Cardiovascular disorders are the major cause of death and disability in patients with chronic renal failure. Hypertension is present in the majority of uremic patients and is a major risk factor for the excessive mortality from heart attack and stroke. On the basis of preliminary studies from the sponsor's laboratory and other recent research the following is proposed as underlying pathophysiological mechanisms: A major cause of hypertension in uremic patients is inhibition of nitric oxide (NO) due to accumulation of asymmetric dimethyl arginine (ADMA), a kidney-derived endogenous inhibitor of NO synthase. NO acts both as a local endothelium-derived relaxing factor and as key neurotransmitter in the vasomotor center, where it tonically restrains sympathetic outflow to the peripheral circulation. the central inhibition is responsible for the increased sympathetic nerve activity (SNA) found in uremic patients. This conceptual framework the stage future assessment of a novel treatment modality for hypertension especially in uremic patients, namely systemic L-arginine (L-Arg), the substrate for NO synthase. Three specific protocols are presented; in two we propose to study human subjects, including uremic dialysis patients, patients with essential hypertension and healthy volunteers; in the third we propose to study conscious rats. The protocols contain pharmacologic intervention on the axis between NO and SNA, with intravenous L-Arg and Ng-monomethyl-L- arginine (L-NMMA), an exogenous inhibitor of NO synthase. The use of microneurography is proposed as the main method to quantitate SNA in both humans and animals, central and peripheral hemodynamics will be monitored, and plasma levels of L-Arg and ADMA will be measured where relevant. Ethical and scientific considerations are presented for human subjects and vertebrate animals.
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