Regulation of coronary vascular tone via redox modulation in the 1-adrenergic-angiotensin-endothelin axis of the myocardium

Yamaguchi O, Kaneshiro T, Saitoh S, Ishibashi T, Maruyama Y, Takeishi Y. Regulation of coronary vascular tone via redox modulation in the 1-adrenergic-angiotensin-endothelin axis of the myocardium. Am J Physiol Heart Circ Physiol 296: H226–H232, 2009. First published November 21, 2008; doi:10.1152/ajpheart.00480.2008.—We hypothesized that 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 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 m) 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 l: 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 1-adrenergic stimulation in cardiac myocytes produces angiotensin I and H2O2 and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the -adrenergic-angiotensin-ET axis appears to require redox-mediated signaling in cardiac and vascular cells.