This research application proposes studies of the mechanisms that underlie early afterdepolarizations (EADs). EADs are triggered depolarizations that occur near action potential plateau voltages. They are thought to cause certain cardiac arrhythmias including """"""""torsades de pointes"""""""". The cellular mechanisms for EADs are unknown. We have developed a model to induce EADs using the Ca++ current agonist Bay k 8644. Experimental results obtained in voltage clamped and non-voltage clamped Purkinje strands with this model have permitted us to hypothesize that EAD induction 1 requires: 1) Lengthening and flattening of the action potential plateau within a voltage range where, 2) there can occur recovery from inactivation and reopening of Ca++ channels within the """"""""window"""""""" of overlap of their activation and inactivation relationships. These findings provide potentially new insights into roles for Ca channels and """"""""window"""""""" currents. This hypothesis, whereby inward current can be activated during repolarization, constitutes a new arrhythmogenic mechanism. This mechanism should participate in the normal action potential plateau. We propose to continue to study the cellular mechanisms that cause EADs. We will investigate further the Bay k 8644 model for EAD induction and we will continue to test our hypotheses against other models that induce EADs. New information about fundamental mechanisms for arrhytmogenesis is likely and this may have clinical impact as well. Because Ca++ channel current is central to the induction of EADs, this research application also proposes detailed studies of Ca currents in isolated Purkinje cells. Initial whole-cell voltage clamp experiments have shown that L- and T-type Ca channel current are present and can be separated. In contrast to ventricular cells, both types of Ca++ current remain large even at physiological Ca. Little information exists about the regulation of T-type current. The roles of voltage and Ca++ in inactivation, activation, and recovery from inactivation will be studied. Steady-state currents will be studied. Interactions between T- and L-type currents will be sought. In the same cell under similar experimental conditions, the metabolic regulation of T- and L-type currents will be investigated. Data will be interpreted in channel models. New information about Ca channel currents and arrhythmogenic mechanisms in Purkinje cells will be obtained.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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University of Chicago
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Xie, J T; Yuan, C S; Zhou, Z et al. (2000) Enhancement of delayed afterdepolarizations and triggered activity by class III antiarrhythmic drugs: multiple effects of E-4031 and dofetilide. Methods Find Exp Clin Pharmacol 22:67-76
Xie, J T; Chen, W; Cunningham, P M et al. (1998) Effect of acetylstrophanthidin on action potential duration and relation with extracellular potassium in sheep isolated Purkinje fibers. Zhongguo Yao Li Xue Bao 19:309-12
Zhou, Z; January, C T (1998) Both T- and L-type Ca2+ channels can contribute to excitation-contraction coupling in cardiac Purkinje cells. Biophys J 74:1830-9
Vorperian, V R; Zhou, Z; Mohammad, S et al. (1996) Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole. J Am Coll Cardiol 28:1556-61
Xie, J T; Cunningham, P M; January, C T (1995) Digoxin-induced delayed afterdepolarizations: biphasic effects of digoxin on action potential duration and the Q-T interval in cardiac Purkinje fibers. Methods Find Exp Clin Pharmacol 17:113-20
Xie, J T; Cunningham, P; Shorofsky, S et al. (1994) Induction of delayed afterdepolarizations and triggered arrhythmias in isolated Purkinje fibers: comparison of resibufogenin and acetylstrophanthidin. Zhongguo Yao Li Xue Bao 15:97-102
Xie, J T; January, C T (1993) The monophasic action potential technique and its application in cardiac electropharmacology. Methods Find Exp Clin Pharmacol 15:557-67
January, C T; Moscucci, A (1992) Cellular mechanisms of early afterdepolarizations. Ann N Y Acad Sci 644:23-32
Hirano, Y; Moscucci, A; January, C T (1992) Direct measurement of L-type Ca2+ window current in heart cells. Circ Res 70:445-55
Shorofsky, S R; January, C T (1992) L- and T-type Ca2+ channels in canine cardiac Purkinje cells. Single-channel demonstration of L-type Ca2+ window current. Circ Res 70:456-64

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