SENSITIVITY TO DIGITALIS-INDUCED ARRHYTHMIAS IN AGING

心脏糖苷(Dig)的临床应用经常与 副作用，其中最严重的是电生理 心率和节律紊乱。它是从 临床经验表明，对地塞米松这些心脏毒性作用的耐受性 在老年患者中降低。该项目的目标是：a) 检查对治疗性心脏和不良心脏的敏感性程度 DIG的作用随年龄的变化，以及b)确定其作用机制(S) 挖掘敏感度的变化。具体地说，实验将确定 如果年龄相关的对DIGH反应的改变是由于 他们的药代动力学或自主神经系统的变化， 肌膜Na，K-ATPase(膜钠泵)和/或跨膜 离子的通量或细胞内的活性。这样的研究显然不能 在人类身上完成。因此，拟议的调查将使用老鼠，一种 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 通过测定肌力和肌力所需的地高辛的剂量进行检查 麻醉成年和老年动物的致心律失常作用 胆碱能和肾上腺素能受体阻断的存在和缺失 探员们。肌膜Na，K-ATPase将通过研究酶来评估 小鼠心肌膜的活性及特异性(~3H)-哇巴因结合部位 成年和老年动物，而钠泵将从86Rb+估计 领悟。细胞内离子活度将用 离子选择性微电极在成人和老年人制剂中的应用 红心。除阐明年龄相关性改变的机制外(S) 在对挖掘的敏感性方面，该项目将促进以下方面的知识：a) 参与地高辛诱导的心律失常的机制，以及b)衰老的变化 心肌。这些信息在临床环境中很重要。 因为它将促进一种更合理的治疗方案 不仅是在老年人身上，而且在所有病人身上。鉴于人数众多， 需要每日服用地塞米松的患者(占总数的5%-10% 国家人口)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，如 这项提议可能会降低飙升的医疗保健成本。

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.