MECHANISM OF DRUG MEDIATED CHANGES/RENAL WATER EXCRETION

药物介导的变化/肾水排泄机制

• 批准号: 3227900
• 负责人: Tomas Berl
• 金额: $ 2.81万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-20 至 1987-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227900
• 关键词: calcium metabolism; carbamazepine; cyclic AMP; cyclic GMP; gel filtration chromatography; glomerular filtration; hemodynamics; hyperkalemias; ionophores; kidney circulation; kidney metabolism; kidney pharmacology; lithium; neurohormones; phosphodiesterases; prostaglandins; radioimmunoassay; renal failure; renin; tritium; vasopressins; verapamil

The objective of the present proposal is to examine te mechanism whereby two water retaining pharmacologic agents (chlorpropamide and carbamazepine) and two agents that cause a water losing disorder (lithium and demeclocycline) exert their effect on water excretion. The experiments are tailored to focus in each case on the to date undefined mechanisms whether central (vasopressin release, thirst) or renal (vasopressin dependent and independent). Methods to be employed include metabolic balance studies, measurements of vasopressin release, use of vasopressin free diabetes insipidus rats, measurements of systemic and renal hemodynamics, determination of inner medullary tonicity and inner medullary blood flow. These in vivo measurements are complemented by biochemical studies performed in dissected vasopressin sensitive segments of the nephron, the medullary ascending limb, the cortical, outer and inner medullary collecting ducts. Both in situ cAMP content as well as the activities of adenylate cyclase and cAMP phosphodiesterase are performed with microassays with the view of defining the effects on the whole system. Both tissues of animals treated with the drugs and acute medium manipulations of the agents in tissues of untreated rats will be undertaken. The roles of prostaglandins and calcium will also be explored. The studies will provide correlates of in vivo water excretion with in vitro biochemical perturbations in the primary effector of vasopressin action - the cAMP system.

本提案的目的是研究机制，据此 两种保水药物（氯丙酰胺和卡马西平） 以及两种导致失水症的药物（锂和 地甲环素）发挥其对水排泄的作用。 实验是 量身定制，以在每种情况下关注迄今为止未定义的机制 中枢（加压素释放、口渴）或肾脏（加压素依赖性和 独立的）。 采用的方法包括代谢平衡研究， 加压素释放的测量、无加压素糖尿病的使用 尿崩症大鼠，全身和肾脏血流动力学的测量， 测定内髓张力和内髓血流量。 这些体内测量得到生化研究的补充 在解剖的肾单位加压素敏感部分进行， 髓质升肢、皮质、外髓和内髓 收集管。 原位 cAMP 含量以及活性 腺苷酸环化酶和 cAMP 磷酸二酯酶通过微量测定进行 着眼于定义对整个系统的影响。 两种组织 用药物治疗的动物和药剂的急性介质操作 将在未经治疗的大鼠组织中进行。 的角色 前列腺素和钙也将被探索。 研究将提供 体内水排泄与体外生化的相关性 加压素作用的主要效应器 - cAMP 的扰动 系统。