressure and volume:
if the volume decreases, pressure increases
if volume increases, pressure decreases:
P1V1 = P2V2.
So, it should be possible to decrease blood pressure by increasing the volume of the circulatory system or by decreasing the volume of fluid within a circulatory system of the same size. Note: In an elastic system like blood vessels, the overall size of the system responds to the volume of its contents somewhat like a balloon with a minimal and maximal overall size. It also responds to access to vessels that can be controlled by muscles. In blood vessels, if something decreases the volume of the blood in the open vessels the pressure will decrease because the size of the overall system decreases only to its lower limit before the pressure exerted by the fluid falls relative to what it would be if the vessel were filled just to that lower limit. Similarly, if something increases the volume of blood in the open vessels the vessels will expand to their limit and then the pressure will increase. So what alters overall circulatory system size?
Overall system growth, selective growth of vessels stimulated by angiogenic factors, e.g., in tumors or expanding fat tissues.
Actions of nerves or adrenal medullary hormones (epinephrine, norepinephrine): These may constrict blood vessels like those at the body surface when exposed to cold – thereby preserving blood flow to central organs and restricting heat loss. And/or, they may open capillary beds in internal organs like the kidney to preserve perfusion. They may also restrict venous outflow allowing local blood accumulation, e.g., during penile erection, while forcing systemic blood pressure decline. What alters blood volume?
Removing H2O from the body decreases the volume of blood; i.e., failing to retain H2O by failing to retrieve it from urine when that is concentrated in the kidney causes blood volume to decrease along with blood pressure. VP/ADH stimulates the kidney distal tubules to recapture the H2O in urine passing through the tubules.
Increasing the osmotic or ionic content of blood will increase blood volume by drawing H2O from body tissues to dilute dissolved materials, e.g., glucose, or ions, e.g., Na+. Sodium ion recovery from urine is stimulated by the Renin-Angiotensin-Aldosterone system which is stimulated by low blood pressure. Brain, heart, & kidney respond to changes in blood pressure via pressure receptors, baroreceptors, & to changes in ionic composition of blood via osmoreceptors.
Baroreceptors exist in large blood vessels, heart, & the kidney glomerulus (maculodensa).
Osmoreceptors occur in hypothalamic & glomerulus (juxtaglomerular) cells. How are changes in blood pressure detected? When osmolality is high or when atrial pressure is low, VP release is increased from the posterior pituitary & VP stimulates reuptake of water from urine in the kidney. This is blocked by ANF when osmolality falls or artrial pressure rises.
Simultaneously, when the kidney juxtaglomerular apparatus detects a drop in renal blood perfusion pressure or a fall in blood sodium levels, it increases production of the enzyme renin. This acts to elevate angiotensins I & II which increases aldosterone which stimulates sodium reuptake from urine in the kidney distal tubules. Renin & aldosterone production is opposed by ANF as blood volume & pressure rise. The specialized cells of the juxtaglomerular apparatus are found surrounding the afferent arteriole (primarily) as well as in the portion of the ascending limb of the distal convoluted tubule that most closely approaches the glomerulus. The juxtaglomerular cells sense arteriole BP while the macula densa cells in the tubule sense urinary Na+ & Cl-. These cells communicate with one another & produce renin when arteriole BP falls, epinephrine is elevated, or when urinary ions fall. Left modified from Figure 47-4, p786, in Robert M. Berne & Matthew N. Levy, Physiology, 2nd Ed., C.V. Mosby Co.: St. Louis, MO, 1988; right modified from Figure15.9, p373, in Mac E. Hadley, Endocrinology, 5th Ed., Prentice Hall: Upper Saddle River, NJ, 2000. The glomerulosa layer of the adrenal cortex responds to Angiotensin II by increasing aldosterone production. Other controls include direct ion effects, inhibition by ANP, & secondary control by ACTH from the corticotrope which links the stress axis including CRH to BP control. More direct links to stress are neural via actions on adrenal medulla & cardiac rate. Renin is an enzyme produced by the kidney glomerular apparatus that cuts the protein angiotensogen from liver to produce a decapeptide angiotensin I. This is cut by a second enzyme from lung & kidney, angiotensin converting enzyme, ACE, to produce angiotensin II an octapeptide that is a powerful vasoconstrictor & stimulator of aldosterone production. ACE inhibitors are drugs that reduce BP. (How would that work?) Angiotensin II can be inactivated by angiotensinases. While it is active it stimulates aldosterone production by the adrenal cortical outer layer & selectively alters blood flow through capillary beds by constricting vascular smooth muscles. The latter actions complement those of bradykinin & several other vasoconstrictor peptides. Interestingly, the same enzyme (kallikrein) cleaves the precursor forms of renin & the vasodilator kinin while a second enzyme (ACE) processes both angiotensin I and kinin. Kallikrein activates both substrates while ACE activates the hormonally inactive antiotensin I but inactives kinin.
Note that locally produced prostaglandins may be direct stimulators of kallikrein actions. The interconnected control loop for BP control by the RAA system is depicted including the intervening roles of the enzymes kallikrein & renin, the vasodilator bradykinin, the local hormones prostaglandins, the vasoconstrictor angiotensin II, & the steroid aldosterone. The actions of the vasoactive peptides are restricted to selected responsive vascular elements, not all blood vessel respond to all agents. Aldosterone is a chemically labile steroid with a short half life in serum; it does not bind to a carrier protein. It acts via a nuclear, mineralocorticoid (MCR), receptor in the cuboidal cells of the kidney distal tubule. The receptor binds equally well to cortisol. Receptor activation stimulates synthesis of multiple systems that synergize with one another to move Na+ from the lumen of the kidney tubule back into the intracellular fluid & blood at the serosal surface of the cells. But what about cortisol (normally very high in circulation & required for glucose homeostasis) activating the MCR? The paradox is resolved by aldosterone target cells expressing 11-steroid oxoreductase which converts cortisol to cortisone a steroid that does not bind to the MCR. Mutations in the oxoreductase enzyme may result in persistent hypertension because cortisol now can activate the MCR. Richard E. Klabunde
Cardiovascular Physiology Concepts: Atrial and Brain Natriuretic Peptides, http://www.cvphysiology.com/Blood%20Pressure/BP017%20ANP%20new.gif The production & role of the ANPs (including BNP) are shown here. These are made by granular cells of the heart atria as a series of peptides that counter the actions of VP/ADH & the RAA system. Though natural BP reducers they are not widely employed clinically. Such peptides are often chemically labile & may produce actions besides those of primary interest. The complete role of ANP and its relatives in BP control under physiological conditions has not yet been fully defined. In considering BP control, think about what would happen in the short and long term, minutes vs hours.
Consider the effect of rapid blood loss by hemorrhage. What effect would burns have?
Would decreasing salt in the diet do anything and how?
Might altering adrenal cortical steroid output do anything?
How might adding a lot of fatty tissue to the body alter BP via the systems mentioned?
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