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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants Phase II (R33)
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Special Emphasis Panel (ZDK1-GRB-6 (J1))
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Eggers, Paul Wayne
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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von Leitner, Eike-Christin; Klinke, Anna; Atzler, Dorothee et al. (2011) Pathogenic cycle between the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine and the leukocyte-derived hemoprotein myeloperoxidase. Circulation 124:2735-45
Billecke, Scott S; D'Alecy, Louis G; Platel, Raylene et al. (2009) Blood content of asymmetric dimethylarginine: new insights into its dysregulation in renal disease. Nephrol Dial Transplant 24:489-96