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(Circulation Research. 2001;89:969.)
© 2001 American Heart Association, Inc.

Clinical Research

Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ET_A Receptor Blockade

Julian P.J. Halcox, Khaled R.A. Nour, Gloria Zalos, Arshed A. Quyyumi

From the Cardiology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Md.

Correspondence to Arshed A. Quyyumi, MD, Professor of Medicine (Cardiology), Emory University Hospital, Suite F606, 1364 Clifton Rd NE, Atlanta, GA 30322. E-mail aquyyum{at}emory.edu

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET_A receptor activation. We hypothesized that ET_A 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 ET_A 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 ET_B receptors. Thus, ET-1 acting via the ET_A receptor contributes to basal human coronary vasoconstrictor tone and endothelial dysfunction. This suggests that ET_A receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

Key Words: endothelin • coronary circulation • endothelial function • atherosclerosis

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