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

730 Normally, GFR is slightly reduced by AngII;
however, during renal artery hypotension, the effects of
AngII on the efferent arteriole predominate so that
AngII increases GFR. Thus, blockade of the RAS may
cause acute renal failure in patients with bilateral renal
artery stenosis or in patients with unilateral stenosis
who have only a single kidney.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Vascular and Cardiac Hypertrophy and Remodeling.
Pathological alterations involving cardiac hypertrophy
and remodeling increase morbidity and mortality. These
morbid changes in cardiovascular structure are due to
increased migration, proliferation (hyperplasia), and
hypertrophy of cells, as well as to increased extracellular
matrix. The cells involved include vascular smooth
muscle cells, cardiac myocytes, and fibroblasts. In this
regard, AngII:
• stimulates the migration, proliferation, and hypertrophy
of vascular smooth muscle cells
• increases extracellular matrix production by vascular
smooth muscle cells
• causes hypertrophy of cardiac myocytes
• increases extracellular matrix production by cardiac
fibroblasts
These effects of AngII are mediated by acting
directly on cells to induce the expression of specific
proto- oncogenes (c-fos, c- jun, c- myc, and egr-1) that
alter the expression of growth factors such as basic FGF,
PDGF, and TGF- β. In addition, AngII alters extracellular
matrix formation and degradation indirectly by
increasing aldosterone.
Hemodynamically Mediated Effects of Angiotensin II on
Cardiovascular Structure. In addition to the direct cellular
effects of AngII on cardiovascular structure, changes
in cardiac preload (volume expansion owing to Na +
retention) and afterload (increased arterial blood pressure)
probably contribute to cardiac hypertrophy and
remodeling. Arterial hypertension also contributes to
hypertrophy and remodeling of blood vessels.
Role of the RAS in Long-Term Maintenance of Arterial
Blood Pressure Despite Extremes in Dietary Na +
Intake. Arterial blood pressure is a major determinant
of Na + excretion. This is illustrated graphically by plotting
urinary Na + excretion versus mean arterial blood
pressure (Figure 26–7), a plot known as the renal pressure–natriuresis
curve. Over the long term, Na + excretion
must equal Na + intake; therefore, the set point for
long- term levels of arterial blood pressure can be
obtained as the intersection of a horizontal line representing
Na + intake with the renal pressure–natriuresis.
As illustrated in Figure 26–7, the RAS plays a major
role in maintaining a constant set point for long- term
levels of arterial blood pressure despite extreme
changes in dietary Na + intake. When dietary Na + intake
is low, renin release is stimulated, and AngII acts on the
kidneys to shift the renal pressure–natriuresis curve to
the right. Conversely, when dietary Na + is high, renin
release is inhibited, and the withdrawal of AngII shifts the
renal pressure–natriuresis curve to the left. When modulation
of the RAS is blocked by drugs, changes in salt
intake markedly affect long- term levels of arterial blood
pressure.
Other Effects of the RAS. Expression of the RAS is
required for the development of normal kidney morphology,
particularly the maturational growth of the renal
papilla (Niimura et al., 1995). AngII causes a marked
anorexigenic effect and weight loss, and high circulating
levels of AngII may contribute to the anorexia, wasting,
and cachexia of heart failure (Brink et al., 1996).
Angiotensin and Vascular Disease
The RAS induces vascular disease by multiple mechanisms,
including directly and indirectly (via aldosterone):
stimulating vascular smooth muscle cell
migration, proliferation, and extracellular matrix production;
increasing the release of plasminogen activator
inhibitor type 1 and enhancing the expression of
monocyte chemoattractant protein 1; augmenting the
expression of adhesion proteins (e.g., ICAM-1, integrins,
and osteopontin) in vascular cells; and stimulating
the production of inflammatory chemokines and
cytokines that enhance the migration of inflammatory
cells (Schmieder et al., 2007). AngII markedly accelerates
the development of atherosclerosis in apolipoprotein
E–deficient mice (Weiss et al., 2001), an animal
model of atherosclerosis.
INHIBITORS OF THE
RENIN–ANGIOTENSIN SYSTEM
Clinical interest focuses on developing inhibitors of the
RAS. Three types of inhibitors are utilized therapeutically
(Figure 26–8):
• ACE inhibitors (ACEIs)
• angiotensin receptor blockers (ARBs)
• direct renin inhibitors (DRIs)