Hydrogen Peroxide

Objective— We tested the hypothesis that hydrogen peroxide (H 2 O 2 ), the dismutated product of superoxide (O 2 ·− ), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O 2 ·− and H 2 O 2 production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H 2 O 2 . Methods and Results— The production of O 2 ·− is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O 2 ·− during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O 2 ·− production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O 2 ·− production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67±8% percent of maximal dilation) that was significantly reduced by catalase (5±0.5%, P <0.05) or the antagonist of Kv channels, 4-aminopyridine (18±4%, P <0.05). In intact animals, tissue concentrations of H 2 O 2 are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H 2 O 2 by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus p o 2 . Conclusions— Taken together, our results demonstrate that O 2 ·− is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H 2 O 2 . Our results further suggest that the production of H 2 O 2 in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.