Antiarrhythmic effects of a novel class III drug, KCB-328, on canine ventricular arrhythmia models.
KCB-328 is a newly synthesized class III drug. To determine whether this drug has antiarrhythmic or proarrhythmic effects, we used canine ventricular arrhythmia models induced by coronary ligation and reperfusion, programmed electrical stimulation (PES), two-stage coronary ligation, digitalis, or epinephrine. KCB-328, in an intravenous infusion of 0.5 mg/kg/30 min, prolonged the QTc interval only 11%, but had antiarrhythmic effects on the reentry arrhythmias induced by PES (12 of 12 dogs with old myocardial infarction; p < 0.05). KCB-328, in an infusion of 1 mg/kg/h, suppressed the occurrence of fatal ventricular fibrillation (VF) induced by coronary ligation and reperfusion under either halothane anesthesia (p < 0.05) or pentobarbital anesthesia (p < 0.05). Under the halothane anesthesia, KCB-328 alone showed proarrhythmic effects [i.e., induction of ventricular premature contractions (VPCs)], but it did not induce a more severe effect such as torsades de pointes-type ventricular tachycardia (VT). In addition, KCB-328 had weak antiarrhythmic effects on the automaticity arrhythmias induced by 24-h coronary ligation but was effective neither on 48-h coronary ligation arrhythmias nor on the digitalis- and epinephrine-induced arrhythmias. Our results indicate that KCB-328 has powerful antiarrhythmic effects with fewer proarrhythmic potencies.
Department of Pharmacology, Yamanashi Medical University, Japan.
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Xue
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Tanabe
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Nabuchi
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Hashimoto
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D004070:Digitalis; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D004837:Epinephrine; D005260:Female; D008026:Ligation; D008297:Male; D015425:Myocardial Reperfusion; D010627:Phenethylamines / Q000627:therapeutic use*; D010946:Plants, Medicinal; D010947:Plants, Toxic; D013449:Sulfonamides / Q000627:therapeutic use*
C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D004837:Epinephrine