Male Sprague-Dawley rats given N?-nitro-L-arginine Me ester (L-NAME) in drinking water for 8 wk 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 redn. of plasma nitrite/nitrate concns.; (4) a redn. of the relaxant activity of acetylcholine (ACh, from 10-10 to 10-4 M) on norepinephrine-precontracted aortic rings (redn. by 48?5%); (5) a marked decrease (-58%) of the basal release of 6-keto-prostaglandin F1? (6-keto-PGF1?) from aortic rings. In L-NAME-treated rats, administration in the last 4 wk 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-PGF1?. Coadministration of icatibant, a bradykinin B2-receptor antagonist (200 ?g/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-PGF1? in L-NAME-treated rats. The generation of 6-keto-PGF1? 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.
|Titolo:||Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in L-NAME-induced hypertensive rats|
|Parole Chiave:||Angiotensin-converting enzyme inhibitor; AT1-receptor antagonist; Bradykinin; Endothelial dysfunction; Hypertension; NO (nitric oxide)|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2005|
|Digital Object Identifier (DOI):||10.1016/j.ejphar.2005.04.004|
|Appare nelle tipologie:||01 - Articolo su periodico|