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PRECLINICAL STUDIES

Important Role of Endogenous Hydrogen Peroxide in Pacing-Induced Metabolic Coronary Vasodilation in Dogs In Vivo

Toyotaka Yada, MD, PhD^_*,_*, Hiroaki Shimokawa, MD, PhD, Osamu Hiramatsu, PhD^_*, Yoshiro Shinozaki, BS, Hidezo Mori, MD, PhD, Masami Goto, MD, PhD^_*, Yasuo Ogasawara, PhD^_* and Fumihiko Kajiya, MD, PhD^_*

^_* Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Japan
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Department of Physiology, Tokai University School of Medicine, Isehara, Japan
Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan

Manuscript received September 11, 2006; revised manuscript received April 25, 2007, accepted May 1, 2007.

^_* Reprint requests and correspondence: Dr. Toyotaka Yada, Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. (Email: yada{at}me.kawasaki-m.ac.jp).

Objectives: We examined whether endogenous hydrogen peroxide (H₂O₂) is involved in pacing-induced metabolic vasodilation in vivo.

Background: We have previously demonstrated that endothelium-derived H₂O₂ is an endothelium-derived hyperpolarizing factor in canine coronary microcirculation in vivo. However, the role of endogenous H₂O₂ in metabolic coronary vasodilation in vivo remains to be examined.

Methods: Canine subepicardial small coronary arteries (100 µm) and arterioles (<100 µm) were continuously observed by a microscope under cyclooxygenase blockade (ibuprofen, 12.5 mg/kg intravenous [IV]) (n = 60). Experiments were performed during paired right ventricular pacing under the following 7 conditions: control, nitric oxide (NO) synthase inhibitor (N^G-monomethyl-L-arginine [L-NMMA], 2 µmol/min for 20 min intracoronary [IC]), catalase (a decomposer of H₂O₂, 40,000 U/kg IV and 240,000 U/kg/min for 10 min IC), 8-sulfophenyltheophylline (SPT) (an adenosine receptor blocker, 25 µg/kg/min for 5 min IC), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA) (K_Ca-channel blocker, 10 µg/kg/min for 10 min IC), and L-NMMA+catalase+8-SPT.

Results: Cardiac tachypacing (60 to 120 beats/min) caused coronary vasodilation in both-sized arteries under control conditions in response to the increase in myocardial oxygen consumption. The metabolic coronary vasodilation was decreased after L-NMMA in subepicardial small arteries with an increased fluorescent H₂O₂ production compared with catalase group, whereas catalase decreased the vasodilation of arterioles with an increased fluorescent NO production compared with the L-NMMA group, and 8-SPT also decreased the vasodilation of arterioles. Furthermore, the metabolic coronary vasodilation was markedly attenuated after L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT in both-sized arteries.

Conclusions: These results indicate that endogenous H₂O₂ plays an important role in pacing-induced metabolic coronary vasodilation in vivo.

Abbreviations and Acronyms   CBF = coronary blood flow   DAR = diaminorhodamine-4M AM   DCF = 2',7'-dichlorodihydrofluorescein diacetate   EDHF = endothelium-derived hyperpolarizing factor   H2O2 = hydrogen peroxide   L-NMMA = NG-monomethyl-L-arginine   LAD = left anterior descending coronary artery   MVO2 = myocardial oxygen consumption   NO = nitric oxide   PGI2 = prostacyclin   SPT = sulfophenyltheophylline   TEA = tetraethylammonium

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