Description: Ventricular fibrillation (VF) in the globally ischemic heart is characterized by a progressive electrical depression manifested as a decline in the VF excitation rate (VFR) and loss of excitability, which occur first in the subepicardium (Epi) and spread to the subendocardium (Endo). Early electrical failure is detrimental to successful defibrillation and resuscitation during cardiac arrest. Hyperkalemia and/or the activation of ATP-sensitive K + (K ATP ) channels have been implicated in electrical failure, but the role of these factors in ischemic VF is poorly understood. We determined the VFR-extracellular K + concentration ([K + ] o ) relationship in the Endo and Epi of the left ventricle during VF in globally ischemic hearts (Isch group) and normoxic hearts subjected to hyperkalemia (HighK group) or a combination of hyperkalemia and the K ATP channel opener cromakalim (HighK-Crom group). In the Isch group, Endo and Epi values of [K + ] o and VFR were compared in the early (0–6 min), middle (7–13 min), and late (14–20 min) phases of ischemic VF. A significant transmural gradient in VFR (Endo 〉 Epi) was observed in all three phases, whereas a significant transmural gradient in [K + ] o (Epi 〉 Endo) occurred only in the late phase of ischemic VF. In the Isch group, the VFR decrease and inexcitability started to occur at much lower [K + ] o than in the HighK group, especially in the Epi. Combining K ATP activation with hyperkalemia only shifted the VFR-[K + ] o curve upward (an effect opposite to real ischemia) without changing the [K + ] o threshold for asystole. We conclude that hyperkalemia and/or K ATP activation cannot adequately explain the heterogeneous electrical depression and electrical failure during ischemic VF.