org-7797 and Ventricular-Fibrillation

Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo. Org 20781 (0.5-2.0mg kg-1, i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5-6 day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2-4 mg kg-1) associated with suppression of late arrhythmias were 6-18 microM, whilst the mean plasma elimination half-life (in normal dogs) was 107 min. It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Electric Stimulation; Electrophysiology; Estrenes; Female; Injections, Intravenous; Male; Myocardial Infarction; Myocardial Ischemia; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

1. The class Ic steroidal antiarrhythmic agent, Org 7797, was compared with two other Ic agents, flecainide and propafenone for intravenous activity against ischaemia-related cardiac arrhythmias and for electrophysiological actions in vivo. In addition the haemodynamic effects of Org 7797 were assessed in greyhounds. 2. Org 7797 (0.5 mg kg-1) significantly reduced the expected incidence of early ischaemia-induced ventricular fibrillation (VF) in rats and greyhound dogs and at doses of 0.5-1.0 mg kg-1 antagonized reperfusion-induced arrhythmias. Comparative studies in rats showed Org 7797 to be 2-4 times more potent than flecainide or propafenone. 3. Org 7797 (0.5 mg kg-1) slowed intracardiac conduction in anaesthetized beagles and again was at least 2-4 times more potent than flecainide or propafenone. 4. Org 7797 (0.5 and 2.0 mg kg-1), flecainide (1.0 and 2.0 mg kg-1) or propafenone (0.5 and 2.0 mg kg-1), did not significantly prevent induction of tachyarrhythmias (VT) in dogs with 5-6 day old myocardial infarcts although all 3 drugs appeared to prevent induced VF. All 3 drugs (notably flecainide) did however reduce the VT rate. 5. All 3 drugs (1-2 mg kg-1) suppressed spontaneous tachyarrhythmias in conscious beagle dogs with 1-2 day old infarcts. Propafenone was the least effective. 6. In an antifibrillatory dose (0.5 mg kg-1), the major haemodynamic effect of Org 7797 was a 10% increase in peripheral vascular resistance. Stroke volume, cardiac output and coronary blood flow were unchanged. In therapeutic doses, Org 7797 was also less negatively chronotropic than flecainide.7. It was concluded that Org 7797 is a potent antifibrillatory agent which is haemodynamically well tolerated. Higher doses are required to suppress late ischaemia-induced tachyarrhythmias which suggest that its antifibrillatory effects are the consequence of an action other than, or in addition to, sodium channel block.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Electric Stimulation; Estrenes; Female; Flecainide; Hemodynamics; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Propafenone; Rats; Rats, Inbred Strains; Tachycardia; Ventricular Fibrillation

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.

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Electric Stimulation; Electrocardiography; Estrenes; Female; Heart Conduction System; Male; Swine; Ventricular Fibrillation