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Angiotensin type 2 receptor-mediated effects of
angiotensin II appear to counteract many of the effects mediated via the
angiotensin type 1 receptor.
Compound 21 (
C21), a selective
angiotensin type 2 receptor agonist, has demonstrated beneficial effects on cardiac function after
myocardial infarction in rodents. We hypothesized that
C21 alone or in combination with an
angiotensin type 1 receptor antagonist would blunt the development of
hypertension and vascular damage in
stroke-prone spontaneously hypertensive rats. Six-week-old
stroke-prone spontaneously hypertensive rats received
C21 (1 mg/kg per day), the
angiotensin type 1 receptor antagonist
losartan (10 mg/kg per day),
C21 plus
losartan, or vehicle PO for 6 weeks. Systolic blood pressure was lower in
losartan and C21-losartan combination groups (P<0.001). Endothelium-dependent relaxation was enhanced (P<0.001) in the C21-losartan combination group at lower
acetylcholine concentrations.
C21 or C21-losartan combination reduced vascular stiffness, aortic medial and myocardial interstitial
collagen content, and aortic
fibronectin (P<0.05).
C21 and
losartan decreased the expression of 2 genes associated with
cardiac hypertrophy,
myosin heavy chain-β (myh7) by 30 to 50%, and α-skeletal muscle actin by 30% to 35% (P<0.05). C21-losartan combination caused an additional 40% reduction in myh7 compared with
C21 (P<0.01). Aortic
superoxide generation was reduced equally by the 3 treatments (P<0.001). Monocyte/macrophage infiltration in the aorta and kidney (P<0.001) and T-lymphocyte infiltration in the renal cortex (P<0.05) were lowered similarly by the 3 treatments. These data suggest that
C21 alone or in combination with
losartan may improve endothelial function and vascular composition and mechanics by reducing oxidative stress,
collagen content,
fibronectin, and inflammatory cell infiltration in
stroke-prone spontaneously hypertensive rats.