PHARMACOLOGIC ALTERATIONS OF SULFATE HOMEOSTASIS

无机硫酸盐是生物合成所必需的一种生理负离子。 反应，特别是在生长和发育中的重要作用。为 内源性化合物(肝素、胃泌素、 胆囊素)，并用于外源物质和 内源性化合物(儿茶酚胺、类固醇、胆汁酸)。 无机硫酸盐浓度的动态平衡主要是 由容量有限的肾脏重吸收维持。通过以下方式治疗 水杨酸盐(阿司匹林)，治疗慢性支气管炎的首选药物 类风湿性关节炎，广泛用作非处方药， 导致血浆中硫酸盐浓度显著降低 在小鼠和大鼠身上。这些血浆硫酸盐的变化 浓度是水杨酸盐(SA)诱导的 增强肾脏对硫酸盐的清除能力。尽管SA是 已知可抑制硫酸盐进入胎盘刷毛边缘 膜小泡在生理浓度下，鲜为人知 关于其或其他药物对硫酸肾的影响 运输。拟议研究的总体目标是检查 水杨酸与无机盐相互作用的肾脏机制 硫酸盐，从而了解哪些生理 影响硫酸盐稳态的因素和药理作用可能存在。 这项研究建议的具体目的是：1)确定 水杨酸对大鼠肾刷缘和肾组织硫酸盐转运的影响 基侧膜小泡，2)检查基侧膜小泡的大小 三个不同阶层的代表的作用 非类固醇抗炎药(布洛芬、甲芬酸、 吡罗昔康)对硫酸盐转运的影响，以及3)确定其机制 SA(和其他药物)之间的肾脏相互作用 试剂)和无机硫酸盐。潜在的机制将 SA对转运蛋白的直接抑制作用 参与肾脏硫酸盐重吸收及其间接抑制作用 通过SA诱导的抑制硫酸盐转运 前列腺素合成，氧化磷酸化去偶联， 或酸碱度改变。我们将研究这些可能的机制， 使用具有特定药理或特定肾脏的探针 大鼠体内和体外研究的转运特性 膜泡制剂的研究。评选结果 拟议的研究将增加我们对肾脏的了解 无机硫酸盐的迁移及外源物质对其的影响 硫酸盐肾重吸收，这一过程对 硫酸盐的动态平衡，从而促进人类的生长和发育。

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.