Endothelial Hyperpolarization in Humans

人类内皮超极化

• 批准号: 7013958
• 负责人: ARSHED A QUYYUMI
• 金额: $ 37.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013958
• 关键词: clinical research; cytochrome P450; eicosanoid metabolism; exercise; human subject; hydrogen peroxide; hypercholesterolemia; nitric oxide; potassium channel; prostacyclins; reactive hyperemia; vascular endothelium; vasodilation; vasodilators

DESCRIPTION (provided by applicant): Endothelial dysfunction from reduced endothelium-derived nitric oxide bioavailability is a hallmark of the abnormal vascular function observed in individuals with hypercholesterolemia and other risk factors for atherosclerosis. Endothelial function is assessed by measuring vasodilation in response to agonists such as bradykinin that promotes release of nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor (EDHF). The contribution of nitric oxide to human vascular tone and function in vivo has been extensively studied, but investigation of EDHF in vivo has been hampered because of controversy surrounding the true identity of EDHF. Recent experimental studies have demonstrated several potential mechanisms underlying endothelium-dependent hyperpolarization; these include (1) release of epoxides from cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid, (2) promotion of endothelial and smooth muscle hyperpolarization by stimulation of small and large calcium-dependent potassium channels (K+cA) on endothelial cells, (3) release of hydrogen peroxide synthesized by dismutation of superoxide anions, and (4) activation of gap junctions. The aim of this proposal is to establish the activity and identity of EDHF in the human forearm circulation, investigate its physiologic role in vasodilation, and study whether its activity is modulated by hypercholesterolemia. Employing specific inhibitors of CYP450, K+CA channels, and hydrogen peroxide, and by measuring forearm vasodilation at rest and with bradykinin, after inhibition of nitric oxide and cyclooxygenase, we will test the following hypotheses in healthy and hypercholesterolemic subjects: Specific Aim l: EDHF activity is due to CYP 450-derived epoxide release; Specific Aim 2: EDHF mediates vasodilation by activation of K+CA channels; Specific Aim 3: EDHF activity is due to hydrogen peroxide release; and Specific Aim 4: whether physiologic vasodilation during sustained hyperemia or exercise, that is known to have a minimal contribution from nitric oxide and prostacyclin, is due to EDHF release.

描述（申请人提供）：减少内皮衍生的一氧化氮生物利用度的内皮功能障碍是在高胆固醇血症和其他动脉粥样硬化危险因素中观察到异常血管功能的标志。 通过对诸如促进一氧化氮，前列环蛋白和内皮衍生的超极化因子（EDHF）的释放的激动剂（例如心动激肽）的响应来评估内皮功能。 一氧化氮对人体血管张力和体内功能的贡献已经进行了广泛的研究，但是由于围绕EDHF的真实身份有争议，对体内EDHF的研究受到了阻碍。 最近的实验研究表明，内皮依赖性超极化的几种潜在机制。 these include (1) release of epoxides from cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid, (2) promotion of endothelial and smooth muscle hyperpolarization by stimulation of small and large calcium-dependent potassium channels (K+cA) on endothelial cells, (3) release of hydrogen peroxide synthesized by dismutation of superoxide anions, and (4) activation of间隙连接。 该提案的目的是建立EDHF在人前臂循环中的活性和认同，研究其在血管舒张中的生理作用，并研究其活性是否受到高胆固醇血症的调节。 在抑制一氧化氮和环氧酶后，采用CYP450，K+CA通道和过氧化氢的特定抑制剂，以及通过测量休息时和双阳极蛋白的前臂血管舒张，通过测量静止状态的前臂血管舒张。 特定的目标L：EDHF活性是由于CYP 450衍生的环氧化物释放造成的。 特定目标2：EDHF通过激活K+CA通道介导血管舒张； 特定目标3：EDHF活性是由于过氧化氢释放引起的。和 特定目标4：持续充血或运动过程中的生理血管舒张是由于EDHF释放所致。