Chronic blockade of endothelin ETA receptors improves flow dependent dilation in resistance arteries of hypertensive rats

Objective: mow (shear stress)-induced dilation (FD) is attenuated in hypertension. Flow triggers the release by endothelial cells of dilators, such as NO or cyclo-oxygenase (COX) derivatives and constrictor factors such as endothelin-1 (ET-1) which might be involved in several cardiovascular diseases. We hypothesized that ET-1 might play a functional role in FD and participate in the endothelial dysfunction in hypertension. Methods: We investigated the effect of a chronic treatment with the ET, receptor blocker LU135252 (50 mg/kg/day) for 2 weeks on the dilator response to flow in normotensive (Wistar-Kyoto; WKY) or hypertensive (SHR, n=7 or 8 per group) rats. Results: Systolic arterial pressure was not significantly affected by chronic ETA receptor blockade in both strains. In mesenteric resistance arteries (diameter: approximately 100 mu m), isolated in vitro, FD was lower and myogenic tone higher in SHR than in WKY rats. Chronic ET, receptor blockade increased FD by 73% (7.5+/-1.5 to 13.0+/-2.7 mu m dilation with a flow-rate of 150 mu l/min) in SHR (no effect in WKY). The participation of NO to FD was increased in SHR and the participation of dilator COX product(s) (blocked by indomethacin 10 mu mol/l) to FD was significantly increased in SHR and in WKY. In control rats FD was improved by acute ET, receptor blockade in WKY rats (18.5+/-2.0 to 23.2+/-1.8 mu m dilation to flow-rate of 150 mu l/min) and significantly more in SHR (6.0+/-1.8 to 15.1+/-1.6 mu m). Acetylcholine-induced dilation was also improved by chronic ET, receptor blockade (no effect of an acute blockade). Myogenic and phenylephrine-induced tone were not affected by chronic or acute ETA receptor blockade. The improvement of endothelium-dependent dilation was not related to a change in blood pressure Conclusion: Chronic ET, receptor blockade increased flow-induced dilation in SHR possibly by suppressing flow-induced ETA stimulation and by improving the release of dilator products by the endothelium. (C) 1998 Published by Elsevier Science B.V. All rights reserved.