My long-range goals are to understand the physiological mechanisms that determine and regulate atrial pacemaker function, particularly with respect to latent atrial pacemakers and their contribution to atrial dysfunction. Thus, primary and/or latent atrial pacemaker activities have been implicated in various types of atrial dysrhythmias such as sick sinus syndrome. Although cholinergic stimulation exerts antiarrhythmic effects on atrial function, it also generates atrial dysrhythmias, the mechanisms of which are not known. Moreover, there are several aspects of cholinergic regulation of atrial pacemaker activity that are not completely understood. As examples, 1) cholinergic inhibition of the heartbeat is followed by a rebound tachycardia, i.e. postvagal tachycardia, 2) digitalis elicits a bradycardia by somehow sensitizing the atria to cholinergic inhibition, 3) nitric oxide may play an obligatory role in the inhibitory effects of ACh, and 4) the mechanisms of accentuated antagonism may not be entirely understood. In the present research, we plan to use a perforated patch/whole cell recording method to analyze cholinergic regulation of K+ and Ca2+ conductances in single pacemaker cells isolated from cat right atrium. We will use voltage clamp protocols, and selective agonist and antagonist to determine the second messenger signaling pathways that underlie cholinergic regulation of both primary (SA node) and latent atrial pacemaker activities. The present proposal will address the following specific questions: 1) What are the second messenger signaling pathways underlying ACh- induced inhibition and the rebound stimulation of I/Ca,L and I/f elicited by withdrawal of ACh? What role does nitric oxide play? 2) What are the second messenger signaling pathways underlying ACh- induced activation of ATP-sensitive K currents (I/K,ATP)? 3) How do agents or interventions that raise intracellular Ca2+ such as isoproterenol, enhance ACh-induced activation of I/K,ATP? How do these mechanisms contribute to accentuated antagonism and digitalis-induced bradycardia? 4) What are the relative contributions of the different second messenger signaling pathways to cholinergic regulation of primary and latent atrial pacemaker function? How do these mechanisms contribute to postvagal tachycardia and dysrhythmias initiated by vagal withdrawal? The proposed experiments will provide a new understanding of how ACh regulates Ca2+ and K+ conductances, and how adrenergic/cholinergic interactions operate to autonomically regulate atrial pacemaker activity. This work will contribute to our understanding of atrial brady-tachy dysrhythmias and dysrhythmias initiated by withdrawal of vagal nerve activity.
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