We have suggested that both the hepatic and renal metabolism of aldosterone are important in the mechanism of action of aldosterone in the kidney. Large quantities of polar and reduced metabolites are present in plasma and kidney during the latent period of hormone action and correlate well with the magnitude of the antinatriuretic and kaliuretic renal responses to aldosterone. The majority are polar neutral metabolites, synthesized in liver and separated by HPLC into at least 10 metabolites; six have been shown by G.C.-Mass Spec. to be monohydroxylated derivatives of aldosterone. Recently we have shown that kidney nuclei and other subcellular fractions also synthesizes many of these polar and reduced metabolites several of which possess significant mineralocorticoid activity. Spironolactone, progesterone, corticosterone and testosterone (all mineralocorticoid antagonists), thyroidectomy, and dietary Na+ and K+ alter both the hepatic and renal metabolism of aldosterone. We plan to continue to investigate these regulatory influences, by studying their effects on (a) temporal changes in the quantities of aldosterone and its metabolites and their subcellular location in kidney, during the course of physiological action (b) the quantities of metabolites in liver and plasma, (c) the quantities of metabolites excreted in the urine (since they will reflect the sequence of metabolites to which the target tissue is exposed) and (d) the capacity and rates of metabolite synthesis in slices and subcellular fractions of liver and kidney. Each metabolite will be tested for their ability (i) to either inhibit or enhance the mineralocorticoid action of aldosterone (ii) for their relative rates of uptake and binding kinetics to cytosolic and nuclear receptors and (iii) for their effects on translocation of aldosterone to the nucleus and its binding to receptors there. Additionally, the hepatic and renal metabolism will be studied in SHR rats, both before and during development of hypertension. The proposed experiments will enable us (a) to correlate the presence of the individual metabolites in the plasma, kidney and urine in these rats with Na+ and K+ homeostasis, (b) to determine which specific metabolites of aldosterone may mediate or regulate each cation effect of the renal responses to aldosterone and whether their relative mineralocorticoid potencies represent their accessability to the kidney, and (c) to determine whether the hepatic and renal metabolites of aldosterone are important in hypertension.
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