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The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ETA receptor activation. We hypothesized that ETA receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis 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 (SNP), and during cold pressor testing, before and after a 60-minute intracoronary infusion of the ETA receptor antagonist BQ-123. BQ-123 dilated the coronary circulation;D increased by 5.6 /-1.0% (P <0.0001), and CVR fell by 12 /-3% (P <0.01). The D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (P =0.03), whereas segments 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], respectively), indicating greater improvement in those with endothelial dysfunction. Similarly, cold pressor testing-mediated epicardial vasoconstriction (-2.0 /-1.1%) was reversed after BQ-123 ( 1.0 /-0.7%), especially in dysfunctional segments (from -5.6 /-0.9% to 2.2 /-0.9%, P <0.001). There was no correlation between any risk factor and the response to BQ-123. An arteriovenous 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 vasoconstrictor tone and endothelial dysfunction. This suggests that ETA receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

(C) 2001 American Heart Association, Inc.