title: Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.
abstract: We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox-mediated signaling in cardiac and vascular cells.
authors.affiliation: First Dept. of Internal Medicine, Fukushima Medical Univ., 1 Hikarigaoka, Fukushima 960-1295, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kaneshiro
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Saitoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000803:Angiotensin I / Q000096:biosynthesis; D000809:Angiotensins / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000378:metabolism; D002469:Cell Separation; D003331:Coronary Vessels / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D003627:Data Interpretation, Statistical; D004579:Electron Transport / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000809:Angiotensins; D019332:Endothelin-1; D016232:Endothelins; D017382:Reactive Oxygen Species; D018340:Receptors, Adrenergic, alpha-1; D000803:Angiotensin I; D006861:Hydrogen Peroxide