Endothelin receptor blockade improves endothelial function in human internal mammary arteries

Objective: Endothelial dysfunction, specifically endothelium-derived contra cting factors have been implicated in the development of arterial conduit v asospasm. The potent vasoconstrictor endothelin-1 (ET-1) has received much attention in this regard. The present study was designed to evaluate the ro le of ET-I in the development of endothelial dysfunction in human internal mammary arteries (IMA). To this aim, we examined the effects of specific an d non-specific ET-receptor antagonists on endothelial function (assessed us ing acetylcholine (ACh)-induced vasodilation) in segments of IMA obtained d uring coronary artery bypass graft (CABG) surgery. Methods: Vascular segmen ts of IMA were obtained from 51 patients undergoing elective coronary arter y bypass graft (CABG) surgery and in vitro endothelium-dependent and -indep endent responses to ACh and sodium nitroprusside (SNP) were assessed. Isome tric dose response curves (DRC) to ACh and SNP were constructed in pre-cont racted rings in the presence and absence of bosentan (ETA/B receptor antago nist, 3 muM), BQ-123 (ETA antagonist, 1 muM) and BQ-788 (ETB antagonist, 1 muM) using the isolated organ bath apparatus. Percent maximum relaxation (% E-max) and sensitivity (pEC(50)) were compared between interventions. Resul ts: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E-ma x 43+/-4, pEC(50) 6.74+/-0.12). In the presence of bosentan, BQ-123 and BQ- 788 ACh-induced relaxation was significantly augmented (%E-max bosentan 60/-3, BQ-123 56+/-4, BQ-788 53+/-5 vs. control 43+/-4, P<0.05) without affec ting sensitivity. The effects of these antagonists were endothelium-specifi c since endothelium-independent responses to SNP remained unaltered. Furthe rmore, the beneficial effects were independently and maximally mediated by ETA and ETB receptors (%E-max BQ-123 56+/-4 vs. BQ-788 53+/-5 vs, bosentan 60+/-3, P>0.05). Conclusions: These data uncover, for the first time, benef icial effects of ET receptor blockade on endothelium-dependent vasorelaxati on in human IMA. (C) 2001 Elsevier Science B.V. All rights reserved.