title: Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase.
abstract: Elevated levels of endothelin-1 (ET-1), a potent vasoactive peptide, are implicated as a risk factor for cardiovascular diseases by exerting vasoconstriction. The aim of this study was to address whether ET-1, at sub-vasomotor concentrations, elicits adverse effects on coronary microvascular function. Porcine coronary arterioles (50-100μm) were isolated, cannulated and pressurized without flow for in vitro study. Diameter changes were recorded using a videomicrometer. Arterioles developed basal tone (60±3μm) and dilated to the endothelium-dependent nitric oxide (NO)-mediated vasodilators serotonin (1nmol/L to 0.1μmol/L) and adenosine (1nmol/L to 10μmol/L). Treating the vessels with a clinically relevant sub-vasomotor concentration of ET-1 (10pmol/L, 60min) significantly attenuated arteriolar dilations to adenosine and serotonin but not to endothelium-independent vasodilator sodium nitroprusside. The arteriolar wall contains ETA receptors and the adverse effect of ET-1 was prevented by ETA receptor antagonist BQ123, the superoxide scavenger Tempol, the NADPH oxidase inhibitors apocynin and VAS2870, the NOX2-based NADPH oxidase inhibitor gp91 ds-tat, or the p38 kinase inhibitor SB203580. However, ETB receptor antagonist BQ788, H2O2 scavenger catalase, scrambled gp91 ds-tat, or inhibitors of xanthine oxidase (allopurinol), PKC (Gö 6983), Rho kinase (Y27632), and c-Jun N-terminal kinase (SP600125) did not protect the vessel. Immunohistochemical staining showed that ET-1 elicited Tempol-, apocynin- and SB203580-sensitive superoxide productions in the arteriolar wall. Our results indicate that exposure of coronary arterioles to a pathophysiological, sub-vasomotor concentration of ET-1 leads to vascular dysfunction by impairing endothelium-dependent NO-mediated dilation via p38 kinase-mediated production of superoxide from NADPH oxidase following ETA receptor activation.
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA; Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand.
authors.forename: Naris
authors.initials: N
authors.lastname: Thengchaisri
authors.affiliation: Department of Surgery, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.affiliation: Department of Surgery, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA; Department of Surgery, College of Medicine, Texas A&M Health Science Center, Temple, TX 76504, USA. Electronic address: lkuo@tamhsc.edu.
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000241:Adenosine / Q000008:administration & dosage; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage; D012701:Serotonin / Q000008:administration & dosage; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D012701:Serotonin; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine
keywords: Arterioles; Endothelin-1; Endothelium; NADPH oxidase; Superoxide