Abstract 5499: Regulation Of Coronary Vascular Tone Via Redox Modulation In The Alpha1 -adrenergic-angiotensin-endothelin Axis Of The Myocardium
We hypothesized that α1-adrenoceptor stimulation on the cardiac myocytes results in the production of an endothelin-releasing factor, which stimulates the coronary vasculature to release endothelin, and may influence the extent of α1-adrenergic-endothelin-1-vasoconstriction by manipulating the redox state of cardiac and vascular cells. Relative dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which was enhanced by a 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), but not by a NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate, an angiotensin converting enzyme inhibitor, did not change DHE and DCF intensities by phenylephrine. Next, we measured vasoconstriction of isolated, pressurized rat coronary arteriole (74±8 μm, diameter) in response to supernatant collected from isolated cardiac myocytes. Addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n=8, each) caused volume-dependent vasoconstriction (500 μl: −14.8±2.2%). Olmesartan and TA0201, endothelin type-A receptor antagonist, converted vasoconstriction into vasodilation (8.5±1.2% and 10.5±0.5%, P < 0.01, respectively) in response to the supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone- or antioxidant N-acetylcysteine-treated myocytes. Treatment of arterioles with apocynin to the myocyte supernatant converted vasoconstriction into vasodilation (7.8±0.8%, P < 0.01). These results suggest that α1-adrenergic stimulation in cardiac myocytes produces angiotensin I and hydrogen peroxide, and that angiotensin releases endothelin-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the α-adrenergic-angiotensin-endothelin axis appears to require redox-mediated signaling in cardiac and vascular cells.