SENSITIVITY TO DIGITALIS-INDUCED ARRHYTHMIAS IN AGING

心脏糖苷(Dig)的临床应用经常与 不良(有毒)副作用，其中最严重的是 心率和节律方面的电生理障碍。这很好 根据临床经验建立了对这些心脏毒性的耐受性 老年患者地塞米松作用减弱。这样做的目的是 项目是：a)检查对治疗的敏感性程度 和Dig随年龄变化的不良影响；以及b)确定 DIG敏感性改变的机制(S)。具体地说，实验 将确定与年龄相关的反应性变化是否会导致 自主神经系统、肌膜Na，K-ATPase( 膜钠泵)，和/或跨膜通量或细胞内 离子的活度。这样的研究显然不能在人类身上进行。 因此，拟议的调查将使用两个物种，这两个物种可以 在足够数量的衰老动物中获得，即大鼠和狗。 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 大鼠心肌细胞膜上的活性和[~3H]哇巴因结合位点 成年和老年动物，而钠泵活动将从 心肌切片摄取~(86)Rb+。细胞内的离子活动将是 离子选择微电极穿刺法测定打浆 成人心脏和老年心脏的制剂。除了澄清 挖掘敏感性随年龄变化的机制(S)，本项目 将促进以下方面的知识：a)参与Dig诱导的机制 心律失常；以及b)心肌的衰老变化。这样的信息是 在临床环境中很重要，因为它将促进更多 合理的治疗方案不仅适用于老年人，而且适用于 所有病人。鉴于每天需要的病人数量很多 迪拜政府(占全国总人口的5%-10%)和 需要住院治疗的副作用的频率提高了 从一项研究中建议的治疗方法可能会减少 医疗保健费用的飙升。

Clinical use of cardiac glycosides (DIG) is frequently associated with adverse (toxic) 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 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 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 two species which can be obtained in sufficient numbers of senescent animals, namely rats and dogs. 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 efforts 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 activity will be estimated from 86Rb+ uptake in slices of myocardium. Intracellular ion activities will be determined using ion-selective micro-electrode impalement in beating preparations of adult and aged hearts. In addition to elucidating mechanism(s) of age-related alterations in sensivity 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.