Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de pointes in models of acquired and congenital long QT syndrome

Electrophysiologic Effects of Pentobarbital, Introduction: Sodium pentobarbital is widely used for anesthesia in experimental studies as well as in clinics, and it is known to prevent the development of torsades de pointes (TdP) in in vivo models of the long QT syndrome (LQTS). Methods and Results: This study examines the effects of pentobarbital on transmural dispersion of repolarization (TDR) and induction of TdP in arterially perfused canine left ventricular wedge preparations in which transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions using floating glass microelectrodes together with a transmural EGG. d-Sotalol and ATX-II were used to mimic the LQT2 and LQT3 forms of congenital LOTS. Both d-sotalol (100 mu mol/L, n = 6) and ATX-II (20 nmol/L, n = 6) preferentially prolonged the action potential duration (APD(90)) of the M cell, thus increasing in the QT interval and TDR, and leading to the development of spontaneous and stimulation-induced TdP. In the absence and presence of d-sotalol, pentobarbital (10, 20, and 50 mu g/mL) prolonged the APD(90) of epicardial and endocardial cells, and, to a lesser extent, that of the M cell, thus prolonging the QT interval but reducing TDR. In the ATX-II model, the effects of pentobarbital on the QT interval and APD(90) were biphasic: 10 mu g/mL pentobarbital further prolonged APD(90) of epicardial and endocardial cells more than that of the M cell; 20 to 50 mu g/mL pentobarbital abbreviated the APD(90) of epicardial and endocardial cells less than that of the M cell, thus abbreviating the QT interval and markedly reducing TDR. Twenty to 50 mu g/mL pentobarbital totally suppressed spontaneous as well as stimulation-induced TdP in both models. Conclusion: Our data indicate that pentobarbital reduces TDR in control and under conditions of congenital and acquired LOTS, and suggest that this mechanism may contribute to the ability of the anesthetic to prevent the development of spontaneous as well as stimulation-induced TdP under conditions mimicking LQT2, LQT3, and acquired (drug-induced) forms of the LOTS. The data also serve to illustrate that there are circumstances under which QT prolongation may not be arrhythmogenic.