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Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide.
J Cardiovasc Pharmacol. 2003 Nov; 42(5):648-55.JC

Abstract

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.

Authors+Show Affiliations

Laboratory of Pharmacology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

14576514

Citation

Lee, Kiho, et al. "Differential Recovery of Action Potential Duration and HERG Currents From the Effects of Two Methanesulfonamide Class III Antiarrhythmic Agents, KCB-328 and Dofetilide." Journal of Cardiovascular Pharmacology, vol. 42, no. 5, 2003, pp. 648-55.
Lee K, Park JB, Jeon BH, et al. Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide. J Cardiovasc Pharmacol. 2003;42(5):648-55.
Lee, K., Park, J. B., Jeon, B. H., Kim, K. J., Ryu, P. D., Kwon, L. S., & Kim, H. Y. (2003). Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide. Journal of Cardiovascular Pharmacology, 42(5), 648-55.
Lee K, et al. Differential Recovery of Action Potential Duration and HERG Currents From the Effects of Two Methanesulfonamide Class III Antiarrhythmic Agents, KCB-328 and Dofetilide. J Cardiovasc Pharmacol. 2003;42(5):648-55. PubMed PMID: 14576514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide. AU - Lee,Kiho, AU - Park,Jin Bong, AU - Jeon,Byeng Hwa, AU - Kim,Kwang-Jin, AU - Ryu,Pan Dong, AU - Kwon,Lae-Sung, AU - Kim,Hak-Yeop, PY - 2003/10/25/pubmed PY - 2004/3/17/medline PY - 2003/10/25/entrez SP - 648 EP - 55 JF - Journal of cardiovascular pharmacology JO - J Cardiovasc Pharmacol VL - 42 IS - 5 N2 - 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. SN - 0160-2446 UR - https://www.unboundmedicine.com/medline/citation/14576514/Differential_recovery_of_action_potential_duration_and_HERG_currents_from_the_effects_of_two_methanesulfonamide_class_III_antiarrhythmic_agents_KCB_328_and_dofetilide_ L2 - https://doi.org/10.1097/00005344-200311000-00011 DB - PRIME DP - Unbound Medicine ER -