Oxygenase Metabolites and Renal Microvascular Reactivity

加氧酶代谢物和肾微血管反应性

• 批准号: 6612681
• 负责人: John D Imig
• 金额: $ 30.11万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6612681
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin II; antihypertensive agents; arachidonate; eicosanoid metabolism; eicosanoids; enzyme activity; enzyme feedback; enzyme inhibitors; epoxide hydrolase; hormone regulation /control mechanism; kidney circulation; kidney function; laboratory rat; microcirculation; nephrectomy; pathologic process; vascular smooth muscle; vasodilators; vasomotion

DESCRIPTION (provided by the applicant): Hypertension that develops following the long-term administration of initially subpressor doses of angiotensin II in rats has many of the same renal and vascular changes that are associated with human essential hypertension. In the past five years, we have provided compelling evidence that CYP45O-derived epoxyeicosatrienoic acids (EETs) have anti-hypertensive properties and play a part in the maintenance of renal microvascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for the conversion of the biologically active EETs to dihydroxyeicosatrienoic acids (DHETs) that are void of effects on the preglomerular vasculature. Recently, a role for soluble epoxide hydrolase (sEH) in the long-term control of arterial blood pressure and the pathogenesis of experimental hypertension has been proposed. Preliminary studies in our laboratory demonstrate increased kidney sEH protein expression during angiotensin II hypertension. In addition, we have observed a decrease in arterial blood pressure in angiotensin II hypertension following administration of a highly selective sEH inhibitor. Based on these observations, we hypothesis that during the development of hypertension increased kidney sEH will decrease kidney EET levels which contributes to increased renal microvascular reactivity, blood pressure and renal vascular injury. We will directly determine the involvement of epoxide hydrolases to the excessive preglomerular vasoconstriction during the development of angiotensin II hypertension using the juxtamedullary nephron preparation. We will also determine renal microvascular EET and DHET levels and the regulation of kidney epoxide hydrolase enzymes during hypertension. The proposed studies will employ newly developed highly selective epoxide hydrolase inhibitors to determine their ability to lower arterial blood pressure and improve renal microvascular function in angiotensin II hypertension. Collectively, these studies will provide a comprehensive understanding of epoxide hydrolases in the long-term regulation of blood pressure and renal hemodynamic function during angiotensin II hypertension.

描述（由申请人提供）：在大鼠长期服用最初的血管紧张素II剂量的长期给药后发展的高血压具有许多与人类本质高血压相关的肾脏和血管变化。在过去的五年中，我们提供了令人信服的证据，表明CYP45O衍生的环氧酸性酸（EET）具有抗高血压性能，并在维持肾脏微血管功能方面起着作用。 提高EET水平的一种新型方法是抑制负责生物活性EET到二羟基二酸酯（DHETS）转化的环氧化物水解酶，这些酶对二羟基二酸酯（DHETS）没有影响对骨前脉管结构的影响。最近，已经提出了可溶性环氧化物水解酶（SEH）在动脉血压的长期控制和实验性高血压的发病机理中的作用。在我们的实验室中的初步研究表明，在血管紧张素II高血压期间，肾脏SEH蛋白表达增加。此外，我们已经观察到高度选择性SEH抑制剂后血管紧张素II高血压的动脉血压降低。基于这些观察结果，我们假设在高血压发展过程中增加肾脏SEH将降低肾脏EET水平，这有助于增加肾脏微血管反应性，血压和肾血管损伤。我们将直接确定在使用近后硫肾上腺肾增强血管紧张素II高血压的过程中，在生血管紧张素II高血压期间，环氧化物水解酶与过度的前血液血管收缩有关。我们还将确定肾脏微血管EET和DHET水平以及高血压期间肾脏环氧化物水解酶的调节。拟议的研究将采用新开发的高度选择性环氧水解酶抑制剂来确定其降低动脉血压的能力并改善血管紧张素II高血压中的肾脏微血管功能。总的来说，这些研究将在血管紧张素II高血压期间长期调节血压和肾血液动力学功能的长期调节中，为环氧水解酶提供全面的了解。