Studies over the last decade suggest that two basic types of sodium transport defects can exist in the vascular smooth muscle cells of hypertensive subjects and that under certain circumstances the two defects may coexist and amplify their individual effects on cell sodium concentration. These defects are 1) increased cell membrane permeability to sodium and 2) decreased active pumping of sodium for a given internal sodium concentration producing electrogenic depolarization. The first seems to be characteristic of heritable essential hypertension and some forms of genetic hypertension in rats and the second appears to be characteristic of low renin hypertension subsequent to an inability to excrete salt normally. Decreased active pumping appears to result from the release of a sodium pump inhibitor from the hypothalamus. Coexistence of the defects occurs when, for example, a patient with heritable essential hypertension also has defective renal function, particularly when salt intake is increased. Coexistence drives internal sodium concentration to higher levels, further increasing internal calcium concentration and contraction. The sodium pump inhibitor may also decrease norepinephrine uptake by peripheral adrenergic nerve terminals, thereby leaving more norepinephrine in the vascular neuromuscular cleft. We propose studies directed at several components of the hypothesis. We will continue our efforts to extract, isolate, and chemically and physiologically characterize the hypothalamic Na+-K+ pump and humoral norepinephrine uptake inhibitor(s). We will continue to measure the membrane potentials of vascular smooth muscle cells in rat tail arteries in vivo, paying particular attention to the electrogenic sodium pump and diffusional components in various types of hypertension. We will assay plasma for the humoral sodium pump inhibitor in black male patients with low renin essential hypertension before and after treatment with hydrochlorothiazide or a low sodium diet. We will continue our efforts to utilize analogs of amiloride, particularly 6-iodo-amiloride, as diagnostic probes and vasodilator-diuretic therapy for those types of hypertension characterized by increase permeability of the vascular smooth muscle cell to sodium. We will determine whether canrenone, a metabolite of spironolactone, lowers pressure by stimulating Na+-K+ pump activity. We will determine the optimal dietary Na/K ratio for vanadate hypertension and whether dietary magnesium deficiency produces both hypertension and a disturbance of the Na+-K+ pump. These studies will increase our understanding of the mechanism and therapy of certain forms of arterial hypertension.
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