DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

722
Angiotensinogen
43 a.a. propeptide
Renin
Prorenin
Ang I
[des-Asp 1 ]
(2-10)
AP
Angiotensin I
(1-10)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
1 2 3 4 5 6 7 8 9 10
ACE2
Ang
(1-9)
ACE
ACE
chymase
E
ACE
PCP
Ang IV
(3-8)
AP
Ang III
(2-8)
AP
Angiotensin II (1-8)
ACE2
Ang
(1-7)
SECTION III
AT 4 (IRAP) AT 2
AT 1
Mas PRR
Figure 26–1. Components of the RAS. The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways.
ACE, angiotensin- converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulin-regulated amino
peptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT 1
, AT 2
, Mas, AT 4
, and PRR.
∗
Exposure of the active site of renin can also occur non-proteolytically; see text and Figure 26-3.
MODULATION OF CARDIOVASCULAR FUNCTION
renal arterial circulation by the granular juxtaglomerular cells
(Figure 26–2) located in the walls of the afferent arterioles that enter
the glomeruli. Renin is an aspartyl protease that cleaves the bond
between residues 10 and 11 at the amino terminus of angiotensinogen
to generate AngI. The active form of renin is a glycoprotein that
contains 340 amino acids. It is synthesized as a preproenzyme of
406 amino acid residues that is processed to prorenin. Prorenin is
proteolytically activated by proconvertase 1 or cathepsin B enzymes
that remove 43 amino acids (propeptide) from its amino terminus to
uncover the active site of renin (Figure 26–3). The active site of
renin is located in a cleft between the two homologous lobes of the
enzyme. Nonproteolytic activation of prorenin, central to the activation
of local (tissue) RAS, occurs when prorenin binds to the
prorenin/renin ((pro)renin) receptor, resulting in conformational
changes that unfold the propeptide and expose the active catalytic
site of the enzyme. (Danser et al., 2005). Both renin and prorenin
are stored in the juxtaglomerular cells and, when released, circulate
in the blood. The concentration of prorenin in the circulation
is ~10-fold greater than that of the active enzyme. The t 1/2
of circulating
renin is ~15 minutes.
Control of Renin Secretion. The secretion of renin from juxtaglomerular
cells is controlled predominantly by three pathways (Figure 26–2):
• the macula densa pathway
• the intrarenal baroreceptor pathway
• the β 1
adrenergic receptor pathway
The first mechanism is the macula densa pathway. The macula
densa lies adjacent to the juxtaglomerular cells and is composed of
specialized columnar epithelial cells in the wall of that portion of
the cortical thick ascending limb that passes between the afferent
and efferent arterioles of the glomerulus. A change in NaCl reabsorption
by the macula densa results in the transmission to nearby
juxtaglomerular cells of chemical signals that modify renin release.
Increases in NaCl flux across the macula densa inhibit renin release,
whereas decreases in NaCl flux stimulate renin release. ATP, adenosine,
and prostaglandins modulate the macula densa pathway. ATP and
adenosine are released when NaCl transport increases ATP acts on
P2Y receptors to inhibit renin release. Adenosine acts via the A 1
adenosine receptor to inhibit renin release. Prostaglandins (PGE 2
,
PGI 2
) are released when NaCl transport decreases and stimulate renin
release through enhancing cyclic AMP formation. Prostaglandin production
is stimulated by inducible cyclooxygenase-2 (COX-2). COX-2
and neuronal nitric oxide synthase (nNOS) participate in the mechanism
of macula densa–stimulated renin release. The expression of
COX-2 and nNOS is upregulated by chronic dietary Na + restriction;
selective inhibition of either COX-2 or nNOS inhibits renin release.
The nNOS/NO pathway, in part, may mediate increases in COX-2
expression induced by a low- Na + diet; however, COX-2 expression in
the macula densa is not attenuated in nNOS knockout mice, which
suggests that other mechanisms can compensate for nNOS in the regulation
of COX-2.
Regulation of the macula densa pathway is more dependent
on the luminal concentration of Cl – than Na + . NaCl transport into
the macula densa is mediated by the Na + –K + –2Cl – symporter
(Figure 26–2B), and the half- maximal concentrations of Na + and
Cl – required for transport via this symporter are 2-3 and 40 mEq/L,
respectively. Because the luminal concentration of Na + at the macula
densa usually is much greater than the level required for halfmaximal
transport, physiological variations in luminal Na +
concentrations at the macula densa have little effect on renin
release (i.e., the symporter remains saturated with respect to Na + ).
On the other hand, physiological changes in Cl – concentrations
(20-60 mEq/L) at the macula densa profoundly affect macula densa–
mediated renin release.