Open Channel Block by KCB-328 [1-(2-Amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane Hydrochloride] of the Heterologously Expressed HumanEther-a-go-go-Related Gene K+ Channels
- Jin-Bong Park1,2,1,
- Han Choe1,3,4,
- Yu-Kyung Lee1,
- Ki-Chan Ha1,
- Kyoung-Suk Rhee2,
- Jae-Ki Ko2,
- Chan-Uhng Joo3,
- Soo-Wan Chae1 and
- Yong-Geun Kwak1
- Departments of 1Pharmacology (J.-B.P., Y.-K.L., K.-C.H., S.-W.C., Y.-G.K.), 2Internal Medicine (K.-S.R., J.-K.K.), and 3Pediatrics (C.-U.J.), and 4Institute of Cardiovascular Research (H.C.), Chonbuk National University Medical School, Chonju, South Korea
- Yong-Geun Kwak, Departments of Pharmacology and Institute of Cardiovascular Research, Chonbuk National University Medical School, Chonju, 561-180, South Korea. E-mail: ygkwak{at}moak.chonbuk.ac.kr
Abstract
KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] is a newly synthesized class III antiarrhythmic drug and is known to be highly effective against various types of arrhythmias induced by coronary artery ligation, reperfusion, and programmed electrical stimulation. To understand the potential ionic mechanisms, we examined the effects of KCB-328, which encodes the rapidly activating delayed rectifier K+ current in cardiac tissues, on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus oocytes. The amplitudes of steady-state currents and tail currents of HERG were decreased by KCB-328 dose dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by KCB-328 is voltage-dependent. IC50 values at −30, −20, −10, 0, +10, +20, +30, and +40 mV were 7.6 ± 0.5, 4.8 ± 0.4, 3.2 ± 0.3, 2.1 ± 0.3, 1.7 ± 0.2, 1.4 ± 0.2, 1.3 ± 0.1, and 1.2 ± 0.1 μM, respectively. Induction of block depended on depolarization beyond the threshold for channel opening. In addition, time-dependent block developed slowly, with τ = 1.7 ± 0.3 s (100 μM) at 0 mV, and was delayed by a stronger depolarization to +80 mV, at which HERG channel is inactivated. We can conclude that KCB-328 preferentially blocks open (or activated) HERG channels. The block of HERG current might in part explain the underlying ionic mechanism for the antiarrhythmic and proarrhythmic effect of KCB-328.
Footnotes
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↵1 Both authors contributed equally to this study.
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↵2 Current address: Department of Physiology, College of Medicine, Chungnam National University, Taejeon, 301-131, South Korea.
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↵3 Current address: Department of Physiology, University of Ulsan College of Medicine, Seoul, 138-736, South Korea.
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This work was supported by grants from the Science and Technology Evaluation Planning Institute of Korea (Grant 97-N1-02-02-A) and from the Korea Science and Engineering Foundation (Grant 98-0403-10-01-5).
- Abbreviations:
- IKr
- the rapidly activating outward rectifier K+ current
- APD
- action potential duration
- HERG
- human ether-a-go-go-related gene
- IK
- the delayed rectifier K+ current
- IKs
- the slowly activating outward rectifier K+current
- KCB-328
- 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride
- LQT syndrome
- long QT syndrome
- MiRP1
- mink-related peptide 1
- E-4031
- 1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl)piperidine
- KCNE2
- the potassium channel gene encoding MinK-related peptide-1
- MK-499
- N-[1′-(6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro(2H-1-benzo-pyran-2,4′-piperidinyl)6-yl]monohydrochloride
- MS-551
- 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl) propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride
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- Received February 5, 2002.
- Accepted March 13, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
