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 > 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 (F(max)) was decreased from 8.3 to 6.2 Hz. During F(max), Org 7797 decreased the conduction velocity by 23% and lengthened ERP by 75%, resulting in a prolongation of the wavelength from 9.8 +/- 2.3 cm (control) to 13.7 +/- 2.6 cm (3 mg/kg/h; p < 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.