SODIUM PUMP INHIBITORS IN BLOOD PRESSURE REGULATION

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SUMMARY OF WORK The origins of sodium sensitive forms of hypertension remain to be clarified. Experimental models of sodium sensitive hypertension have been created in laboratory animals that are characterized by elevations in endogenous digitalis-like factors (EDLF) that can inhibit sodium transport across vascular smooth muscle. Previous studies in our laboratory have shown that both a cardenolide (a ouabain-like compund or OLC) and a bufodienolide ( a marinobufagenin-like compound or MBG) can be stimulated acutely in large animals by expansion of saline plasma volume and by acute increases in pCO2. These studies have also shown that alpha-1 and alpha-3 isoforms of Na/K ATPase in vascular smooth muscle and nerve endings of rat tissues, respectively, are found to have different sensitivites to various EDLF. During the current year, the differential effects of saline volume expansion on OLC and MBG in brain cortex and blood plasma of rats were analyzed. During saline infusion, plasma levels of MBG increased while plasma OLC decreased. Concurrently, OLC in hypothalamus and brain cortex increased, but central nervous system MBG did not change. These findings indicate that MBG and OLC are both involved in the regulation of circulating fluid volume, but OLC has its predominant effect in the central nervous system, while MBG is responsible for inhibition of the alpha-1 isoform of the Na/K ATPase in vascular smooth muscle. A second study investigated the separate and combined effects of six weeks of high sodium diet and social isolation on urinary MBG in rats. High sodium diet in isolated rats tripled urinary MBG and increased systolic blood pressure throughout the study period, while sodium loading of group-housed animals or isolation with normal sodium diet had no effects on urinary MBG or blood pressure. No long term effects on vascular smooth muscle Na/K pump activity were observed under any condition. This study shows that high sodium intake produce sustained effects on circulating bufodienolide EDLF, but that this effect alone is not sufficient to inhibit vascular Na/K pump activity over the long term. Future research will focus on the role of OLC and MBG in Na/K pump activity in Dahl hypertension, which involves a genetic sensitivity to high sodium diet. In addition, the effects of chronic MBG administration on blood pressure, OLC, MBG and Na/K pump activity will be investigated.