Effects of the Class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes

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,I-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,I-L elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nm, 1 mum and 10 mum I-Ca,I-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,I-L was also unaffected by 10 pm dofetilide. Heterologously expressed HERG current (I-HERG) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 mum dofetilide, with inhibition at 1 mum not significantly different from 100 % (P > 0.1). It is concluded that dofetilide produced no I-Ca,I-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.