Hydrogen peroxide as an endothelium-derived hyperpolarizing factor

The endothelium plays an important role in maintaining cardiovascular homeostasis by synthesizing and releasing several vasodilating substances, including vasodilator prostaglandins, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). Since the first report on the existence of EDHF, several substances/mechanisms have been proposed for the nature of EDHF, including epoxyeicosatrienoic acids (metabolites of arachidonic P450 epoxygenase pathway), K ions, and electrical communications through myoendothelial gap junctions. We have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans. For the synthesis of H2O2/EDHF, endothelial NO synthase system that is functionally coupled with Cu,Zn-superoxide dismutase plays a crucial role. Importantly, endothelium-derived H2O2 plays important protective roles in the coronary circulation, including coronary autoregulation, protection against myocardial ischemia/reperfusion injury, and metabolic coronary vasodilatation. Indeed, our H2O2/EDHF theory demonstrates that endothelium-derived H2O2, another reactive oxygen species in addition to NO, plays important roles as a redox-signaling molecule to cause vasodilatation as well as cardioprotection. In this review, we summarize our current knowledge on H2O2/EDHF regarding its identification and mechanisms of synthesis and actions.