Abstract 9790: Endothelin-1 Inhibits Endothelium-Dependent NO-Mediated Dilation of Coronary Arterioles via p38 Kinase Linked Superoxide Production From NAD(P)H Oxidase
Elevated levels of endothelin (ET)-1, a potent constrictor peptide, are associated with higher risk of cardiovascular diseases by promoting vasoconstriction and oxidative stress. However, it remains unknown whether ET-1, at subvasomotor concentrations, exerts adverse effects on coronary vasomotor function. To address this issue without confounding influences from systemic and local factors, porcine coronary arterioles (50-100 μm) were isolated, cannulated and pressurized without flow for in vitro study. Diameter changes were recorded using a videomicrometer. Dihydroethidium (DHE) staining was used to detect superoxide production. Arterioles developed basal tone (60±3 µm) and dilated dose-dependently to the endothelium-dependent NO-mediated vasodilators serotonin (1 nM to 0.1 µM) and adenosine (1 nM to 10 µM). Extraluminal incubation with a clinically relevant subvasomotor concentration of ET-1 (10 pM, 60 minutes) significantly attenuated arteriolar dilation to adenosine and serotonin but not to endothelium-independent vasodilator sodium nitroprusside. The adverse effects of ET-1 on serotonin- and adenosine-induced dilations were prevented by pretreating the vessels with the ETA receptor antagonist BQ123 (1 μM), the superoxide scavenger TEMPOL (1 mM), the NAD(P)H oxidase inhibitor apocynin (100 μM) or the p38 kinase inhibitor SB203580 (0.1 μM). However, the adverse effects of ET-1 were not prevented by pretreating the vessels with ETB receptor antagonist BQ788 (0.1 μM), H2O2 scavenger catalase (1000 units/ml), xanthine oxidase inhibitor allopurinol (10 μM) or c-Jun N-terminal kinase inhibitor SP600125 (5 μM). DHE immunohistochemical staining showed that ET-1 generated TEMPOL- and SB203580-sensitive superoxide production in the arteriolar endothelium. Collectively, our data indicate that exposure of coronary arterioles to a pathophysiological concentration of ET-1 inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activation of ETA receptors leading to the production of superoxide from NAD(P)H oxidase, which appears to be linked with p38 kinase activation.
- © 2011 by American Heart Association, Inc.