The maximal upstroke of transmembrane voltage (dV mdt max) has been used as an indirect measure of sodium current I Na upon activation in cardiac myocytes. However, sodium influx generates not only the upstroke of V m, but also the downstroke of the extracellular potentials V e including epicardial surface potentials V es. The purpose of this study was to evaluate the magnitude of the maximal downstroke of V es (|dV es/dt min) as a global index of electrical activation, based on the relationship of dV m/dt max to I Na. To fulfill this purpose, we examined dV es/dt \rm min experimentally using isolated perfused mouse hearts and computationally using a 3-D cardiac tissue bidomain model. In experimental studies, a custom-made cylindrical "cage" array with 64 electrodes was slipped over mouse hearts to measure V es during hyperkalemia, ischemia, and hypoxia, which are conditions that decrease I Na. Values of dV es/dt min from each electrode were normalized ( dV esmin) and averaged (dV es/dt minna). Results showed that dV es/dt minna decreased during hyperkalemia by 28, 59, and 79% at 8, 10, and 12mM K +, respectively. dV es/ dt min also decreased by 54 and 84% 20 min after the onset of ischemia and hypoxia, respectively. In computational studies, dV es/ dt \rm min was compared to dV mmax at different levels of the maximum sodium conductance G Na, extracellular potassium ion concentration [K +]o, and intracellular sodium ion concentration [Na +] i, which all influence levels of I Na. Changes in dV es/ dt min|n were similar to dV m/ dt max during alterations of G Na, [K +]o, and Na +i. Our results demonstrate that dV es/dt minna is a robust global index of electrical activation for use in mouse hearts and, similar to dV m / dt max, can be used to probe electrophysiological alterations reliably. The index can be readily measured and evaluated, which makes it attractive for characterization of, for instance, genetically modified mouse hearts and drug effects on cardiac tissue. © 2011 IEEE.