['This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS).', 'A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291+/-14 to 354+/-35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51+/-15 to 72+/-17 ms). QT interval increased from 320+/-13 to 385+/-37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280+/-25 to 609+/-49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40+/-5 to 168+/-40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 micromol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 micromol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 micromol/L) totally suppressed stimulation-induced TdP.'] Is sodium channel block with mexiletine effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome?