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: 3070469
• 负责人: Richard H Kennedy
• 金额: $ 4.81万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-05-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3070469
• 关键词: adenosinetriphosphatase; adrenergic receptor; anticholinergic agent; arrhythmia; autonomic nervous system; digitalis; dogs; dosage; drug adverse effect; heart disorder chemotherapy; heart pharmacology; heart rate; heart rhythm; human old age (65+); ion transport; laboratory rat; membrane permeability; muscarinic receptor; muscle relaxants; muscle stimulant; myocardium; ouabain; sarcolemma; sodium potassium exchanging ATPase; sympathetic block; tritium

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.

强心苷（DIG）的临床使用经常与以下因素相关： 不良（毒性）副作用，其中最严重的是 心率和节律的电生理紊乱。 公 根据临床经验，对这些心脏毒性药物的耐受性 DIG的作用在老年患者中降低。 这一目标 项目是：a）检查对治疗敏感性的程度 和DIG随老化而变化的不利影响;和B）确定 DIG敏感性改变的机制。 具体来说，实验 将确定是否年龄相关的变化，反应DIG的结果 自主神经系统、肌膜Na，K-ATP酶（ 膜钠泵）和/或跨膜通量或细胞内 离子的活动。 这样的研究显然不能在人身上进行。 因此，拟议的调查将使用两个物种， 在足够数量的衰老动物，即大鼠和犬中获得。 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， 在麻醉的成年和老年动物中的促肾上腺皮质激素作用 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 心肌细胞膜中[3 H]哇巴因的活性和特异性结合位点 成年和老年动物，而钠泵活性将根据 心肌切片中~（86）Rb ~+摄取。 细胞内离子活动将是 离子选择性微电极穿刺法测定 成年人和老年人的心脏。 除了阐明 年龄相关的DIG敏感性改变的机制，本项目 将推进知识：a）机制参与DIG-induced 心律失常;和B）心肌的衰老变化。 该等资料不 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 全组 鉴于每天都有大量的病人需要 行政部门的DIG（全国总人口的5-10%）和 需要住院治疗的副作用频率改善 从一项研究中提出的治疗方法可能会减少 飞涨的医疗费用