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 h ypertension. Flow triggers the release by endothelial cells of dilator s, such as NO or cyclo-oxygenase (COX) derivatives and constrictor fac tors such as endothelin-1 (ET-1) which might be involved in several ca rdiovascular diseases. We hypothesized that ET-1 might play a function al role in FD and participate in the endothelial dysfunction in hypert ension. Methods: We investigated the effect of a chronic treatment wit h the ET, receptor blocker LU135252 (50 mg/kg/day) for 2 weeks on the dilator response to flow in normotensive (Wistar-Kyoto; WKY) or hypert ensive (SHR, n=7 or 8 per group) rats. Results: Systolic arterial pres sure was not significantly affected by chronic ETA receptor blockade i n both strains. In mesenteric resistance arteries (diameter: approxima tely 100 mu m), isolated in vitro, FD was lower and myogenic tone high er 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 wa s increased in SHR and the participation of dilator COX product(s) (bl ocked by indomethacin 10 mu mol/l) to FD was significantly increased i n SHR and in WKY. In control rats FD was improved by acute ET, recepto r 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 chr onic ET, receptor blockade (no effect of an acute blockade). Myogenic and phenylephrine-induced tone were not affected by chronic or acute E TA receptor blockade. The improvement of endothelium-dependent dilatio n 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 Elsevie r Science B.V. All rights reserved.