EFFECTS OF ORGANIC ACIDS ON LOOP DIURETIC OTOTOXICITY

有机酸对袢利尿剂耳毒性的影响

• 批准号: 3216558
• 负责人: LEONARD P RYBAK
• 金额: $ 13.59万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3216558
• 关键词: acoustic nerve; action potentials; chinchilla; chromatography; cochlea; diuretics; drug adverse effect; drug metabolism; electrolytes; electron microscopy; electrophysiology; endolymph; furosemide; high performance liquid chromatography; ion transport; organic acid; ototoxin

The loop diuretics are weak organic acids which cause ototoxicity in humans as well as in experimental animal models. Unfortunately, the molecular basis for these ototoxic effects has not yet been elucidated. Recent experimental findings have shown that certain organic acid compounds can reduce the cochlear effects of the sulfamoyl benzoic acid loop diuretic furosemide, but not those caused by the phenoxyacetic acid derivative ethacrynic acid. These two chemical classes of loop diuretics interact with renal receptors in different ways. The proposed studies will extend these findings to study additional members of these two loop diuretic chemical classes --piretanide, which is closely related to furosemide, and indacrinone, which is a phenoxyacetic acid derivative. The proposed studies will examine whether organic acid transport inhibitors reduce the ototoxicity or piretanide and indacrinone. The specific eletrophysiologic studies will measure changes in endocochlear potential, eighth nerve action potential and intracellular potentials recorded from marginal cells. Effects on in transport will be assessed by measuring concentrations and changes of ion conductances and permeabilities of the cochlear duct, using ion-sensitive microelectrodes. Correlation of these findings with ultrastructural stereologic studies of the volume density of each cell layer of the stria vascularis to further clarify the sites of action on the stria will be made. The blood levels of loop diuretics will be measured by high pressure liquid chromatography to determine whether the concentrations of diuretics in blood are altered by organic acids which reduce cochlear toxicity of the loop diuretic. The diuretic effects in control and experimental animals will be evaluated to determine whether protection against ototoxicity has an effect on the diuretic response by the kidney. Recent intracellular studies of the stria vascularis have provided startling new data which mandate re-evaluation of models of normal ion transport in the cochlea and the effects of inhibitors such as loop diuretics. The combination of the study of the effects of loop diuretics on the marginal cell potentials will provide new information on the cellular locus of action of loop diuretics. The correlation of the ultrastructural volume density analysis of the cellular components of the stria vascularis with the intracellular studies will provide novel insights into the mechanisms of loop diuretic ototoxicity.

环状利尿剂是会引起耳毒性的弱有机酸。 在人类和实验动物模型中也是如此。 不幸的是，这些耳毒性作用的分子基础 尚未被阐明。最近的实验发现 研究表明，某些有机酸性化合物可以减少 磺胺甲酰苯甲酸环状利尿剂的耳蜗性作用 速尿，但不是由苯氧乙酸引起的 乙丙烯酸衍生物。这两类化学环路 利尿剂以不同的方式与肾脏受体相互作用。这个 拟议的研究将把这些发现扩展到研究其他 这两类环状利尿剂的成员--哌拉尼特， 它与速尿密切相关，以及吲哚利酮，它是一种 苯氧乙酸衍生物。拟议的研究将审查 有机酸转运抑制剂是否降低耳毒性 或者是匹拉尼德和吲哚喹诺酮。特定的电生理学 第八项研究将测量耳蜗内电位的变化 记录的神经动作电位和细胞内电位 边缘细胞。将通过以下方式评估对运输的影响 测量离子电导的浓度和变化 用离子敏感法测定耳蜗管的通透性 微电极。这些发现与 三者体密度的超微结构体视学研究 血管纹细胞层进一步明确血管纹的位置 将对条纹采取行动。Loop的血药浓度 利尿剂将用高压液相色谱检测 以确定血液中利尿剂的浓度是否 由有机酸改变，降低耳蜗毒性 环状利尿剂。利尿剂在对照和实验中的作用 将对动物进行评估，以确定是否保护动物免受 耳毒性对肾脏的利尿反应有影响。 最近对血管纹的细胞内研究提供了 令人震惊的新数据要求对模型进行重新评估 耳蜗内正常离子转运及抑制剂的作用 例如环状利尿剂。结合对中国传统文化的研究 环状利尿剂对边缘细胞电位的影响 提供有关环路的细胞活动轨迹的新信息 利尿剂。超微结构体密度的相关性 血管纹的细胞成分分析 细胞内的研究将为我们提供对 环状利尿剂耳毒性的机制。