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The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na(+) channel, which includes an in-frame deletion of three amino acids (Lys-1505, Pro-1506, and Gln-1507; DeltaKPQ). The potential for selective suppression of the mutant was examined by heterologous expression of DeltaKPQ-Na(+) channels in Chinese hamster fibroblast cells via single-channel recording. In a single-channel cell-attached patch study, DeltaKPQ-Na(+) channels yielded currents that peaked at approximately 1 ms after voltage steps to 0 mV with aberrant late currents, which were composed of burst and isolated openings. The affinity of certain anesthetics (pilsicainide and lidocaine) to the late currents of the mutant channels was examined. It was revealed that 1) pilsicainide (1 microM), an open channel blocker of voltage-dependent Na(+) channels, remarkably decreased the late currents primarily by the shortening of burst duration without suppressing the initial peak current; and 2) lidocaine (1 microM), an inactivated channel blocker, decreased the late currents primarily by the suppression of isolated channel openings. Because the late currents in DeltaKPQ mutants are mainly composed of the burst openings, we conclude that pilsicainide is capable of selectively blocking the late currents in the mutant Na(+) channels that show dominant abnormal burst openings such as in DeltaKPQ mutants.

The effects of bepridil, a potent antiarrhythmic drug, on the activity of ATP-sensitive K(+) (K(ATP)) channels and Na(+)-activated K(+) (K(Na)) channels were examined in isolated patches from guinea pig ventricular myocytes. In inside-out membrane patches, K(ATP) channel currents were recorded with 140 mM [K(+)](i) and 140 mM [K(+)](o) solutions, and K(Na) channel currents were recorded by increasing [Na(+)](i) to 100 mM with 40 mM [K(+)](i), respectively. Bepridil (1-100 microM) inhibited the K(ATP) channel current in a concentration-dependent manner. The IC(50) value of bepridil was estimated to be 10.5 microM for outward K(ATP) channel currents (holding potential, +60 mV) and 6.6 microM for inward K(ATP) channel currents (holding potential, -60 mV). Bepridil (0.1-30 microM) also inhibited K(Na) channel currents measured at the holding potential of -60 mV, in a concentration-dependent manner with an IC(50) value of 2.2 microM. In coronary-perfused guinea pig right ventricular preparations, the metabolic inhibition (MI) achieved with the application of 0.1 microM carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone shortened the action potential duration (APD) in a time-dependent manner. When bepridil (10 microM) was applied 5 min after the introduction of MI, the APD shortening was significantly blunted. The concomitant application of a K(ATP) channel antagonist (glibenclamide, 1 microM) and a K(Na) channel antagonist (R56865, 10 microM) could mimic the effect of bepridil and attenuated the shortening otherwise produced by MI. These results suggest that bepridil inhibits both K(ATP) channels and K(Na) channels and blunts the shortening of APD during MI. These effects of bepridil may partly account for the alleged antiarrhythmic action of this drug during ischemia.