Positive influence of AT1 receptor antagonism upon the impaired celiprolol-induced vasodilatation in aorta from spontaneously hypertensive rats

Abstract

We evaluated celiprolol-induced vasodilatation in aorta taken from 12-week-old spontaneously hypertensive rats (SHR) and the effect of AT1 angiotensin II receptor antagonism on the vasodilatory action of celiprolol in Wistar Kyoto (WKY) rats and SHR. In WKY rats, the celiprolol-induced relaxation was greatly decreased in denuded aorta, and completely abolished in intact aorta by Nω-nitro-l-arginine methyl ester (l-NAME, 100μM). In SHR, celiprolol-induced relaxation was reduced compared to WKY rats (Emax (value obtained for the highest concentration, 300μM)=39.1±3.78%, n=21 vs. 80.4±3% in WKY rats, n=10; P<0.0001). Endothelium removal or pre-treatment with l-NAME did not alter celiprolol-induced relaxation in SHR. In both strains, relaxation to celiprolol was decreased in the presence of nadolol (a β1/β2-adrenoceptor antagonist, 10μM). N-[[3-[(2S)-2-hydroxy-3-[[2-[4-[(phenylsulfonyl)amino] phenyl]ethyl]amino] propoxy]phenyl]methyl]-acetamide (L748337, a β3-adrenoceptor antagonist, 7μM) had no effect. A 12-day treatment with candesartan cilexetil (an AT1 receptor antagonist, 0.37 or 1mg/kg/day) reduced systolic blood pressure in both strains, but only improved relaxation to celiprolol in SHR, and only at the highest dose (Emax=64.2±3.9%, n=10, P<0.0001 vs. SHR control). In both strains, local aortic AT1 receptor antagonism with candesartan CV11974 (100μM) had no effect. The endothelial β1/β2 relaxation induced by celiprolol was therefore impaired in SHR aorta and AT1 receptor antagonism improved the response to celiprolol, in conjunction with a reduction in blood pressure. This work highlights the need to analyse the potential benefit of a combination of celiprolol/AT1 receptor antagonist in the treatment of hypertension.