Electrophysiologic effects of SD-3212, a new class I antiarrhythmic drug, on canine atrial flutter and atrial action-potential characteristics.
SD-3212 (levo-semotiadil fumarate) is a newly developed compound that exhibits potent antiarrhythmic activity because of its inhibitory action on sodium and calcium channels. In animal models, SD-3212 suppressed ventricular tachyarrhythmias, but the effects of this drug on atrial tachyarrhythmias have not been reported. We investigated the electrophysiologic effects of SD-3212 on canine atrial flutter induced after placement of the intercaval obstacle and on atrial action-potential characteristics. In all seven dogs, SD-3212 (1.9 +/- 0.3 mg/kg) terminated atrial flutter after significant increase in atrial flutter cycle length from 126 +/- 5 to 166 +/- 14 ms (increase, 31 +/- 8%; p < 0.005). SD-3212 increased right atrial effective refractory period (RAERP) significantly from 126 +/- 7 to 149 +/- 11 ms at a basic cycle length of 300 ms. The increases in RAERP after SD-3212 at basic cycle lengths of 300, 200, and 150 ms did not differ (increase, 18 +/- 4%, 17 +/- 3%, and 19 +/- 3%, respectively). Interatrial conduction time (IACT) was prolonged after SD-3212 from 63 +/- 4 to 81 +/- 6 ms (increase, 31 +/- 6%) at a basic cycle length of 150 ms. Prolongation of IACT was frequency dependent. The plasma concentration of SD-3212 after the termination of atrial flutter was 187 +/- 56 ng/ml in four dogs tested. In vitro study by using standard microelectrode techniques showed SD-3212 at concentrations of 1-3 microM significantly prolonged action-potential duration at 90% repolarization. Vmax was decreased by SD-3212 in a concentration-dependent manner (0.3-3 microM), and the inhibitory effect on Vmax was greatest at the highest stimulation frequency of 3.3 Hz. These results indicate that a new antiarrhythmic drug, SD-3212, is effective in interrupting canine atrial flutter, possibly by suppressing atrial conduction, and might be effective for the treatment of clinical atrial tachyarrhythmias.
Fujiki
A
A
Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Japan.
Tani
M
M
Hayashi
H
H
Mizumaki
K
K
Inoue
H
H
Uemura
H
H
Nakaya
H
H
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001282:Atrial Flutter / Q000188:drug therapy*; D016275:Atrial Function; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006325:Heart Atria / Q000187:drug effects*; D006329:Heart Conduction System / Q000187:drug effects*; D026941:Sodium Channel Blockers; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D026941:Sodium Channel Blockers; D013844:Thiazoles; C064356:sesamodil