Abstract 246: Metabolic Regulation of Coronary Vascular Tone: Role of Hydrogen Peroxide, Adenosine, and Angiotensin
Cardiac myocytes act as oxygen sensors and modulate coronary vascular tone by producing vasodilator and vasoconstrictor signals to titrate oxygen needs to demands. We hypothesized that 3 substances produced by cardiac myocytes, the vasodilators, hydrogen peroxide (H2O2) and adenosine, and the vasoconstrictor, angiotensin (AI), regulate coronary vascular tone in proportion to metabolism. To test this hypothesis, we measured changes in diameter of isolated, pressurized coronary arterioles (74 ± 8 μm, diameter) to supernatant collected from enzymatically isolated cardiac myocytes from rats (unpaced or stimulated 20, 60, 120 min at 400 beats/min with or without catalase 10000U/ml, n=10, each). Pacing significantly increased oxygen consumption of cardiac myocytes and increased production of reactive oxygen species (dihydroethidium and dichlorodihydrofluorescein fluorescence for superoxide and H2O2, respectively). Changes in diameter of arterioles were determined under control conditions and following treatment of the isolated arterioles with adenosine receptor antagonist, 8-parasulfophenyl-theophilline (8PSPT, 50 μM) or angiotensin receptor-1 antagonist, olmesartan (1 μM). The addition of supernatant (500 μl to a 2 ml bath) from 20, 60, 120 min-stimulated myocytes caused graded vasodilation (58 ± 6 %, 78 ± 5 %, 98 ± 6 %, increase in diameter, respectively, P<0.01 vs unpaced). Administration of catalase to the myocyte chamber eliminated vasodilation to supernatant from 20 min-stimulated myocytes (0.2 ± 1.2 %) or converted vasodilation to vasoconstriction with supernatant from 60 min-stimulated myocytes (15 ± 4 %, P<0.01), which (vasoconstriction) was eliminated by olmesartan (0.3 ± 1 %). Catalase reduced vasodilation to supernatant from 120 min-stimulated myocytes (65 ± 8 %, P<0.01), but did not completely inhibit the dilation. This remaining vasodilation converted to vasoconstriction with 8PSPT (24 ± 5 %, P<0.01). Olmesartan eliminated vasoconstriction to supernatant from 120 min-stimulated myocytes treated with catalase and 8PSPT (0.5 ± 1.2 %). Taken together, we speculate that cardiac myocytes modulate vascular tone via production of the dilators H2O2 and adenosine, and the constrictor, AI, according to myocardial oxygen demands.