Mechanisms of Hypertension in Chronic Kidney Disease

慢性肾脏病高血压的机制

• 批准号: 7258381
• 负责人: CRYSTAL A. GADEGBEKU
• 金额: $ 34.86万
• 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/7258381
• 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显著导致慢性肾脏病（CKD）患者的高血压和过度心血管疾病负担。一氧化氮（NO），神经血管功能的调节剂，可能与肾上腺素能血管反应性。中心假设是CKD患者内皮一氧化氮（NO）生物利用度的降低有助于增强α 1肾上腺素受体血管舒张功能。具体目的：在轻度至中度CKD患者中，与匹配的高血压和血压正常的无CKD对照组相比：1。确定α 1-肾上腺素受体血管反应性是否：a）通过抑制内皮NO而增强较少，B）通过补充NO前体L-精氨酸而降低，c）通过抗氧化剂抗坏血酸而降低，d）通过L-精氨酸和抗坏血酸的组合协同降低。 2.确定α 1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：以I（125）-碘酞酸盐肾小球滤过率为指标确诊CKD。将通过静脉体积描记法，使用分级动脉内输注α 1-肾上腺素受体激动剂苯肾上腺素，评估局部α 1-肾上腺素受体血管反应性（灵敏度[EC 50]，反应性[斜率]）。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%体脂匹配的高血压和肾功能正常的血压正常受试者之间比较基线时、输注这些NO调节剂和外源性NO期间的血管反应性。此外，将在伴和不伴CKD的高血压受试者中测量内源性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。 意义这些研究将提供深入了解的发病机制的α 1血管反应性增强的受试者进行性肾脏疾病。进一步支持一氧化氮和交感神经活性之间的潜在联系，将为快速增长的CKD患者群体中治疗和预防血管疾病的新策略奠定基础。