Background: A greater depression of the action of potential (AP) of ventricular epicardium (Epi) vs. endocardium (Endo) is readily observed in experimental models of acute ischemia and the Brugada syndrome. Endo and Epi differences in Ito and/or I_K-ATP are believed to contribute to the differential response. The present study tests the hypothesis that the greater sensitivity of Epi is due in part to its functionally distinct early I_Na (fast sodium current). Methods: APs were recorded from isolated Epi and Endo tissue-slices and coronary-perfused wedge preparations before and after exposure to elevated [K⁺]₀ (6 to 12 mM). I_Na was recorded from Epi and Endo myocytes using whole cell patch-clamp techniques. Results: In tissue-slices, increasing K⁺]₀ to 12 mM reduced Vmax 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 the wedge preparation (n= 12), the increase in K⁺]₀ caused selective depression of Epi AP 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). Conclusion: Our data suggest that a reduced Na+ current availability in ventricular epicardium 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.