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Functionally distinct sodium channels in ventricular epicardial and endocardial cells contribute to a greater sensitivity of the epicardium to electrical depression

Masonic Medical Research Laboratory, Utica, New York

Submitted 12 November 2007 ; accepted in final form 29 April 2008

A greater depression of the action potential (AP) of the ventricular epicardium (Epi) versus endocardium (Endo) is readily observed in experimental models of acute ischemia and Brugada syndrome. Endo and Epi differences in transient outward K⁺ current and/or ATP-sensitive K⁺ channel current are believed to contribute to the differential response. The present study tested the hypothesis that the greater sensitivity of Epi is due in part to its functionally distinct early fast Na⁺ current (I_Na). APs were recorded from isolated Epi and Endo tissue slices and coronary-perfused wedge preparations before and after exposures to elevated extracellular K⁺ concentration ([K⁺]_o; 6–12 mM). I_Na was recorded from Epi and Endo myocytes using whole cell patch-clamp techniques. In tissue slices, increasing [K⁺]_o to 12 mM reduced V_max to 51.1 ± 5.3% and 26.8 ± 9.6% of control in Endo (n = 9) and Epi (n = 14), respectively (P < 0.05). In wedge preparations (n = 12), the increase in [K⁺]_o caused selective depression of Epi APs and transmural conduction slowing and block. I_Na density was not significantly different between Epi (n = 14) and Endo (n = 15) cells, but Epi cells displayed a more negative half-inactivation voltage [–83.6 ± 0.1 and –75.5 ± 0.3 mV for Epi (n = 16) and Endo (n = 16), respectively, P < 0.05]. Our data suggest that reduced I_Na availability in ventricular Epi may contribute to its greater sensitivity to electrical depression and thus may contribute to the R-ST segment changes observed under a variety of clinical conditions including acute myocardial ischemia, severe hyperkalemia, and Brugada syndrome.

Brugada syndrome; acute ischemia; severe hyperkalemia

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				K. Calloe, J. M. Cordeiro, J. M. Di Diego, R. S. Hansen, M. Grunnet, S. P. Olesen, and C. Antzelevitch A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome Cardiovasc Res, December 25, 2008; (2008) cvn339v2. [Abstract] [Full Text] [PDF]