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,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 Ni2+ ions. Three concentrations of dofetilide were tested: 100 nM, 1 microM and 10 microM. 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 microM dofetilide. Heterologously expressed HERG current (I(HERG)) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 microM dofetilide, with inhibition at 1 microM 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.
Paul
A A
AA
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, Bristol, UK.
Leishman
D J
DJ
Witchel
H J
HJ
Hancox
J C
JC
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D027682:Cation Transport Proteins; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000032:analysis; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C063533:dofetilide