Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide.
A novel pure class III antiarrhythmic agent, 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphen-ethyl)-N-methylamino]ethane hydrochloride (KCB-328) prolongs action potential duration (APD) by blocking the rapid component delayed rectifier K+ current (IKr). However, KCB-328 manifests little of the reverse frequency dependence (RFD) that is a general characteristic of class III antiarrhythmic agents. We have studied the onset and recovery kinetics of KCB-328 and dofetilide on APD in guinea-pig papillary muscle and on human ether-a-go-go-related gene (HERG) channel, which encodes IKr, expressed in Xenopus oocytes. KCB-328 (1 microM) and dofetilide (0.1 microM) progressively increased the duration of post-rest AP at 1-Hz stimulation, with onset time constants of 6.4 +/- 0.6 seconds and 20.7 +/- 1.8 seconds, respectively. With a 100-second resting period, the effect of KCB-328 recovered by 70% with a time constant of 13.2 +/- 4.2 seconds, whereas that of dofetilide recovered only by 25%. Both drugs blocked activated HERG channels in a biexponential decay fashion, with faster time constants for KCB-328 (3 microM) than for dofetilide (0.3 microM). After a 300-second resting period, HERG current inhibited by KCB-328 was recovered more at depolarized membrane potentials than at hyperpolarized ones, with a time constant of 179.9 seconds during the rest at -60 mV. In contrast, recovery after dofetilide was negligible at all voltages tested. These results suggest that KCB-328 binds to IKr at a preferentially open state in a use-dependent manner, but that KCB-328 unbinds from the resting state more readily than dofetilide. The less striking RFD of KCB-328 than of dofetilide might be related to the faster recovery from its effect on IKr.
Laboratory of Pharmacology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, South Korea.
Kiho
K
Lee
Jin Bong
JB
Park
Byeng Hwa
BH
Jeon
Kwang-Jin
KJ
Kim
Pan Dong
PD
Ryu
Lae-Sung
LS
Kwon
Hak-Yeop
HY
Kim
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology*; D014982:Xenopus laevis
C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010627:Phenethylamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C036871:methanesulfonamide; C063533:dofetilide