Experimental and Clinical Studies on the Significance of Endothelium-Derived Hyperpolarizing Factor (EDHF)

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1.Role of Endothelial NO synthases system in the production of EDHF/H_2_O2(1)We have demonstrated that endothelial Cu, Zn-SOD plays an important role in the synthesis of EDHF/H_2O_2 not only in animals but also in humans.(2)We have demonstrated that long-term inhibition of Rho-kinase, which down-regulates eNOS, ameliorates endothelial function in various animal models of cardiovascular diseases.(3)We have demonstrated that EDHF/H_2O_2 is involved in the effects of ACE inhibitors.(4)We have developed mice lacking all NO synthases. Those mice showed impaired survival with hypertension and myocardial infarction.(5)In those triply NOSs-KO mice, EDHF responses were abolished, demonstrating the importance of endothelial NOSs system in the synthesis of EDHF/H_2O_2.2.Mechanisms of Physiological and Pathological H_2O_2 Synthesis(1)We were able to demonstrate that endothelial cells release H_2O_2 and NO at p.M order and that the two factors interact synergistically to maintain coronary flow in dogs in vivo.(2)We have demonstrated that other endothelial oxidases system (e.g.NADPH) are not involved in the EDHF/H_2O_2 responses.3.In vivo imaging of H_2O_2We were able to demonstrate endothelial production of H_2O_2 using DCF fluorescence imaging in vivo.4.Role of EDHF/H_2O_2 in animalsWe have demonstrated that EDHF/H_2O_2 plays an important protective role in myocardial ischemia/reperfusion and metabolic coronary vasodilatation as well.5.Role of EDHF/H_2O_2 in humans(1)We have demonstrated that in cultured vascular smooth muscle cells from human coronary arteries, estrogen down-regulates while nicotine up-regulates Rho-kinase.(2)We have demonstrated that selective Rho-kinase inhibitors acutely reduces pulmonary vascular resistance without systemic hemodynamic effects in patients with pulmonary hypertension.