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

728 state, AngII may increase, decrease, or not change cardiac
contractility, heart rate, and cardiac output. Changes
in cardiac output therefore contribute little, if at all, to
the rapid pressor response induced by AngII.
AngII also causes a slow pressor response that
helps to stabilize arterial blood pressure over the long
term. A continuous infusion of initially subpressor
doses of AngII gradually increases arterial blood pressure,
with the maximum effect requiring days to
achieve. This slow pressor response probably is mediated
by a decrement in renal excretory function that
shifts the renal pressure–natriuresis curve to the right
(see the next section). AngII stimulates the synthesis of
endothelin-1 and superoxide anion, which may contribute
to the slow pressor response.
In addition to its effects on arterial blood pressure,
AngII stimulates remodeling of the cardiovascular
system, causing hypertrophy of vascular and cardiac
SECTION III
cells and increased synthesis and deposition of collagen
by cardiac fibroblasts.
Mechanisms by Which Angiotensin II Increases Total
Peripheral Resistance. AngII increases total peripheral
resistance (TPR) via direct and indirect effects on blood
vessels (Figure 26–6).
Rapid Pressor Response
Direct Vasoconstriction. AngII constricts precapillary
arterioles and, to a lesser extent, postcapillary venules
by activating AT 1
receptors located on vascular smooth
muscle cells and stimulating the G q
–PLC–IP 3
–Ca 2+
pathway. AngII has differential effects on vascular beds.
Direct vasoconstriction is strongest in the kidneys
(Figure 26–5) and somewhat less in the splanchnic vascular
bed; blood flow in these regions falls sharply
when AngII is infused. AngII- induced vasoconstriction
is much less in vessels of the brain and still weaker in
MODULATION OF CARDIOVASCULAR FUNCTION
Altered
Peripheral
Resistance
Angiotensin II
MECHANISMS MECHANISMS MECHANISMS
I. Direct vasoconstriction
II. Enhancement of
peripheral noradrenergic
neurotransmission:
A. Increased NE release
B. Decreased NE reuptake
C. Increased vascular
responsiveness
III. Increased sympathetic
discharge (CNS)
IV. Release of catecholamines
from adrenal medulla
Altered
Renal
Function
I. Direct effect to increase Na +
reabsorption in proximal
tubule.
II. Release of aldosterone
from adrenal cortex
(increased Na + reabsorption
and increased K + excretion
in distal nephron)
III. Altered renal hemodynamics:
A. Direct renal vasoconstriction
B. Enhanced noradrenergic
neurotransmission in
kidney
C. Increased renal sympathetic
tone (CNS)
Altered
Cardiovascular
Structure
I. Non-hemodynamicallymediated
effects:
A. Increased expression of
proto-oncogenes
B. Increased production of
growth factors
C. Increased synthesis of
extracellular matrix
proteins
II. Hemodynamicallymediated
effects:
A. Increased afterload
(cardiac)
B. Increased wall tension
(vascular)
RESULT RESULT RESULT
Rapid Pressor Response
Slow Pressor Response
Vascular and Cardiac
Hypertrophy and Remodeling
Figure 26–6. Summary of the three major effects of AngII and the mechanisms that mediate them. NE, norepinephrine.