Abstract
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.
Footnotes
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Send reprint requests to: Katsushige Ono, M.D., Ph.D., Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 8795593, Japan. E-mail: ono{at}oita-med.ac.jp
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↵1 Current address: Department of Physiology, Oita Medical University, Hasama, Oita 8795593, Japan.
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↵2 Current address: Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 0608638, Japan.
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This study was supported in part by Grants-in-aid for scientific research (09670049 and 10877207) from the Ministry of Education, Science, Sports and Culture, and a grant from the Uehara Memorial Foundation, Japan.
- Abbreviations:
- ΔKPQ
- deletion of residues Lys-1505, Pro-1506, and Gln-1507
- LQT syndrome
- long QT syndrome
- WT
- wild type
- CHW
- Chinese hamster fibroblast
- INa
- initial peak current of the Na+ current
- NPo
- open probability of channel
- bNPo
- open probability of channel derived from bursting openings
- iNPo
- open probability of channel derived from isolated openings
- τf
- fast time constant
- τs
- slow time constant
- Received June 9, 1999.
- Accepted November 11, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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