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
-
↵1 Both authors contributed equally to this study.
-
↵2 Current address: Department of Physiology, College of Medicine, Chungnam National University, Taejeon, 301-131, South Korea.
-
↵3 Current address: Department of Physiology, University of Ulsan College of Medicine, Seoul, 138-736, South Korea.
-
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
- Received February 5, 2002.
- Accepted March 13, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|