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.
