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: 3216560
• 负责人: LEONARD P RYBAK
• 金额: $ 11.56万
• 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/3216560
• 关键词: acoustic nerve; action potentials; chinchilla; chromatography; cochlea; diuretics; 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.

髓袢利尿剂是一种引起耳毒性的弱有机酸 在人类和实验动物模型中。 不幸的是，这些耳毒性作用的分子基础 尚未阐明。 最近的实验结果表明， 表明某些有机酸化合物可以降低 氨磺酰苯甲酸袢利尿剂的耳蜗效应 呋塞米，但不是那些由苯氧乙酸引起的 衍生物依他尼酸。 这两种化学循环 利尿剂以不同方式与肾受体相互作用。 的 拟议的研究将扩展这些发现，以研究更多的 这两种髓袢利尿剂化学类别的成员--哌瑞他尼， 与呋塞米密切相关，而茚达酮是一种 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 或吡瑞他尼和茚达酮。 特异性电生理 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 对运输的影响将通过以下方式进行评估： 测量离子电导的浓度和变化， 耳蜗导管的渗透性，使用离子敏感 微电极 这些发现与 超微结构体视学研究的体积密度， 细胞层的血管纹，以进一步澄清的网站 将对条纹进行操作。 循环血液水平 利尿剂将通过高压液相色谱法测量 以确定血液中利尿剂的浓度是否 改变的有机酸，减少耳蜗毒性的 髓袢利尿剂 对照和实验中的利尿作用 将对动物进行评估，以确定是否对 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，要求重新评估模型， 耳蜗中的正常离子转运和抑制剂的作用 例如髓袢利尿剂。 研究的结合， 袢利尿剂对边缘细胞电位的影响将 提供了新的信息的细胞轨迹的行动环 利尿剂 超微结构体密度的相关性 血管纹细胞成分分析 细胞内的研究将提供新的见解， 袢利尿剂耳毒性的机制。