Mechanisms of Hypertension in Chronic Kidney Disease

慢性肾脏病高血压的机制

• 批准号: 7084589
• 负责人: CRYSTAL A. GADEGBEKU
• 金额: $ 34.91万
• 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/7084589
• 关键词: adrenergic receptor; antioxidants; arginine; ascorbate; cardiovascular pharmacology; chronic renal failure; clinical research; dietary supplements; human subject; kidney function; neuropharmacology; nitric oxide; nutrition related tag; pathologic process; patient oriented research; protein structure function; renal hypertension; sympathetic nervous system; vascular endothelium; vascular smooth muscle nervous control; vasomotion

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）：