Time - and voltage-dependent K+ currents in heart are of fundamental importance in the development of the pacemaker potential, in triggering and controlling repolarization and in the responses of the heart to various autonomic transmitters and other pharmacologic agents. In spite of this, quantitative information concerning the number, the time-course, and the size(s) of K+ currents in mammalian heart is not complete. In this proposal, previous work on K+ currents will be extended, by further exploring the nature and the possible second messengers of the potassium current induced by muscarinic agonists, and by identifying the types of potassium current present in a mammalian model for human myocardium: the rabbit atrium. In these experiments, single cells obtained by enzymatic dispersion from bullfrog atrium or rabbit atrium will be used and both whole-cell voltage clamp recordings and single channel patch clamp recordings will be made. In addition, attempts will be made to """"""""hold"""""""" populations of cells using short-term incubation techniques so that pre-treatment with biochemical pathway inhibitors can be carried out in certain stages of the work. Success in the proposed experiments will yield new data further defining the mechanism by which muscarinic agonists inhibits isoproterenol-induced current changes, and providing quantitative information concerning details of repolarization in the rabbit atrium. In all physiological states and certain pathological conditions adrenergic tone is present and can be modulated by a variety of mechanisms, including changes in cholinergic nerve activity. These results will be of considerable pharmacological and pathophysiological importance in the understanding and control of arrythmias.
