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

1.内皮细胞一氧化氮合酶系统在EDHF/H_2O_2产生中的作用（1）内皮细胞Cu，Zn-SOD在EDHF/H_2O_2的合成中起重要作用。(2)We已经证明长期抑制Rho激酶（其下调eNOS）改善各种心血管疾病动物模型中的内皮功能。(3)We EDHF/H_2O_2参与了ACE抑制剂的作用。(4)We已经培育出缺乏所有NO合成酶的小鼠。这些小鼠表现出高血压和心肌梗死的存活率受损。(5)In 2. H_2O_2合成的生理和病理机制（1）在犬体内，内皮细胞以p.M顺序释放H_2O_2和NO，二者协同作用维持冠状动脉血流。(2)We已经证明其他内皮氧化酶系统H_2O_2的体内显像利用DCF荧光显像技术，我们可以在体内证实内皮细胞产生H_2O_2。4. EDHF/H_2O_2在动物体内的作用5. EDHF/H_2O_2在人冠状动脉平滑肌细胞中的作用（1）在体外培养的人冠状动脉平滑肌细胞中，雌激素下调Rho激酶，而尼古丁上调Rho激酶。(2)We已经证明，选择性Rho激酶抑制剂急性降低肺动脉高压患者的肺血管阻力，而不影响全身血流动力学。

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.