SENSITIVITY TO DIGITALIS-INDUCED ARRHYTHMIAS IN AGING

对洋地黄引起的衰老心律失常的敏感性

• 批准号: 3115821
• 负责人: Richard H Kennedy
• 金额: $ 9.93万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1989-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3115821
• 关键词: adenosinetriphosphatase; aging; arrhythmia; autonomic nervous system; digitalis; digoxin; drug adverse effect; drug metabolism; heart electrical activity; heart pharmacology; heart rate; heart rhythm; ion transport; sarcolemma

Clinical use of cardiac glycosides (DIG) is frequently associated with adverse side-effects, the most serious of which are electrophysiological disturbances in cardiac rate and rhythm. It is well established from clinical experience that tolerance to these cardiotoxic actions of DIG is decreased in elderly patients. The objectives of this project are: a) to examine the degree to which sensitivity to therapeutic and adverse cardiac effects of DIG changes with aging, and b) to determine the mechanism(s) of alterations in DIG sensitivity. Specifically, experiments will determine if age-related changes in responsiveness to DIG result from alterations in their pharmacokinetics or from changes in the autonomic nervous system, sarcolemmal Na,K-ATPase (the membrane sodium pump), and/or transmembrane fluxes or intracellular activities of ions. Such a study obviously cannot be done in man. Therefore, the proposed investigation will use rats, a species which can be obtained in sufficient numbers of senescent animals. Sensitivity to DIG and the role of the autonomic nervous system will be examined by determining the dose of digoxin necessary for inotropic and arrhythmogenic effects in anesthetized adult and aged animals in the absence and presence of cholinergic and adrenergic receptor blocking agents. Sarcolemmal Na,K-ATPase will be evaluated by studying enzyme activity and specific (3H)-ouabain binding sites in myocardial membranes of adult and aged animals, while sodium pump will be estimated from 86Rb+ uptake. Intracellular ion activities will be determined using ion-selective microelectrode impalement in preparations of adult and aged hearts. In addition to elucidating mechanism(s) of age-related alterations in sensitivity to DIG, this project will advance knowledge of: a) mechanisms involved in DIG-induced arrhythmias, and b) senescent changes in myocardium. Such information is important in the clinical environment because it will promote a more rational approach to therapeutic regimens not only in the elderly, but in all patients. In view of the large numbers of patients which require daily administration of DIG (5-10% of the total population of the nation) and the frequency of side-effects which require hospital treatment, improved methods of therapy suggested from a study like the one proposed may reduce the soaring costs of health care.

强心苷（DIG）的临床使用经常与以下因素相关： 不良副作用，其中最严重的是电生理 心率和节律紊乱。 它是建立在 临床经验表明，对DIG的这些心脏毒性作用的耐受性 老年患者减少。 该项目的目标是：a） 检查对治疗和不良心脏反应的敏感性程度， DIG的作用随老化而变化，和B）确定 DIG敏感性的改变。 具体来说，实验将确定 如果年龄相关的DIG反应性变化是由于 它们的药代动力学或自主神经系统的变化， 肌膜Na，K-ATP酶（膜钠泵），和/或跨膜 离子的通量或细胞内活动。 这样的研究显然不能 因此，拟议的研究将使用大鼠， 可以在足够数量的衰老动物中获得的物种。 对DIG的敏感性和自主神经系统的作用将是 通过确定变力所需的地高辛剂量进行检查， 麻醉的成年和老年动物中的致瘤作用 存在和不存在胆碱能和肾上腺素能受体阻滞 剂. 肌膜Na，K-ATP酶的研究 活性和特异性（3 H）-哇巴因结合位点的心肌细胞膜 成年和老年动物，而钠泵将从86 Rb+估计 摄取。 细胞内离子活性将使用 离子选择性微电极穿刺在成人和老年人制剂中应用 心中 除了阐明年龄相关变化的机制外， 出于对DIG的敏感性，该项目将促进以下方面的知识：a） DIG诱导的心律失常的机制，和B） 心肌 这些信息在临床环境中很重要 因为它将促进更合理的治疗方案 不仅在老年人中，而且在所有患者中。 鉴于人数众多， 需要每日给予DIG的患者（占总数的5- 10 国家的人口）和副作用的频率，需要 医院治疗，从一项研究中建议的改进的治疗方法， 这项提议可能会降低飙升的医疗保健费用。