Antiarrhythmic and Electrophysiological Effects In-vivo of the Major Metabolite of Org 7797 Found in Canine and Rodent Liver Homogenate Preparations

Abstract

Abstract Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo. Org 20781 (0·5–2·0 mg 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 2–4mg kg−1) associated with suppression of late arrhythmias were 6–18 μm, 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.