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

724
AGT
Ang I
43 amino acid
propeptide
AGT
Ang I
AGT
AGT
Aliskiren
Prorenin
PRR
Prorenin
Renin
Renin
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Prorenin
(inactive)
Non-proteolytic activation
(reversible)
The second mechanism controlling renin release is the
intrarenal baroreceptor pathway. Increases and decreases in blood
pressure or renal perfusion pressure in the preglomerular vessels
inhibit and stimulate renin release, respectively. The immediate
stimulus to secretion is believed to be reduced tension within the
wall of the afferent arteriole. The release of renal prostaglandins and
biomechanical coupling via stretch- activated ion channels may mediate
in part the intrarenal baroreceptor pathway (Wang et al., 1999).
The third mechanism, the β adrenergic receptor pathway, is
mediated by the release of norepinephrine from postganglionic sympathetic
nerves; activation of β 1
receptors on juxtaglomerular cells
enhances renin secretion.
The three mechanisms regulating renin release are embedded
in a feedback regulation (Figure 26–2A). Increased renin secretion
enhances the formation of AngII, which stimulates AT 1
receptors on
juxtaglomerular cells to inhibit renin release, an effect termed shortloop
negative feedback. AngII increases arterial blood via AT 1
receptors;
this effect inhibits renin release by:
• activating high- pressure baroreceptors, thereby reducing renal
sympathetic tone
• increasing pressure in the preglomerular vessels
• reducing NaCl reabsorption in the proximal tubule (pressure
natriuresis), which increases tubular delivery of NaCl to the
macula densa
The inhibition of renin release owing to AngII- induced
increases in blood pressure has been termed long- loop negative
feedback.
The physiological pathways regulating renin release are influenced
by arterial blood pressure, dietary salt intake, and a number of
pharmacological agents (Figure 26–2A). Loop diuretics stimulate
renin release by decreasing arterial blood pressure and by blocking
the reabsorption of NaCl at the macula densa. Nonsteroidal
anti- inflammatory drugs (NSAIDs; see Chapter 34) inhibit
prostaglandin synthesis and thereby decrease renin release. ACE
inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors
Proteolytic activation
(irreversible)
Inhibition of renin by
direct renin inhibitor
(Aliskiren)
Figure 26-3. Biological activation of prorenin and pharmacological inhibition of renin. Pro-renin (black segment) is inactive; accessibility
of angiotensinogen (AGT) to the active is blocked by the propeptide (black segment). The blocked catalytic site can be activated
non-proteolytically by the binding of prorenin to the (pro) renin receptor (PRR) or by proteolytic removal of the propeptide. The
competitive renin inhibitor, aliskiren, has a higher affinity (~0.1μm) for the active site of renin than does AGT (~1 μm).
interrupt both the short- and long- loop negative feedback mechanisms
and therefore increase renin release. Increasing cyclic AMP in
the juxtaglomerular cells stimulates renin. Centrally acting sympatholytic
drugs (see Chapter 12), as well as β adrenergic receptor
antagonists, decrease renin secretion by reducing activation of
β adrenergic receptors on juxtaglomerular cells.
Angiotensinogen. The substrate for renin is angiotensinogen, an
abundant globular glycoprotein (MW = 55,000-60,000). AngI is
cleaved from the amino terminus of angiotensinogen. The human
angiotensinogen contains 452 amino acids and is synthesized as preangiotensinogen,
which has a 24– or 33–amino acid signal peptide.
Angiotensinogen is synthesized and secreted primarily by the liver,
although angiotensinogen transcripts also are abundant in fat, certain
regions of the central nervous system (CNS), and the kidneys.
Angiotensinogen synthesis is stimulated by inflammation, insulin,
estrogens, glucocorticoids, thyroid hormone, and AngII. During
pregnancy, plasma levels of angiotensinogen increase several- fold
owing to increased estrogen.
Circulating levels of angiotensinogen are approximately
equal to the K m
of renin for its substrate (~1 μM). Consequently,
the rate of AngII synthesis, and therefore blood pressure, can be
influenced by changes in angiotensinogen levels. For instance,
knockout mice lacking angiotensinogen are hypotensive, and there
is a progressive relationship among the number of copies of the
angiotensinogen gene, plasma levels of angiotensinogen, and arterial
blood pressure. Oral contraceptives containing estrogen increase circulating
levels of angiotensinogen and can induce hypertension. A
missense mutation in the angiotensinogen gene (a methionine to
threonine at position 235 of angiotensinogen) that increases plasma
levels of angiotensinogen is associated with essential and pregnancyinduced
hypertension (Sethi et al., 2003). Angiotensinogen shares
sequence homologies that have anti- angiogenic properties with the
serpin protein family (Célérier et al., 2002).
Angiotensin-Converting Enzyme (ACE, Kininase II, Dipeptidyl
Carboxypeptidase). ACE is an ectoenzyme and glycoprotein with