Comparative Antidysrhythmic and Haemodynamic Effects of Orally or Intravenously Administered Mexiletine and Org 6001 in the Anaesthetized Rat

1 The antidysrhythmic and haemodynamic effects of the aminosteroid, Org 6001, were studied in the rat anaesthetized with pentobarbitone. Mexiletine was used for comparison. 2 Both Org 6001 (2--10 mg/kg) and mexiletine (1 mg/kg) given intravenously antagonized the development of dysrhythmias evoked by acute coronary artery ligation in rats. 3 In antidysrhythmic doses, Org 6001 and mexiletine exerted only moderate and transient hypotension and depression of cardiac contractility (assessed from LV dP/dtmax). Org 6001 did, however, induce a more sustained bradycardia. 4 Effective oral doses of Org 6001 (20--100 mg/kg) were similar to those of mexiletine, disopyramide and propafenone. 5 Oral Org 6001 (100 mg/kg) was effective for 18 h whereas mexiletine (100 mg/kg) failed to protect against evoked dysrhythmias 3 h after dosing. 6 Org 6001 and mexiletine differed in their actions on ventricular fibrillation threshold (VFT). Org 6001 (100 mg/kg orally 12 h before ligation) prevented the decrease in VFT produced by coronary ligation whereas mexiletine (100 mg/kg orally) had no effect. When administered intravenously, mexiletine (but not ORg 6001) increased VFT in normal ventricular muscle.