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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2614.)
© 2006 American Heart Association, Inc.

Vascular Biology

Hydrogen Peroxide

A Feed-Forward Dilator That Couples Myocardial Metabolism to Coronary Blood Flow

Shu-ichi Saitoh; Cuihua Zhang; Johnathan D. Tune; Barry Potter; Takahiko Kiyooka; Paul A. Rogers; Jarrod D. Knudson; Gregory M. Dick; Albert Swafford; William M. Chilian

From the Departments of Physiology, Anesthesiology, and Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Correspondence to William M. Chilian, Professor and Head, Department of Physiology, LSU Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112. E-mail Chilian{at}lsuhsc.edu

Objective— We tested the hypothesis that hydrogen peroxide (H₂O₂), the dismutated product of superoxide (O₂^·–), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O₂^·– and H₂O₂ 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 H₂O₂.

Methods and Results— The production of O₂^·– is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O₂^·– 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 O₂^·– production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O₂^·– 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 H₂O₂ are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H₂O₂ 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 pO₂.

Conclusions— Taken together, our results demonstrate that O₂^·– is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H₂O₂. Our results further suggest that the production of H₂O₂ in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.

We tested the hypothesis that H₂O₂ couples myocardial oxygen consumption to coronary flow. Isolated myocytes produced O₂^·– and H₂O₂ in proportion to metabolism, and produced dilation that was eliminated by catalase. In intact animals tissue concentrations of H₂O₂ were linearly related to myocardial oxygen consumption and directly linked to coronary blood flow. We conclude that H₂O₂ couples coronary blood flow to myocardial oxygen consumption.

Key Words: reactive oxygen species • coronary circulation • vasodilation • microcirculation

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