Cardiac arrhythmias are a major health problem. Triggered arrhythmias may cause some of the arrhythmias associated with acute myocardial infarction and some supraventricular and ventricular tachycardias. Triggered arrhythmias are caused by delayed after depolarizations, but the origin of the transient inward current that causes the afterdepolarizations is still under study, even though a phasic rise in intracellular (Ca) is now known to play a role. Ca-activated non-specific ion channels may give rise to the inward current but the inward current may instead be generated by electrogenic Na/Ca exchange. We propose to evaluate the contribution made by Na/Ca exchange to that current. Almost all studies of that current have been done on cardiac preparations Na-loaded by poisoning with digitalis. For ten years, we have studied a more stable model of triggered arrhythmias, i.e. normal myocardium from the canine coronary sinus, exposed to norepinephrine. We have recently isolated healthy single coronary sinus cells suitable for whole-cell current recording under voltage-clamp and have also begun to characterize the Na/Ca exchange current in voltage-clamp guinea-pig ventricular cells internally dialyzed via wide-tipped patch pipettes, using a similar approach to that we developed to investigate Na/K pump current in the same cells. Using Noma's device for quickly changing the solution inside the pipette, we control the composition of both intracellular and extracellular solution as well as membrane potential. After characterizing the Na/Ca exchange current in guinea-pig ventricular cells, we will do the same in single coronary sinus cells, and then characterize the transient inward current in coronary sinus cells exposed to norepinephrine. We will compare the responses of current to changes in internal and external ion concentrations, or in membrane potential, or to pharmacological interventions, and compare those effects with observations on delayed afterdepolarizations and triggered activity in single cells and multicellular coronary sinus preparations. These will be the first investigations using a novel preparation, single cells from the canine coronary sinus, the first studies of transient inward current in healthy single cells not poisoned with digitalis, and the first comparison of Na/Ca exchange current and transient inward current in single cells. We will also pursue our ongoing investigation of K conductances modulated by acetylcholine and/or alpha- and beta-catecholamines, and of the possibility of interactions between the modulatory pathways, in either single canine coronary sinus cells or small canine cardiac Purkinje fibers suspended in a fast-flow system and voltaged-clamped with two microelectrodes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Rockefeller University
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New York
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