We determined the antidysrhythmic activity of acute or prolonged administration of
Org 6001 on dysrhythmias following coronary artery
ligation in conscious and anesthetized rats. Intravenous doses of 5 and 10 mg/kg of
Org 6001 markedly protected against postligation dysrhythmias in anesthetized rats, whereas a single oral dose of 10 mg/kg given 1 hr prior to
ligation did not. Prolonged
oral administration of
Org 6001, 10 mg/kg twice daily for 10 days, the last dose given 1 hr before
ligation, reduced the incidence of
ventricular fibrillation and increased survival in both conscious and anesthetized animals. This effective antidysrhythmic dose regimen resulted in
drug concentrations of 335 +/- 68 ng/ml in plasma and 2,940 +/- 408 ng
Org 6001/g in the whole heart. At 24 hr after the last dose no protection against the dysrhythmias remained, and
drug levels in both plasma and heart tissue were low. A good correlation was observed between the levels of
Org 6001 in the heart and the reduction in the rate of rise of phase zero of cardiac action potentials obtained from
drug-pretreated animals. It is concluded that prolonged administration of
Org 6001 is effective against postligation dysrhythmias and that this effect may be associated with the
drug's Class I activity.