Page 315 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 301

Active renin is released by exocytosis immediately upon stimula-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 tion of the juxtaglomerular apparatus. Prorenin is released con-
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn–R stitutively, usually at a rate higher than that of active renin, thus
Angiotensinogen accounting for the fact that prorenin can constitute 80–90% of
the total renin in the circulation. The significance of circulating
prorenin and a unique prorenin receptor is discussed at the end
Prorenin Renin of this section. Active renin release is controlled by a variety of
factors, including the macula densa, a renal vascular receptor, the
sympathetic nervous system, and ANG II.
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin I A. Macula Densa
Renin release is controlled in part by the macula densa, a structure
Converting enzyme that has a close anatomic association with the afferent arteriole.
The initial step involves the detection of some function of NaCl
concentration in, or delivery to, the distal tubule, possibly by the
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Na /K /2Cl cotransporter. The macula densa then signals changes
−
+
+
Angiotensin II in renin release by the juxtaglomerular cells such that there is an
inverse relationship between NaCl delivery or concentration and
Aminopeptidase
renin release. Potential candidates for signal transmission include
prostaglandin E (PGE ) and nitric oxide, which stimulate renin
2
2
release, and adenosine, which inhibits it. Because the sodium
Arg-Val-Tyr-Ile-His-Pro-Phe intake in the general population is high, macula densa-mediated
Angiotensin III
renin secretion is usually at basal levels, increasing only when
sodium intake decreases.
Angiotensinases
B. Renal Baroreceptor
The renal vascular baroreceptor mediates an inverse relationship
Peptide fragments
between renal artery pressure and renin release. The mechanism is
not completely understood, but it appears that the juxtaglomeru-
FIGURE 17–1 Chemistry of the renin-angiotensin system. The lar cells are sensitive to stretch and that increased stretch results
amino acid sequence of the amino terminal of human angiotensino- in decreased renin release. The decrease may result from influx
gen is shown. R denotes the remainder of the protein molecule. See of calcium which, somewhat paradoxically, inhibits renin release.
text for additional steps in the formation and metabolism of angio- The paracrine factors PGE , nitric oxide, and adenosine have also
2
tensin peptides. been implicated in the baroreceptor control of renin release. At
normal blood pressure, renal baroreceptor-mediated renin secre-
Active renin in the circulation originates in the kidneys and tion is low; it increases in hypotensive states.
disappears entirely after nephrectomy. Within the kidney, renin
is synthesized and stored in the juxtaglomerular apparatus of the C. Sympathetic Nervous System
nephron. Specialized granular cells called juxtaglomerular cells Norepinephrine released from renal sympathetic nerves stimulates
are the site of synthesis, storage, and release of renin. The macula renin release indirectly by α-adrenergic activation of the renal
densa is a specialized segment of the nephron that is closely associ- baroreceptor and macula densa mechanisms, and directly by an
ated with the vascular components of the juxtaglomerular appara- action on the juxtaglomerular cells. In humans, the direct effect
tus. The vascular and tubular components of the juxtaglomerular is mediated by β 1 adrenoceptors. Through this mechanism, reflex
apparatus, including the juxtaglomerular cells, are innervated by activation of the sympathetic nervous system by hypotension or
the sympathetic nervous system. hypovolemia leads to activation of the renin-angiotensin system.
Prorenin is present in the circulation at levels higher than those
of active renin. Plasma prorenin levels decrease after nephrec- D. Angiotensin
tomy, but significant amounts remain. The remaining prorenin ANG II inhibits renin release. The inhibition results from increased
is thought to originate in extrarenal tissues including the adrenal blood pressure acting by way of the renal baroreceptor and macula
gland, ovaries, testes, placenta, and retina. Plasma prorenin may densa mechanisms, and from a direct action of the peptide on the
exert actions via a unique prorenin receptor. juxtaglomerular cells. The direct inhibition is mediated by increased
2+
intracellular Ca concentration and forms the basis of a short-loop
Control of Renin Release negative feedback mechanism controlling renin release. Interrup-
The rate at which renin is released by the kidneys is the pri- tion of this feedback with drugs that inhibit the renin-angiotensin
mary determinant of activity of the renin-angiotensin system. system results in stimulation of renin release.