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Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo

¹Department of Medical Engineering and Systems Cardiology and ²Division of Nephrology and Rheumatology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki; ³Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai; ⁴Department of Physiology, Tokai University School of Medicine, Isehara; and ⁵Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan

Submitted 22 February 2006 ; accepted in final form 18 April 2006

We have recently demonstrated that endogenous H₂O₂ plays an important role in coronary autoregulation in vivo. However, the role of H₂O₂ during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H₂O₂ also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (100 µm) and arterioles (<100 µm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade (n = 50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor N^G-monomethyl-L-arginine (L-NMMA), catalase (a decomposer of H₂O₂), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), L-NMMA + catalase, L-NMMA + tetraethylammonium (TEA, an inhibitor of large-conductance Ca²⁺-sensitive potassium channels), and L-NMMA + catalase + 8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P < 0.01); L-NMMA reduced the small arterial vasodilatation (both P < 0.01), whereas it increased (P < 0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H₂O₂ production after I/R. Catalase increased the small arterial vasodilatation (P < 0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R (P < 0.01). L-NMMA + catalase, L-NMMA + TEA, or L-NMMA + catalase + 8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P < 0.01). L-NMMA + catalase, L-NMMA + TEA, and L-NMMA + catalase + 8-SPT significantly increased myocardial infarct area compared with the other four groups (control, L-NMMA, catalase, and 8-SPT; all, P < 0.01). These results indicate that endogenous H₂O₂, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.

endothelium-derived relaxing factor; myocardial infarction; vascular endothelial function

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