KCB-328: a novel class III antiarrhythmic agent with little reverse frequency dependence in isolated guinea pig myocardium.
The effects of 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxypheneth yl)-N-methylamino] ethane hydrochloride (KCB-328), in comparison with those of dofetilide, were studied on the action potentials (APs) of isolated guinea pig papillary muscles. KCB-328 (0.003-3 microM) concentration-dependently prolonged the AP duration at 90% repolarization (APD90) at 1- and 3-Hz pacing, and the concentration-response relations at 1 and 3 Hz resemble each other. Dofetilide (0.001-1 microM) also produced the concentration-dependent prolongation of APD90 but more pronouncedly at 1 than at 3 Hz, demonstrating the reverse frequency-dependent effect. KCB-328 at 0.03, 0.1, 0.3, and 1 microM increased APD90 by 11 +/- 1, 19 +/- 1, 25 +/- 1, and 29 +/- 1% at 3 Hz and by 9 +/- 1, 19 +/- 2, 27 +/- 2, and 33 +/- 2% at 1 Hz, respectively. Prolongation of the effective refractory period (ERP) by each drug is parallel to those of APD90 at each pacing frequency. KCB-328 modified neither the maximal velocity of depolarization, amplitude of AP, and resting membrane potential in the fast APs, nor any parameters of the slow APs. In a separate experiment, the effects of KCB-328 on the ERP of contractile response (ERPc) of excised guinea-pig papillary muscles also were studied at 1 and 3 Hz. KCB-328 (0.01-10 microM) lengthened the ERPc in a concentration-dependent and frequency-independent manner as in the electrophysiologic results. This frequency-independent ERPc prolongation by KCB-328 was not influenced by increased extracellular K+ concentration from 4 to 10 mM. These results suggest that KCB-328 might be a selective class III agent with effects that are relatively frequency independent.
Lee
K
K
C & C Research Laboratories, Kyunggi-do, Korea.
Lee
J Y
JY
Kim
H Y
HY
Kwon
L S
LS
Shin
H S
HS
Tanabe
S
S
Kozono
T
T
Park
S D
SD
Chung
Y S
YS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D013449:Sulfonamides / Q000494:pharmacology*
C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D009467:Neuromuscular Depolarizing Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide