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Keywords:

  • CPUY11018;
  • sodium channels;
  • calcium channels;
  • ventricular myocytes;
  • arrhythmia

Abstract

Strategy, Management and Health Policy
Enabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV

In the present study, the potential antiarrhythmic activities of a new multiple ion channel blocker, CPUY11018 (Y18) were investigated. The effects of Y18 on ICa,L and INa were studied using whole-cell patch clamp techniques in ventricular muscle cells from normal rats and guinea pigs. The antiarrhythmic effects were tested using a rat model of aconitine-induced arrhythmias. The effects of Y18 on induction of QT prolongation and torsades de pointes (TdP) were investigated in anesthetized rabbits during stimulation with methoxamine. Y18 produced a concentration-dependent inhibition of ICa,L and INa in rat ventricular myocytes with IC50 values of 88 μmol/l and 6.5 μmol/l, respectively. In the Y18 treatment group, the development of arrhythmias was significantly delayed. Doses of aconitine that induced ventricular fibrillation were decreased following treatment with 6 mg/kg Y18 (3.8 ± 0.4 μg/100 g vs 6.2 ± 1.3 μg/kg). A significant decrease in the occurrence of atrial fibrillation (100% to 33%; P <0.05) occurred following Y18 administration. Y18 induction of TdP was significantly less than that seen with dofetilide and azimilide (Az). Thus, Y18 significantly inhibited the production of aconitine-induced arrhythmias with a low potency for TdP induction. These results suggest that Y18 is a multiple channel blocker with promising antiarrhythmic potential.