PT - JOURNAL ARTICLE AU - Katsushige Ono AU - Toshihiko Kaku AU - Naomasa Makita AU - Akira Kitabatake AU - Makoto Arita TI - Selective Block of Late Currents in the ΔKPQ Na<sup>+</sup>Channel Mutant by Pilsicainide and Lidocaine with Distinct Mechanisms DP - 2000 Feb 01 TA - Molecular Pharmacology PG - 392--400 VI - 57 IP - 2 4099 - http://molpharm.aspetjournals.org/content/57/2/392.short 4100 - http://molpharm.aspetjournals.org/content/57/2/392.full SO - Mol Pharmacol2000 Feb 01; 57 AB - 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; ΔKPQ). The potential for selective suppression of the mutant was examined by heterologous expression of ΔKPQ-Na+ channels in Chinese hamster fibroblast cells via single-channel recording. In a single-channel cell-attached patch study, ΔKPQ-Na+ channels yielded currents that peaked at ∼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 μM), 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 μM), an inactivated channel blocker, decreased the late currents primarily by the suppression of isolated channel openings. Because the late currents in ΔKPQ 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 ΔKPQ mutants. The American Society for Pharmacology and Experimental Therapeutics