The pathogenesis of low-renin essential hypertension, which has a disproportionately higher incidence in blacks, remains unknown, but is presumed to reflect relative arterial volume expansion (1,2). A genetic predisposition to develop high blood pressure while on a high salt diet has been demonstrated (1,2). The Dahl/Rapp rat is a useful model of genetically induced low-renin salt-sensitive hypertension. On a high salt (8% NaCl) diet, Dahl/Rapp salt-sensitive (SS/Jr) rats uniformly and rapidly develop hypertension and die from renal failure secondary to arteriolosclerosis and glomerulosclerosis, unless provided either parenteral or oral L-arginine. L-arginine completely prevents this hypertensive response in a concentration-dependent fashion and prevents hypertensive nephrosclerosis in these animals on the high salt diet. This nonessential amino acid serves as the metabolic precursor of nitric oxide (NO), the endogenous nitrovasodilator that is a major regulator of vascular smooth muscle tone (3-6) in vivo. The key hypothesis in this project is that salt-sensitive hypertension and resultant renal failure occur in SS/Jr rats because of a genetic defect in NO production that is overcome with provision of L-arginine, the substrate for NO synthase. Using the Dahl/Rapp rat, the broad, long-term objectives include: 1) understand the role of the endogenous nitrovasodilator, NO, and its metabolic precursor, L-arginine, in the pathogenesis of salt-sensitive hypertension; 2) demonstrate modulation of NO production in response to changes in dietary sodium chloride intake and/or L-arginine and determine the role of NO and L-arginine on renal handling of sodium chloride in rats; and 3) characterize further the role of NO and L-arginine on progression of end-organ (kidney) damage in salt-sensitive hypertension. The ultimate goal will be to apply these results to defined populations of human low-renin essential hypertension (7). To accomplish these goals, we will perform the following experiments. a ) Examine the enzyme kinetics of the inducible form of NO synthase in vascular smooth muscle cells from SS/Jr, SR/Jr and Sprague-Dawley rats. b) Correlate, in SS/Jr rats on a high salt diet with and without L-arginine, the time-course of smooth muscle and mesangial cell proliferation with histopathologic changes and cGMP concentrations in glomeruli, aortae, plasma and urine. We will also examine the effects of L-arginine, angiotensin II, atrial natriuretic peptide, and 8-bromo-cGMP on growth of cultured vascular smooth muscle cells obtained from SS/Jr and SR/Jr rats. c) Determine whether dietary sodium chloride and L-arginine induce the expression of the inducible form of NO synthase in vascular smooth muscle and kidney in vitro and in vivo. d) Determine whether L-arginine corrects the defect in renal sodium chloride excretion seen in prehypertensive SS/Jr rats and examine the role of NO and cGMP on sodium absorption by inner medullary collecting duct cells.
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