Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in l-NAME-induced hypertensive rats

Male Sprague-Dawley rats given Nω-nitro-l-arginine methyl ester (l-NAME) in drinking water for 8 weeks showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell nitric oxide synthase (eNOS) gene expression in aortic tissue; (3) a marked reduction of plasma nitrite/nitrate concentrations; (4) a reduction of the relaxant activity of acetylcholine (ACh, from 10−10 to 10−4 M) on norepinephrine-precontracted aortic rings (reduction by 48 ± 5%); (5) a marked decrease (−58%) of the basal release of 6-keto-prostaglandin F1α (6-keto-PGF1α) from aortic rings. In l-NAME-treated rats, administration in the last 4 weeks of either the angiotensin-converting enzyme (ACE) inhibitor enalapril (10 mg/kg/day in tap water) or the angiotensin AT1-receptor antagonist losartan (10 mg/kg/day in tap water) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue and plasma nitrite/nitrate levels, and allowed a consistent recovery of both the relaxant activity of acetylcholine and the generation of 6-keto-PGF1α. Coadministration of icatibant, a bradykinin B2-receptor antagonist (200 μg/kg/day), with enalapril blunted the stimulatory effect of the ACE inhibitor on eNOS mRNA expression, circulating levels of nitrite/nitrate, the relaxant activity of ACh and the release of 6-keto-PGF1α in l-NAME-treated rats. The generation of 6-keto-PGF1α from aortic rings was also decreased in rats coadministered icatibant with losartan. These findings indicate that (1) the ACE inhibitor enalapril and the angiotensin AT1-receptor blocker losartan are equally effective to reverse NAME-induced endothelial dysfunction; (2) the beneficial effect of enalapril on the endothelial vasodilator function in l-NAME-treated rats is mediated by bradykinin B2-receptor activation; and (3) the enhanced endothelial generation of prostacyclin induced by losartan in l-NAME rats is also mediated by bradykinin B2-receptor activation.