MECHANISMS OF SALT SENSITIVE HYPERTENSION

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Hypertension continues to be a major cardiovascular risk factor in the United States. Although the arterial pressure of a large percentage of hypertensives is sensitive to a high sodium diet, the mechanisms underlying the pathogenesis of salt-sensitive hypertension are unknown. Recent studies in humans in human and animal models of hypertension indicate that a deficient production of nitric oxide (NO) may contribute to salt-sensitive hypertension. The primary hypothesis is that deficient amounts of the various isoforms of NO synthase (NOS), particularly those in renal the renal medulla, play a major role in the development of salt- sensitive hypertension. The Dahl salt-sensitive (S) rat will be used as a model of salt-sensitive hypertension to test this hypothesis, since it has may characteristics in common with salt-sensitive humans including decreased NO production and a suppressed renin-angiotensin system. Specific Aim 1 will determine if the blunted increased in NO in the kidney of the Dahl S rat during high sodium intake results from attenuated levels of endothelial NOS, brain NOS (bNOS) or inducible NOS (iNOS) in the main renal parenchymal zones. Messenger RNA, protein amounts and activities of the NOS isoforms will be measured in renal cortical and medullary tissues in 5 to 6 week old Dahl S and R and Lewis rats on a low or high sodium intake. Specific Aims 2 and 3 will determine the roles of iNOS, bNOS and the renin-angiotensin system in causing salt-sensitivity in Dahl S hypertension by examining the long-term responses of arterial pressure, renal hemodynamics, tubular sodium reabsorption, urinary nitrate/nitrite excretion and plasma renin activity to changes in sodium intake in the presence or absence of selective systematic or intramedullary iNOS inhibition or bNOS inhibition. Also, intramedullary L-arginine infusion with or without selective intramedullary iNOS or bNOS inhibition will determine whether medullary production of NO by iNOS or bNOS are important in preventing Dash S hypertension. These studies will provide new information about intrarenal mechanisms that can lead to impaired pressure natriuresis and salt-sensitive hypertension.