Mechanisms of Hypertension in Chronic Kidney Disease

慢性肾脏病高血压的机制

• 批准号: 7471513
• 负责人: CRYSTAL A. GADEGBEKU
• 金额: $ 35.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471513
• 关键词: Acids; Adrenergic Agents; Adrenergic Receptor; Age; Agonist; Antioxidants; Area; Arginine; Ascorbic Acid; Biological Availability; Blood Vessels; Body fat; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Clinical Research; Defect; Development; Ethnic Origin; Funding; Gender; Glomerular Filtration Rate; Hypertension; Individual; Infusion procedures; Intra-Arterial Infusions; Iothalamate; Kidney Diseases; Lead; Link; Measures; Mentored Clinical Oncology Award; Mentored Clinical Scientist Award; Mentored Patient-Oriented Research Career Development Award; Methods; N,N-dimethylarginine; Nephrology; Nitric Oxide; Nitric Oxide Synthase; Pathogenesis; Patients; Personal Satisfaction; Pharmacotherapy; Phenylephrine; Plasma; Population; Positioning Attribute; Prevention; Renal function; Research; Research Personnel; Staging; Supplementation; Vascular Diseases; Vasomotor; Venous; adrenergic; career; dimethylarginine; inhibitor/antagonist; innovation; insight; neurogenic hypertension; non-diabetic; normotensive; pressure; programs; research study; response

DESCRIPTION (provided by applicant): Enhanced adrenergic vascular reactivity may significantly contribute to hypertension and the excessive cardiovascular disease burden in patients with chronic kidney disease (CKD). Nitric oxide (NO), a modulator of neurovascular function, may be linked to adrenergic vascular responsiveness. The central HYPOTHESIS is that the reduction in endothelial nitric oxide (NO) bioavailability contributes to the enhancement of alpha1-adrenoceptor vasomotor function in patients with CKD. Specific Aims: In patients with mild to moderate CKD, compared to matched hypertensive and normotensive controls without CKD: 1. Determine if alpha1-adrenoceptor vasoreactivity is: a) enhanced less by inhibition of endothelial NO, b) reduced by supplementation with the NO precursor, L-arginine, c) reduced by the anti-oxidant, ascorbic acid, d) reduced by the combination of L-arginine and ascorbic acid, synergistically. 2. Determine whether alpha1adrenoceptor vasoreactivity correlates with plasma levels of the endogenous NO inhibitor, asymmetrical dimethylarginine. Methods: CKD will be confirmed by I(125)-iothalamate glomerular filtration rate. Regional alpha1-adrenoceptor vasoreactivity (sensitivity [EC50], reactivity [slope]) will be assessed by venous plethsymography using a graded intra-arterial infusion of the alpha1-adrenoceptor agonist, phenylephrine. Comparisons of vasoreactivity at baseline, during infusions of these NO modulating agents and exogenous NO will be made between hypertensive non-diabetic subjects with glomerular filtrations rates between 30-70 ml/min age-, gender-, ethnicity- and % body fat-matched hypertensive and normotensive subjects with normal kidney function. In addition, plasma levels of the endogenous NO inhibitor, asymmetric dimethylarginine will be measured in the hypertensive subjects with and without CKD and compared to vasoreactivity. Significance These studies will provide insight into the mechanisms of the pathogenesis of enhanced alpha1 vasoreactivity in subject with progressive renal disease. Further support for a potential link between nitric oxide and sympathetic activity will lay the groundwork for new strategies in the treatment and prevention of vascular disease among the rapidly growing group of individuals with CKD.

描述（由申请人提供）： 肾上腺素能血管反应性增强可能会显着导致慢性肾病（CKD）患者的高血压和心血管疾病负担过重。一氧化氮（NO）是神经血管功能的调节剂，可能与肾上腺素能血管反应性有关。中心假设是内皮一氧化氮 (NO) 生物利用度的降低有助于 CKD 患者的 α1-肾上腺素受体血管舒缩功能增强。具体目标：在轻度至中度 CKD 患者中，与无 CKD 的匹配高血压和正常血压对照相比： 1. 确定 α1 肾上腺素受体血管反应性是否：a) 抑制内皮 NO 增强较小，b) 补充 NO 前体 L-精氨酸减弱，c) 抗氧化剂抗坏血酸减弱，d) 联合用药减弱 L-精氨酸和抗坏血酸具有协同作用。 2. 确定 α1 肾上腺素受体血管反应性是否与内源性 NO 抑制剂、不对称二甲基精氨酸的血浆水平相关。 方法：通过I(125)-碘酞酸盐肾小球滤过率确诊CKD。区域α1-肾上腺素受体血管反应性（敏感性[EC50]、反应性[斜率]）将通过静脉体积描记法使用α1-肾上腺素受体激动剂去氧肾上腺素的分级动脉内输注进行评估。将在肾小球滤过率在 30-70 ml/min 之间的高血压非糖尿病受试者与年龄、性别、种族和体脂百分比匹配且肾功能正常的高血压和正常血压受试者之间进行基线、输注这些 NO 调节剂和外源性 NO 期间血管反应性的比较。此外，还将测量患有或不患有 CKD 的高血压受试者的内源性 NO 抑制剂、不对称二甲基精氨酸的血浆水平，并与血管反应性进行比较。 意义 这些研究将深入了解进行性肾病患者 α1 血管反应性增强的发病机制。对一氧化氮和交感神经活动之间潜在联系的进一步支持将为在快速增长的 CKD 人群中治疗和预防血管疾病的新策略奠定基础。