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

The Mas receptor mediates the effects of Ang(1–7), which
include vasodilation and anti- proliferation. Deletion of the Mas gene
in transgenic mice reveals cardiac dysfunction (Santos et al., 2008).
The AT 4
receptor (IRAP; see Figure 26-2) mediates the
effects of AngIV. This receptor is a single transmembrane protein
(1025 amino acids) that co- localizes with the glucose transporter
GLUT4. AT 4
receptors are detectable in a number of tissues, such as
heart, vasculature, adrenal cortex, and brain regions processing sensory
and motor functions (Chai et al., 2004).
Angiotensin Receptor–Effector Coupling. AT 1
receptors activate a
large array of signal- transduction systems to produce effects that
vary with cell type and that are a combination of primary and secondary
responses. AT 1
receptors couple to several heterotrimeric
G proteins, including G q
, G 12/13
, and G i
. In most cell types, AT 1
receptors
couple to G q
to activate the PLCβ–IP 3
–Ca 2+ pathway. Secondary
to G q
activation, activation of PKC, PLA 2
, and PLD and eicosanoid
production, as well as activation of Ca 2+ -dependent and MAP
kinases and the Ca 2+ –calmodulin–dependent activation of NOS may
occur. Activation of G i
may occur and will reduce the activity of
adenylyl cyclase, lowering cellular cyclic AMP content; however,
there also is evidence for G q
→ G s
cross- talk such that activation of
the AT 1
–G q
–PLC pathway enhances cyclic AMP production
(Meszaros et al., 2000; Epperson et al., 2004). The βγ subunits of G i
and activation of G 12/13
lead to activation of tyrosine kinases and
small G proteins such as Rho. Ultimately, the JAK/STAT pathway
may be activated and a variety of transcriptional regulatory factors
induced. By these mechanisms, angiotensin influences the expression
of a host of gene products relating to cell growth and the production
of components of the extracellular matrix. AT 1
receptors also
stimulate the activity of a membrane- bound NADH/NADPH oxidase
that generates reactive oxygen species (ROS). ROS may contribute
to biochemical effects (activation of MAP kinase, tyrosine
kinase, and phosphatases; inactivation of NO; and expression of
monocyte chemoattractant protein-1) and physiological effects
(acute effects on renal function, chronic effects on blood pressure,
and vascular hypertrophy and inflammation) (Mehta and Griendling,
2007; Higuchi et al., 2007). The relative importance of these myriad
signal- transduction pathways in mediating biological responses to
AngII is tissue specific. The presence of other receptors may alter the
response to AT 1
receptor activation. For example, AT 1
receptors heterodimerize
with bradykinin B 2
receptors, a process that enhances
AngII sensitivity in preeclampsia (AbdAlla et al., 2002).
Less is known about AT 2
receptor–effector coupling.
Signaling from AT 2
receptors is mediated by G protein- dependent
and independent pathways. Consequences of AT 2
receptor activation
include activation of phosphoprotein phosphatases, K + channels, synthesis
of NO and cyclic GMP, bradykinin production, and inhibition
of Ca 2+ channel functions (Jones et al., 2008). AT 2
receptors may possess
constitutive activity. Overexpression of AT 2
receptors has been
reported to induce NO production in vascular smooth muscle cells
and hypertrophy in cardiac myocytes through an intrinsic activity of
the AT 2
receptor independent of angiotensin binding (D’Amore et al.,
2005; Jones et al., 2008). Homo- oligomerization of AT 2
receptors
also has been reported to induce apoptosis (Miura et al., 2005). The
AT 2
receptor may bind directly to and antagonize the AT 1
receptor
(AbdAlla et al., 2001) and can form heterodimers with the bradykinin
B 2
receptor to enhance NO production (Abadir, 2006).
Functions and Effects of the
Renin–Angiotensin System
The main effects of AngII on the cardiovascular system
include:
• rapid pressor response
• slow pressor response
• vascular and cardiac hypertrophy and remodeling
Modest increases in plasma concentrations of
AngII acutely raise blood pressure; on a molar basis,
AngII is ~40 times more potent than NE (see Chapter 12);
the EC 50
of AngII for acutely raising arterial blood pressure
is ~0.3 nM. When a single moderate dose of AngII
is injected intravenously, systemic blood pressure
begins to rise within seconds, peaks rapidly, and returns
to normal within minutes (Figure 26–5). This rapid
pressor response to AngII is due to a swift increase in
total peripheral resistance— a response that helps to
maintain arterial blood pressure in the face of an acute
hypotensive challenge (e.g., blood loss or vasodilation).
Although AngII increases cardiac contractility directly
(via opening voltage- gated Ca 2+ channels in cardiac
myocytes) and increases heart rate indirectly (via facilitation
of sympathetic tone, enhanced adrenergic neurotransmission,
and adrenal catecholamine release), the
rapid increase in arterial blood pressure activates a
baroreceptor reflex that decreases sympathetic tone and
increases vagal tone. Thus, depending on the physiological
RBF (ml/min) BP (mm Hg)
250
200
150
100
50
100
50
0
1 min
ANG II
Figure 26–5. Effect of a bolus intravenous injection of AngII
(0.05 μg/kg) on arterial blood pressure (BP) and renal blood flow
(RBF) in a conscious dog. (Reproduced with permission, from
Zimmerman BG. Absence of adrenergic mediation of agonist
response to [Sar 1 ,Ala 8 ] angiotensin II in conscious normotensive
and hypertensive dogs. Clin Sci, 1979, 57:71–81. © the
Biochemical Society.)
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CHAPTER 26
RENIN AND ANGIOTENSIN