Coronary vasodilation and improvement in endothelial dysfunction with endothelin ETA receptor blockade

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ETA receptor activation. We hypothesized t hat ETA receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclero sis or its risk factors. Epicardial diameter (D) and Doppler flow velocity were measured, and coronary vascular resistance (CVR) was calculated during intracoronary infusions of acetylcholine (ACH) and sodium nitroprusside (S NP), and during cold pressor testing, before and after a 60-minute intracor onary infusion of the ETA receptor antagonist BQ-123. BQ-123 dilated the co ronary circulation; D increased by 5.6+/-1.0% (P<0.0001), and CVR fell by 1 2+/-3% (P<0.01). The D response to ACH, corrected for the SNP response, imp roved in segments that constricted with ACH at baseline (P=0.03), whereas s egments that initially dilated with ACH did not change with BQ-123 (P=NS). Improvement in D and CVR responses to ACH with BQ-123 inversely correlated with baseline ACH responses (r=-0.44 [P=0.006] and r=-0.78 [P=0.001], respe ctively), indicating greater improvement in those with endothelial dysfunct ion. Similarly, cold pressor testing-mediated epicardial vasoconstriction ( -2.0+/-1.1%) was reversed after BQ-123 (+1.0+/-0.7%), especially in dysfunc tional segments (from -5.6+/-0.9% to +2.2+/-0.9%, P<0.001). There was no co rrelation between any risk factor and the response to BQ-123. An arterioven ous difference in ET-1 levels developed after BQ-123, which was consistent with enhanced cardiac clearance of ET-1, probably via ETB receptors. Thus, ET-1 acting via the ETA receptor contributes to basal human coronary vasoco nstrictor tone and endothelial dysfunction. This suggests that ETA receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.