Effects of Org 7797 on early, late and inducible arrhythmias following coronary artery occlusion in rats and dogs.
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.
Winslow
E
E
Organon Laboratories Limited, Newhouse, Lanarkshire.
Campbell
J K
JK
Barron
E
E
Marshall
R J
RJ
Muir
A W
AW
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D004558:Electric Stimulation; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D005424:Flecainide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications; D011405:Propafenone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013610:Tachycardia / Q000517:prevention & control; D014693:Ventricular Fibrillation / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D004963:Estrenes; D011405:Propafenone; C061028:Org 7797; D005424:Flecainide