The sodium ion has been implicated in the pathogenesis and maintenance of elevated blood pressure in some individuals. A variety of techniques for classification of hypertensives into sodium sensitive or sodium resistant subgroups have been reported. However, the mechanisms for, and markers of sodium sensitivity or resistance in normotensive and hypertensive humans have not been identified. This application will examine the mechanisms and markers of sodium sensitivity and resistance in both normotensive and hypertensive humans in several ways. Two different techniques for the classification of sodium sensitivity and resistance will be utilized to determine their reproducibility and congruence. One procedure utilizes rapid volume expansion induced by intravenous infusion of 2 liters of normal saline over 4 hours followed by sodium and volume depletion induced the following day by a low sodium diet (10 mEq) and 3 doses of oral furosemide (40 mg each). The blood pressure changes at the end of each maneuver will be utilized for classification. The second technique will be the blood pressure response to modest (less than or equal to 80 mEq/d) dietary sodium restriction. We hypothesize that sodium sensitivity of blood pressure is associated with enhanced renal tubular sodium reabsorption and that this sodium avidity is induced by one of several physiological mechanisms: increased proximal tubular sodium-reabsorption (as evidenced by abnormal renal lithium clearance and sodium-lithium countertransport of erythrocytes); increased renal noradrenergic and/or decreased renal dopaminergic activity (as refelected by urinary excretion of norepinephrine and dopamine and their metabolites); impaired suppression of atrial natriuretic factor or by an alteration in the renin-angiotensin-aldosterone system. Studies are proposed to examine the genetic basis for sodium sensitivity or resistance of blood pressure and the responsible mechanisms. Studies are proposed to determine if the enhanced renal sodium reabsorption can be modified by other nutrients, specifically calcium, potassium and non-chloride-containing conjugate base anions and the mechanisms associated with such modifications. Finally, pharmacologic interventions will confirm the significance of abnormalities identified. These studies will provide new information concerning the mechanisms of sodium sensitivity and resistance of blood pressure in humans and of nutritional modifiers thereof. These observations will have immense clinical relevance in the treatment and prevention of hypertension for many individuals.
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