Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo

Background - Recent studies in vitro have demonstrated that endothelium-derived hydrogen peroxide (H₂O₂) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans. The aim of this study was to evaluate our hypothesis that endothelium-derived H₂O₂ is an EDHF in vivo and plays an important role in coronary autoregulation. Methods and Results - To test this hypothesis, we evaluated vasodilator responses of canine (n=41) subepicardial small coronary arteries (≥100 μm) and arterioles (<100 μm) with an intravital microscope in response to acetylcholine and to a stepwise reduction in coronary perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO synthesis with N^G-monomethyl-L-arginine (L-NMMA). After L-NMMA, the coronary vasodilator responses were attenuated primarily in small arteries, whereas combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates H₂O₂ into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large-conductance K_Ca channels) attenuated the vasodilator responses of coronary arteries of both sizes. Residual arteriolar dilation after L-NMMA plus catalase or TEA was largely attenuated by 8-sulfophenyltheophylline, an adenosine receptor inhibitor. Conclusions - These results suggest that H₂O₂ is an endogenous EDHF in vivo and plays an important role in coronary autoregulation in cooperation with NO and adenosine.