The antiarrhythmic effects of
Org 6001 following
oral administration in the rat have been assessed and correlated with plasma, myocardial and skeletal muscle
drug concentrations. Arrythmias were induced by coronary artery
ligation in anaesthetized rats.
Org 6001 (10, 20, 50 and 100 mg/kg given 1 h before
ligation) significantly reduced mortality and the incidence of
ventricular fibrillation in the 0-30 min post
ligation period. Only the highest dose of
drug also significantly reduced the number of
ventricular ectopic beats following
ligation. A linear relationship was observed between the oral dose and the
Org 6001 concentrations in plasma and skeletal muscle determined 90 min after
drug administration. The
Org 6001 concentration in the myocardium was not linearly related to the administered dose and
Org 6001 appeared to be concentrated to a higher extent in cardiac than in skeletal muscle at that time. No statistically significant difference in
drug levels in the ischaemic left ventricle and normal right ventricle plus septum was observed. The antiarrythmic effect of
Org 6001, as measured by changes in the incidence of
ventricular fibrillation, correlated with myocardial concentrations of the
drug.