Mechanisms of Hypertension in Chronic Kidney Disease

描述(由申请人提供)： 肾上腺素能血管反应性增强可能是慢性肾脏病(CKD)患者高血压和心血管疾病负担过重的重要原因。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α1肾上腺素受体血管舒缩功能的增强。具体目的：轻、中度慢性肾脏病患者，与无慢性肾脏病的高血压和正常血压对照组相比：1.确定α1-肾上腺素能受体血管反应性是否为：a)抑制内皮NO而增强较少，b)补充NO前体L-精氨酸降低，c)抗氧化剂抗坏血酸降低，d)L-精氨酸和抗坏血酸联合应用协同降低。 2.确定α1肾上腺素受体血管反应性是否与血浆内源性NO抑制物非对称性二甲基精氨酸水平相关。方法：用~(125)I-硫代氨基甲酸肾小球滤过率确定慢性肾功能不全。局部α1肾上腺素受体血管反应性(敏感性[EC50]，反应性[斜率])将通过静脉血管造影进行评估，方法是动脉内分级注入α1肾上腺素受体激动剂苯肾上腺素。肾小球滤过率在30-70毫升/分钟之间的高血压非糖尿病受试者和肾功能正常的高血压受试者和正常血压受试者之间，将比较基线、输注这些NO调节剂和外源性NO时的血管反应性。此外，还将检测合并和不合并CKD的高血压患者血浆中内源性NO抑制物不对称二甲基精氨酸的水平，并与血管反应性进行比较。意义这些研究将为进行性肾脏疾病受试者α1血管反应性增强的发病机制提供洞察力。进一步支持一氧化氮和交感神经活动之间的潜在联系，将为在快速增长的慢性肾脏病患者群体中治疗和预防血管疾病的新策略奠定基础。

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.