title: Selective inhibition of potassium currents in rat ventricle by clofilium and its tertiary homolog.
abstract: The effects of clofilium and its tertiary homolog, LY97119 (LY), on K+ currents in isolated ventricular myocytes from adult rat were examined using the whole-cell patch-clamp technique. Acute exposure (less than 30 min) to high concentrations of clofilium (30-100 microM) produced a slowly developing reduction in the peak of the transient outward current (Ito) and an apparent increase in the rate of current inactivation. In addition, inhibition exhibited a marked dependence on the frequency of stimulation (i.e., use-dependent inhibition). For "short" exposure times (i.e., less than 30 min), steady-state inhibition was not attained. Therefore, myocytes were preincubated with clofilium for at least 3 hr before use. Under these conditions, the median inhibitory concentration for steady-state use-dependent inhibition of Ito was 0.5 microM. Recovery of Ito from use-dependent inhibition followed a biexponential time course; tau fast = 75 msec, tau slow = 17 sec. The relative magnitude of the slow component (but not its time constant) increased with higher clofilium concentrations. LY, like clofilium, also induced a time-dependent inhibition of Ito (median inhibiting concentration 0.9 microM). However, unlike clofilium, steady state with LY was reached within 5 min. Furthermore, LY (3 microM) produced very little use-dependent inhibition (29% at 1 Hz compared with 92% for clofilium). This is possibly due to a "fast" unbinding rate upon repolarization (tau = 1.8 s). In contrast to clofilium, LY (1-10 microM) also inhibited the inward rectifier (IK1). The present results suggest that inhibition of Ito may contribute to clofilium's class III antiarrhythmic action.
authors.affiliation: Department of Anesthesia Research Laboratories, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: N A
authors.initials: NA
authors.lastname: Castle
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D015221:Potassium Channels / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; C056527:LY 97119; C022799:clofilium