section 32.1
Adrenal Cortex
P rep ro -ren in (4 0 6 a m in o acid s)
P ro -ren in (3 8 6 a m in o acid s)
P ro rein p ro cessin g e n z y m e -------------► |
R e n in (M .W . - 4 2 0 0 0 , 3 4 3 a m in o acid s)
A n g io ten sin o g en (renin s u b stra te )
(M .W . -6 1 ,0 0 0 )
+H ,N -A sp-A rg-V al-T yr-lle-H is-Pro-Phe-H is-L eu-V al-lle-H is-R *
R enin
I (dec
H is-P
j^ H is -l
V al-lle-H is-R
A ngiotensin I (d e c ap e p tid e )
N -A sp-A rg-V al-T yr-lie-H is-P ro-P he-H is-L eu-C O O -
C onverting
en zy m e
l'-*-H is-L eu
A ngiotenisin II (o ctap ep tid e)
(activ e)
R N -A sp -A rg -V al-T y r-lle-H is-P ro -P h e-C O O ”
A rteriolar
co n strictio n
A ld o stero n e
s ec re tio n
F I G U R E 3 2 - 3
Renin-angiotensin system. R* is the remainder of the amino acid sequence.
excretion of potassium, lowers serum potassium levels,
and thereby completes the negative feedback circuit.
Potassium ions are believed to act by causing depolar-
ization of the zona glomerulosa cells, allowing calcium
ions to enter the cells through voltage-gated calcium
channels. This increase in intracellular calcium ions fu-
els the calcium-dependent intracellular events triggered by
angiotensin II (see below), and would explain why the an-
giotensin II effect on aldosterone secretion is augmented in
hyperkalemic states and attenuated in hypokalemic states.
syste/raconsists of components
derived from precursor molecules produced by the liver
and kidney. The juxtaglomerular apparatus of the kidney
is a specialized region of the afferent arteriole that releases
an aspartyl protease (about M.W. 42,000), in re-
sponse to several stimuli (see below). Renin, derived from
an inactive precursor (prorenin) by the action of prorenin
processing enzyme (Figure 32-3), acts on the Leu-Val
bond at the amino terminus of a circulating a
or renin substrate secreted by the
liver. The liberated amino terminal segment is an inac-
tive decapeptide called angiotensin I. The physiologically
important fate of this decapeptide is realized during pas-
sage through capillary beds in the lung and other tissues,
where converting enzyme, a dipeptidyl carboxypeptidase
present in endothelial cells, splits off the carboxy terminal
dipeptide (His-Leu) to yield the highly active octapeptide
angiotensin II
(Figure 32-3).
Angiotensin II exerts
sodium-dependent arteriolar constriction, and it acts
glomerulosa to
secretion of aldosterone. Both of these effects are me-
diated by membrane-bound receptors coupled via a Gs
subunit to the phospholipase C-phosphatidylinositol 4,5-
biphosphate (PLC-PIP
) complex, which utilizes calcium
ions and protein kinase C (PKC) as intracellular effectors.
The effect of angiotensin II on aldosterone secretion in-
volves an activation of both CYP11A and CYP11B2 (al-
dosterone synthase) activities in the zona glomerulosa
and is influenced by dietary sodium intake; a low-sodium
diet enhances the aldosterone response to angiotensin II,
whereas a high-sodium diet tends to attenuate it.
Because renin release leads to formation of angiotensin
II and secretion of aldosterone, and because, under nor-
mal conditions, the concentrations of angiotensinogen and
converting enzyme are not rate limiting, any factor that
influences the release of renin influences the secretion of
aldosterone. Two important regulators of renin release are
the mean renal arterial blood pressure and the extracellu-
lar fluid volume (blood volume). A decrease in the mean
renal arterial blood pressure is sensed by baroreceptors
in the juxtaglomerular apparatus, which responds by re-
lease of renin. A decrease in blood volume, such as that
caused by hemorrhage or by standing from a reclining
position, results in diminished venous return to the heart.
Baroreceptors in the atrial walls of the heart signal this
change via cranial nerves to the vasomotor center in the
medulla oblongata, which then relays the information to
the juxtaglomerular apparatus via /(-adrenergic fibers, and
renin output is stimulated. Aldosterone, which is secreted
in response to renin release, promotes potassium excretion
and extracellular fluid retention and thus inhibits further
release of renin (Figure 32-4).
Regulation o f Cortisol Secretion
The principal regulator of cortisol secretion is ACTH
(see Chapter 31), the release of which is regulated by CRH
and by circulating unbound cortisol. The balance of the
effects of CRH and cortisol on the anterior pituitary main-
tains fairly constant ACTH stimulation of the adrenals
and circulating levels of cortisol. This closed-loop feed-
back system is superseded by neural signals from higher
regions of the brain in nonsteady-state conditions (e.g.,
circadian rhythm, stress).
ACTH exerts effects on the zona fasciculata by surface
binding, calcium-dependent activation of membrane-
bound adenylate cyclase and intracellular cAMP media-
tion. It increases activities of cholesterol esterase and
thereby stimulating production of pregnenolone. Choles-
terol side-chain cleavage enzyme is a cytochrome P-450
enzyme present in mitochondria. ACTH promotes the
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