Mechanism of antifibrillatory action of Org 7797 in regionally ischemic pig heart

Abstract

Org 7797 is effective against ventricular fibrillation (VF) induced during ischemia. In Langendorff-perfused pig hearts, application of three premature stimuli to nonischemic myocardium between 3 and 5 min after coronary occlusion always resulted in VF in the absence of drug. In no instance when Org 7797 was present (2-10 microM) could VF be induced, although sustained and nonsustained ventricular tachycardias (VTs) could still be initiated in about two thirds of treated hearts. We determined the effects of Org 7797 on wavelength in normal and ischemic myocardium during regular driving at a cycle length of 350 ms. Wavelength, the algebraic product of conduction velocity and refractory period, is considered a useful parameter in assessing efficacy of antiarrhythmic agents in preventing reentrant arrhythmias. Conduction velocity was obtained by analyzing the spread of activation under 121 unipolar electrodes (1 mm apart) placed around a central stimulus electrode. Refractory periods were determined with premature test stimuli at an intensity of twice diastolic threshold. Both in normal and ischemic myocardium Org 7797 (5-10 microM) produced a marked shortening of wavelength. This should predispose to reentry. However, Org 7797 prolonged the refractory period at the fastest possible driving rate from 154 to 247 ms and attenuated (5 microM) or prevented (10 microM) shortening of the refractory period during application of subsequent premature stimuli. The antifibrillatory effect of the drug may be explained by prolongation of wavelength at very short cycles.