title: Hydrogen peroxide: a feed-forward dilator that couples myocardial metabolism to coronary blood flow.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Physiology, LSU Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112, USA.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Saitoh
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
authors.forename: Barry
authors.initials: B
authors.lastname: Potter
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kiyooka
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rogers
authors.forename: Jarrod D
authors.initials: JD
authors.lastname: Knudson
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: Albert
authors.initials: A
authors.lastname: Swafford
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D014475:Uncoupling Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D014665:Vasodilator Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C056165:acetovanillone; D006861:Hydrogen Peroxide; D002374:Catalase