Received for publication April 2, 2004.
Revised July 21, 2004.
Accepted for publication July 27, 2004.

A Common Antitussive Drug, Clobutinol, Precipitates the Long-QT2 Syndrome

Abstract

QT prolongation, a classical risk factor for arrhythmias can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K⁺ channel HERG. Here, we identified the arrhythmogenic potential of a non-opioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, diagnosed with congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K⁺ current with a half-maximum block concentration (IC₅₀) of 2.9 µM. In the proband, we identified a novel A561P HERG mutation. Two others LQT mutations (A561V and A561T) had previously been reported at the same position. Neither of the three HERG mutants led to sizeable current in heterologous expression system. When co-expressed with wild-type (WT) HERG channels, the three A561 mutants reduce the trafficking of WT and mutant heteromeric channels resulting in decreased K⁺ current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a 'drug to be avoided by congenital long QT patients' rather than as a 'drug with risk of torsades de pointes'.

Key words: Ion channel regulation, Potassium, Func. analysis receptor/ion channel mutants, Immunocytochemistry

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