Endothelin-receptor blockade improves endothelial vasomotor dysfunction inheart failure

Objectives: To elucidate the effect of selective endothelin ETA- and mixed ETA/B-receptor antagonists on endothelial vasomotor dysfunction in rats wit h heart failure after myocardial infarction (MI). Methods: Vasoreactivity a nd superoxide anion formation were determined in aortic rings from Wistar r ats 12 weeks after extensive MI (>46% of left ventricle) compared to sham-o perated animals. Rats were either treated with the selective ETA-receptor a ntagonist LU 135352 (30 mg/kg/day), the mixed ETA/B-receptor antagonist Bos entan (100 mg/kg/day) or placebo. Results: In MI rats, the concentration-re sponse curve of the endothelium-dependent, nitric oxide-mediated relaxation induced by acetylcholine was significantly shifted to the right and the ma ximum relaxation was attenuated. Long-term treatment with both ET antagonis ts significantly improved acetylcholine-induced relaxation in MI rats. LU 1 35251 was more effective than Bosentan. Endothelium-independent relaxations induced by sodium nitroprusside as well as endothelin- and phenylephrine-i nduced contractions were similar in all groups of rats. Plasma renin activi ty and aortic superoxide formation, which were enhanced in rats with heart failure, were normalized by LU 135252, but not by Bosentan treatment. Concl usions: Long-term treatment with ET-receptor antagonists improves endotheli al vasomotor dysfunction in rats with chronic MI. This mechanism may essent ially contribute to the beneficial effects of ET receptor blockade in heart failure. (C) 2000 Elsevier Science B.V. All rights reserved.