PHARMACOLOGIC ALTERATIONS OF SULFATE HOMEOSTASIS

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Inorganic sulfate is a physiologic anion necessary for biosynthetic reactions, especiailly important in grcwth and development. For the biologic activity of endogenous compounds (heparin, gastrin, cholecystokinin), and for the detoxification of xenobiotics and endogenous compounds (catecholamines, steroids, bile acids). Homeostasis of inorganic sulfate concentrations is predominantly maintained by capacity-limited renal reabsorption. Treatment with salicylate (aspirin), the drug of choice in the therapy of rheumatoid arthritis and widely-used as a nonnprescription drug, causes a pronounced decrease in the plasma concentration of sulfate in mice and rats. These alterations in plasma sulfate concentrations are the result of a salicylate (SA)-induced enhancement of the renal clearance of sulfate. Although SA is known to inhibit sulfate uptake into placental brush border membrane vesicles at physiological concentrations, little is known concerning its effect or that of other drugs on renal sulfate transport. The overall goal of the proposed research is to examine the mechanism of the renal interaction between SA and inorganic sulfate, and thereby, to gain an understanding of which physiologic factors and pharmacologic agents may influence sulfate homeostasis. The specific aims of this research proposal are 1) to determine the effect of SA on sulfate transport in rat renal brush border and basolateral membrane vesicles, 2) to examine the magnitude of the effect of representatives of three different classes of nonsteroidal anti-inflammatory agents (ibuprofen, mefenamic acid, piroxicam) on sulfate transport, and 3) to determine the mechanism of the renal interaction between SA (and other pharmacologic agents) and inorganic sulfate. The potential mechanisms which will be examined are the direct inhibition by SA of a transporter involved in renal sulfate reabsorption and the indirect inhibitior of sulfate transport mediated via a SA-induced inhibition of prostoglandin synthesis, uncoupling of oxidative phosphorylation, or pH alteration. These possible mechanisms will be examined, using probes with specific pharmacologic or specific renal transport properties, by in vivo studies in the rat and in vitro studies with membrane vesicle preparations. The results of the proposed research will increase our understanding of the renal transport of inorganic sulfate and the effect of xenobiotics on sulfate renal reabsorption, a process which is important for sulfate homeostasis and therefore for human growth and development.