Selectivity of Class-III Antiarrhythmic Action of Clofilium in Guinea Pig Ventricular Myocytes

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Abstract
Clofilium is an antiarrhythmic agent with a supposedly predominant class-III action which is related to impairment of K+ channel function. We investigated membrane currents in cardiac myocytes isolated from guinea pig ventricle to evaluate the selectivity of action of clofilium on K+ currents. For measurement of action potentials or membrane currents, the single electrode patch clamp technique was applied in current- or voltage-clamp mode, respectively. Clofilium (30 mu M) irreversibly prolonged the action potential duration in guinea pig myocytes. In contrast, the concomitant reduction in plateau phase was completely reversible. The delayed rectifier K+ current Ikappa, was reduced. The rapidly activating component of Ikappa, which has been defined by its sensitivity to the compound E-4031, was also reduced by clofilium. The inward rectifier was slightly inhibited by the drug. Clofilium reversibly reduced L-type Ca2+ current. Sodium current was inhibited in a use-dependent manner. This effect was not reversible but proceeded after washout of the compound. Therefore, clofilium affects both inward and outward currents in mammalian cardiac myocytes in a similar concentration range. The effects on multiple membrane currents may contribute to the antiarrhythmic action of the drug.