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

Abstract

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 (>or=100 microm) and arterioles (<100 microm) 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 NG-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.

Edaravone Preserves Coronary Microvascular Endothelial Function After Ischemia/Reperfusion on the Beating Canine Heart In Vivo

“…However, the regulation of coronary vascular tone may be mediated, not only by NO, but also by the endothelium derived hyperpolarizing factor (EDHF) and adenosine (24). Yada et al have demonstrated that endogeneous H 2 O 2 , an EDHF, and rhokinase inhibition mediated coronary vasodilation to a greater extent in arterioles than in small arteries (7,8,24). In the present study, preservation of endotheliumdependent vasodilation by edaravone was noted to a greater extent in the small arteries (Fig.…”

“…4). Previous studies from our institution have also demonstrated a decrease in eNOS protein expression in ischemic myocardium following I / R (7,8). An in vitro study in HUVEC has shown that edaravone may increase eNOS expression via the inhibition of LDL oxidation (25).…”

“…Myocardial tissue samples from the LAD and LCX area in each group were isolated for western blotting to assess endogenous NO synthase (eNOS) protein expression after I / R, as previously described (8,16). Briefly, myocardial tissues were homogenized in the lysis buffer.…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…Moreover, H 2 O 2 enhances the expression of both CD11b and CD18 on eosinophils (Nagata et al 2000). It has also been reported that H 2 O 2 plays an important role in cardioprotection against coronary I/R injury in vivo (Yada et al 2006). While this latter evidence supports an antiinflammatory role for H 2 O 2 , a greater body of evidence indicates a pro-inflammatory function for this molecule.…”

Essential Role of Bone Marrow for Microvascular Endothelial and Metabolic Functions in Mice

“…12 Other investigators confirmed the importance of H 2 O 2 as an EDHF 13 in human 14 and canine 15,16 coronary microvessels and porcine pial arteries. 17 We also have demonstrated that endothelial nitric oxide synthase (eNOS) is a major source of EDHF/H 2 O 2 , 10 where copper, zincsuperoxide dismutase plays an important role to dismutate eNOS-derived superoxide anions to EDHF/H 2 O 2 18,19 and that endothelial NOSs system plays different roles depending on the vessel size, serving as the NO-generating system in large arteries and as the EDHF/H 2 O 2 -generating system in microvessels in mice.…”