Mode of action of a new class IC drug (ORG 7797) against atrial fibrillation in conscious dogs.
In five chronically instrumented conscious dogs, we studied the antifibrillatory action of the experimental class IC drug Org 7797 ((16 alpha,17 beta)-17-methylamino-oestra-1,3,5(10)-triene-3,16-diol- (Z)-2-butenedioate). Under control conditions, paroxysms of atrial fibrillation were induced by burst pacing (50 Hz; inducibility 100%) and persisted on the average for greater than 3 min. Org 7797 (1, 2, and 3 mg/kg/h) significantly reduced both inducibility and duration of atrial fibrillation to 25 and 10%, respectively. To elucidate the electrophysiologic mechanisms of this potent antifibrillatory action, we measured the effects of Org 7797 on conduction velocity, effective refractory period (ERP), and wavelength of the atrial impulse. Org 7797 decreased atrial conduction velocity significantly by 18-25% and lengthened ERP by 18-29% (pacing 2-5 Hz). The maximal pacing frequency (Fmax) was decreased from 8.3 to 6.2 Hz. During Fmax, Org 7797 decreased the conduction velocity by 23% and lengthened ERP by 75%, resulting in a prolongation of the wave-length from 9.8 +/- 2.3 cm (control) to 13.7 +/- 2.6 cm (3 mg/kg/h; p less than 0.01). These results indicate that the antifibrillatory action of Org 7797 is based on diminution of the physiologic rate-dependent shortening of refractoriness, resulting in a prolongation of the wavelength during maximal heart rates (HRs). This electrophysiologic effect of the drug will decrease the number of multiple wavelets during fibrillation, thus increasing the statistical chance of spontaneous termination of the fibrillatory process.
Kirchhof
C
C
Department of Physiology, University of Limburg, Maastricht, The Netherlands.
Wijffels
M
M
Brugada
J
J
Planellas
J
J
Allessie
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D016275:Atrial Function / Q000187:drug effects; D001283:Atrioventricular Node / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000008:administration & dosage / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male
D000889:Anti-Arrhythmia Agents; D004963:Estrenes; C061028:Org 7797