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

Abstract

We have recently demonstrated that endogenous H 2 O 2 plays an important role in coronary autoregulation in vivo. However, the role of H 2 O 2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H 2 O 2 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 H 2 O 2 ), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), l-NMMA + catalase, l-NMMA + tetraethylammonium (TEA, an inhibitor of large-conductance Ca 2+ -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 H 2 O 2 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 H 2 O 2 , in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.