Alpha-Adrenoceptor Vascular Function In Chronic Kidney Disease Focus On The Role Of Endothelial Nitric Oxide

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 α1-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 α1-adrenoceptor vasoreactivity is enhanced less by inhibition of endothelial NO 2. Determine whether α1-adrenoceptor vasoreactivity correlates with plasma levels of the endogenous NO inhibitor, asymmetrical dimethylarginine. Methods: CKD will be confirmed by I125-iothalamate glomerular filtration rate. Regional α1-adrenoceptor vasoreactivity (sensitivity \[EC50\], reactivity \[slope\]) will be assessed by venous plethsymography using a graded intra-arterial infusion of the α1-adrenoceptor agonist, phenylephrine. Comparisons of vasoreactivity at baseline and during infusions of L-NMMA 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 α1 vasoreactivity in subjects with progressive renal disease.