PHARMACOLOGIC ALTERATIONS OF SULFATE HOMEOSTASIS

无机硫酸根是生物合成所必需的生理阴离子 反应，特别是重要的生长和发育。 为 内源性化合物（肝素，胃泌素， 胆囊收缩素），以及用于异生物质的解毒， 内源性化合物（儿茶酚胺、类固醇、胆汁酸）。 无机硫酸盐浓度的稳态主要是 通过容量有限的肾重吸收维持。 治疗 水杨酸盐（阿司匹林），药物的选择，在治疗 类风湿性关节炎和广泛使用的非处方药， 导致血浆硫酸盐浓度显著降低 在小鼠和大鼠中。 这些血浆硫酸盐的变化 浓度是水杨酸（SA）诱导的结果 增强硫酸盐的肾清除率。 虽然SA是 已知抑制胎盘刷状缘吸收硫酸盐 膜囊泡在生理浓度，鲜为人知 关于其或其他药物对肾硫酸盐的影响 运输 本研究的总体目标是研究 SA与无机物肾相互作用的机制 硫酸盐，从而了解生理 因素和药理学试剂可影响硫酸盐体内平衡。 本研究建议的具体目标是：1）确定 水杨酸对大鼠肾刷状缘硫酸盐转运影响 基底外侧膜囊泡，2）检查 三种不同类别的代表的影响 非甾体抗炎药（布洛芬，甲芬那酸， 吡罗昔康）对硫酸盐转运的影响，以及3）确定机制 SA（和其他药物）之间的肾脏相互作用 试剂）和无机硫酸盐。 潜在的机制， SA对转运蛋白的直接抑制作用 参与肾硫酸盐重吸收和间接抑制 硫酸盐转运介导的SA诱导的抑制 前列腺素合成，氧化磷酸化解偶联， 或pH改变。 将对这些可能的机制进行审查， 使用具有特定药理学或特定肾功能的探针 通过大鼠体内研究和体外研究确定的转运特性 膜囊泡制剂的研究。 的结果 拟议的研究将增加我们对肾脏疾病的理解， 无机硫酸盐的迁移和外源物质对 硫酸盐肾重吸收是一个重要的过程， 硫酸盐体内平衡和因此对人类生长和发育。

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.