org-7797 and Myocardial-Infarction

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

Double-wave reentry (DWR) can be a mechanism for acceleration of ventricular tachycardia (VT) with a large excitable gap (EG). The purpose of this study was to determine the effects of heptanol, class Ic, and class III drugs on the inducibility of DWR.. In 11 Langendorff-perfused rabbit hearts, a thin ring of anisotropic left ventricular epicardium was created by a cryoprocedure. VT with a revolution time of 180 +/- 26 milliseconds and an EG of 106 +/- 8 milliseconds was induced by incremental pacing. During control, entrainment with 10 stimuli at a 99 +/- 15-millisecond interval terminated VT in seven hearts. In four hearts VT was accelerated from 205 +/- 24 to 115 +/- 14 milliseconds by introduction of a second circulating wave in the ring. In the seven VTs that could not be accelerated, 0.5 mumol/L Org7797 (class Ic) and 1.0 mmol/L heptanol (uncoupling agent) prolonged the cycle length of VT by 32% and 37%, respectively. Because the refractory period (RP) only increased by 11%, the EG prolonged by 71% and the ratio between EG and RP was increased from 0.66 to 1.00. Under these conditions, DWR could be induced in all seven hearts. In the four VTs that could be accelerated during control, administration of the class III drug D-sotalol (35 mumol/L) only slightly slowed VT by 6%. Because the RP was prolonged by 15%, the ratio between the EG and the RP decreased from 0.76 to 0.63. Entrainment now failed to accelerate VT in two of four hearts, whereas in the two other hearts, double-wave reentry self-terminated within eight cycles.. Drugs that increase the ratio of EG and RP enhance the susceptibility to acceleration of VT, whereas drugs that decrease this ratio prevent induction of sustained double-wave reentry.

Topics: Alcohols; Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Electrocardiography; Estrenes; Heart Conduction System; Heptanol; Myocardial Infarction; Perfusion; Rabbits; Sotalol; Tachycardia, Ventricular

The hemodynamic effects of a new Ic antiarrhythmic agent (Org 7797) were compared with those of flecainide and propafenone in anesthetized pigs with developing myocardial infarcts. One hour after acute coronary artery occlusion, the only significant hemodynamic effect of an intravenous (i.v.) dose of Org 7797 (0.5 mg/kg) known to prevent ischemia-induced ventricular fibrillation (VF) in dogs was a decrease in heart rate (HR) (of 3%) while cardiac output (CO), stroke volume (SV), and left ventricular (LV) dP/dtP-1 were unchanged. At four times this dose, the only sustained and significant responses to Org 7797 were decreased CO and bradycardia, whereas decreases in arterial and LV pressures (BP and LVP) and LVdP/dtP-1 were transient. In contrast, a therapeutic dose of flecainide (2 mg/kg) induced sustained reductions in CO, SV, LVdP/dtP-1, and LVP whereas a similar (therapeutic) dose of propafenone decreased LVP, reduced CO partly as a result of bradycardia and decreased LVdP/dtP-1 but not sufficiently to decrease SV. Two electrical deaths occurred in each of the propafenone (n = 6) and flecainide (n = 7) groups, but arrhythmic deaths did not occur in Org 7797- or saline-treated animals. We conclude that Org 7797 in therapeutic doses, unlike propafenone and especially flecainide, is not cardiodepressant in animals whose cardiac function is already compromised. In addition, there was no evidence of proarrhythmogenicity at the doses of Org 7797 used.

Topics: Animals; Anti-Arrhythmia Agents; Coronary Disease; Dose-Response Relationship, Drug; Estrenes; Female; Flecainide; Heart Ventricles; Hemodynamics; Male; Myocardial Infarction; Organ Size; Propafenone; Swine; Time Factors; Ventricular Function, Left

1. The electrophysiological effects of intravenously administered Org 7797 were compared with those of disopyramide (class Ia), mexiletine (Ib) and propafenone (Ic) in anaesthetized dogs with 5-6 day-old left ventricular myocardial infarcts. 2. Org 7797 (0.5 mg kg-1) slowed conduction at all levels of the myocardium as shown by increases in St-A, AH, HV and QRS intervals, very modestly prolonged atrial and ventricular refractory periods and slightly shortened ventricular repolarization. Sinus node recovery time was increased whilst the RR interval was unchanged. A higher dose (2 mg kg-1) prolonged RR and rendered 5 out of 8 dogs unable to follow an atrial pacing stimulus of mean cycle length 322 ms. 3. Electrophysiological changes induced by propafenone (2 mg kg-1) were qualitatively similar to those of Org 7797 (0.5 mg kg-1). 4. Electrophysiological changes induced by mexiletine (2 mg kg-1) were small or insignificant. The most noticeable effect was a modest increase in the St-A interval and a slight shortening of ventricular repolarization. A higher dose (8 mg kg-1) additionally slowed conduction in the His-Purkinje system and in the ventricular myocardium. 5. Disopyramide (2 and 5 mg kg-1) prolonged all cardiac intervals including JTc, QTc and QT during pacing and prolonged cardiac refractory periods. 6. It was concluded that the electrophysiological profile of Org 7797 is more like that of the Ic agent propafenone than that of the class Ia and Ib drugs, disopyramide and mexiletine.

Topics: Anesthetics; Animals; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Disopyramide; Dogs; Electrocardiography; Estrenes; Female; Male; Mexiletine; Myocardial Infarction; Propafenone; Ventricular Function