Prolonged blockade of endothelin ETA receptors decreases vascular reactivity in the aorta of spontaneously hypertensive rats in vitro

We investigated the effect of prolonged endothelin-l type A (ETA) receptors blockade on the constrictor response to phenylephrine and the dilator resp onse to acetylcholine (ACh) in isolated aortic rings from normotensive [Wis tar-Kyoto (WKY)] rats and spontaneously hypertensive rats (SHRs). Animals w ere treated for 2 weeks with the ETA- receptor blocker LU135252 (50 mg/kg/d ay; n = 8). LU135252 treatment did not affect blood pressure in both strain s. In isolated aortic segments, dilation to ACh and contractions to phenyle phrine were decreased only in SHRs. Nitric oxide (NO) synthesis blockade (L -NAME, 0.1 mM) inhibited 90 +/- 11% (WKY rats) and 76 +/- 8% (SHRs) of ACh- induced dilation. Cyclooxygenases blockade (indomethacin, 10 mu M) had no e ffect in both strains. Endothelium-derived hyperpolarizing factor(s) (EDHF) blockade (KCI, 20 mM) suppressed the remaining ACh-induced dilation in bot h strains. Treatment with LU135252 significantly decreased NO-dependent dil ation, as compared with controls [70 +/- 8% vs. 90 +/- 11% (WKY rats) and 5 4 +/- 6% vs. 76 +/- 8% (SHRs) of total dilation; p < 0.05]. On the other ha nd, EDHF-dependent dilation was significantly higher in the LU135252 groups [29 +/- 5% vs. 10 +/- 3% (WKY rats) and 44 +/- 7% vs. 19 +/- 4% (SHRs) of total dilation; p < 0.05]. Thus prolonged ETA-receptor blockade decreased t he responsiveness to phenylephrine and ACh in SHR aortas and changed the pr oportion of dilator agents in ACh-induced dilation.