Open AccessEffects of the Class III antiarrhythmic agent dofetilide (UK‐68,798) on L‐type calcium current from rabbit ventricular myocytes
Author(s) -
Paul A. A.,
Leishman D. J.,
Witchel H. J.,
Hancox J. C.
Publication year - 2001
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1211/0022357011778061
Subject(s) - dofetilide , herg , pharmacology , chemistry , patch clamp , medicine , potassium channel , electrophysiology , qt interval
The methanesulphonanilide agent dofetilide (UK‐68,798) exerts Class III antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (I Kr ) encoded by HERG . The aim of the present study was to determine whether dofetilide also exhibits Class IV (L‐type calcium‐channel blocking) effects. L‐type calcium current (I Ca,L ) was measured from rabbit isolated ventricular myocytes, using the whole‐cell patch‐clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of I Ca,L elicited by pulses to + 10 mV by both nifedipine and externally applied Ni 2+ ions. Three concentrations of dofetilide were tested: 100 nm, 1 μm and 10 μm. I Ca,L magnitude was not significantly reduced by any of the concentrations tested ( P >0.05; n = minimum of seven cells per drug concentration). The inactivation time‐course of I Ca,L was also unaffected by 10 μm dofetilide. Heterologously expressed HERG current (I HERG ) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 μm dofetilide, with inhibition at 1 μm not significantly different from 100% ( P > 0.1). It is concluded that dofetilide produced no I Ca,L blocking effects at concentrations up to and exceeding that required for maximal I HERG inhibition. The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity.