The antifibrillatory properties of short-term intravenous (10 mg/kg/hr) and long-term (10 mg/kg/day for 24 days) oral amiodarone administration were examined in a conscious canine preparation of sudden coronary death. In this preparation, ventricular fibrillation was produced by electrically induced left circumflex intimal injury and thrombosis in the presence of previous anterior myocardial infarction. On day 4 after anterior myocardial infarction animals were assigned to receive short-term intravenous or long-term oral amiodarone treatment. Animals within each group were randomly assigned to control or drug treatment. Neither short-term intravenous nor long-term oral amiodarone treatment prevented the development of ST segment changes or premature ventricular beats, but both short-term intravenous amiodarone and long-term oral amiodarone administration significantly reduced the incidence of ventricular fibrillation (short-term intravenous amiodarone [n = 10], incidence of 60% vs control [n = 10] incidence of 100%, p < .05; long-term oral amiodarone [n = 10], incidence of 20% vs control [n = 11] incidence of 91%, p < .002). Both short-term intravenous and long-term oral amiodarone administration produced increases in the PR and ratecorrected QT intervals. However, prolongation of the corrected QT interval in the group receiving long-term oral amiodarone (61 + 18 msec) was greater than in the group receiving short-term intravenous drug (31 ± 11 msec, p < .05). This discrepancy between effects of long-term oral and short-term intravenous amiodarone could not be based on differences in plasma (1.9 0.2 vs 2.7 + 0.5 gg/ml, respectively) or right ventricular myocardial concentrations (13 + 2 vs 24 + 4 ,g/g, respectively). These data suggest that while both long-term oral amiodarone and short-term intravenous amiodarone prevent ventricular fibrillation in the conscious dog subjected to acute myocardial ischemia in the presence of previous anterior myocardial infarction, long-term oral amiodarone may have an additional electrophysiologic action and therefore greater efficacy.Circulation 68, No. 4, 857-864, 1983. AMIODARONE HYDROCHLORIDE is a benzofuran derivative originally developed as an antianginal drug. It is both a coronary vasodilator and a vasodilator of the peripheral vasculature.'-3 Amiodarone also exerts noncompetitive blockade of the actions of 38-adrenergic agonists and reduces the inotropic and chronotropic response of other inotropic drugs such as glucagon.

In anesthetized dogs, a 30 gauge silver wire was inserted into the lumen of the left circumflex (LC) coronary artery and myocardial ischemic injury was produced by subsequent occlusion of the left anterior descending (LAD) coronary artery for 90 minutes followed by reperfusion through a critical stenosis. Four days after acute myocardial infarction, with the dog ambulatory, the intimal surface of the LC coronary artery was injured by applying a 150 PA anodal current. Coronary artery thrombosis and subsequent reduction in coronary artery blood flow were accompanied by S-T segment changes at 132 f 65 minutes (mean f standard deviation [SD]) with ventricular fibrillation (VF) occurring in 29 of 30 dogs (97 %) at 141 f 60 minutes. Infarct mass in the LAD distribution was 15 f 8% of total left ventricular mass with no histochemical evidence of irreversible ischemic injury in the LC coronary artery distribution. VF was preceded by the development of de-From the

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart. When chronically infarcted hearts were subjected to programmed electrical stimulation, 1 mg/kg of clofilium inhibited the re-induction of either ventricular tachycardia or ventricular fibrillation in 5 of 6 animals and slowed the rate of the induced tachycardia in the sixth. Clofilium, however, failed to alter ventricular refractory periods of normal myocardium at either twice diastolic threshold current (176 +/- 5 ms control vs. 187 +/- 9 ms post-clofilium, P greater than 0.05) or at 10 mA (134 +/- 6 ms control vs. 137 +/- 13 ms post-clofilium, P greater than 0.05). In addition, chronic administration of clofilium (2 mg/kg, i.v., followed by 1 mg/kg every 12 h) was ineffective in decreasing mortality in a canine model of sudden coronary death. Of 10 saline-treated conscious animals subjected to an electrically-induced intimal lesion of the left circumflex coronary artery in the presence of a previous ischemic insult, all 10 died suddenly of ventricular fibrillation within 173 +/- 45 min after current application. Under similar conditions, 7 clofilium-treated animals died suddenly within 249 +/- 88 min (P greater than 0.05) after current application while 3 animals survived (P greater than 0.10). Clofilium did, however, elevate the effective refractory period in these animals (150 +/- 3 ms saline-treated vs. 195 +/- 7 ms clofilium-treated). It is concluded from our data that there is little relationship between clofilium's electrophysiologic actions in normal myocardium and antiarrhythmic effects. Furthermore, simple prolongation of refractoriness in normal non-ischemic myocardium may be insufficient for the prevention of ventricular fibrillation which develops in response to a transient ischemic event superimposed on a chronically injured myocardium.

The antifibrillatory properties of UM-272 (dimethylpropranolol; Pranolium) were evaluated in a conscious canine model of sudden coronary death. The initial preparation of the animal model was carried out under surgical anesthesia and involved the intraluminal implantation of a Teflon-coated silver wire into the circumflex coronary artery so that 3 mm of the bared electrode was in contact with the endothelial surface. The left anterior descending coronary artery then was occluded for a period of 90 min and reperfused in the presence of a critical stenosis. Three days after myocardial infarction, they were randomized into two groups. One group (n = 10) served as controls and received saline. The second group (n = 10) received UM-272 in a dose of 5 mg/kg every 6 h. On day 4, a 150 microA current was applied to the intimal surface of the left circumflex coronary artery, resulting in transient or permanent alterations in circumflex coronary blood flow accompanied by electrocardiographic evidence of regional myocardial ischemia. The time to onset of ST-segment changes in the saline control group was 99 +/- 34 min and was followed by the appearance of premature ventricular complexes (111 +/- 34 min) and subsequent ventricular tachycardia (131 +/- 37 min) which terminated in ventricular fibrillation in each of the 10 dogs. Animals treated with UM-272 likewise developed ST-segment changes (156 +/- 28 min) and premature ventricular complexes (168 +/- 29 min), but 4 of 10 animals failed to develop ventricular fibrillation (P less than 0.05 vs. saline). These results demonstrate that UM-272, the dimethyl quaternary analog of propranolol, is effective in reducing the incidence of ventricular fibrillation in a conscious canine model in which the superimposition of a transient ischemic event upon an already jeopardized heart leads to the development of sudden death.

In anesthetized dogs, the cumulative intravenous administration of 1.0–40.0 mg/kg sulphinpyrazone failed to alter the ventricular excitation threshold, ventricular refractory period and ventricular fibrillation threshold determined during nonobstructed coronary blood flow. Sulphinpyrazone, however, did attenuate the reduction in the ventricular fibrillation threshold occuring during transient myocardial ischemia. G25671, the sulfide metabolite of sulphinpyrazone, failed to alter ventricular refractoriness and ‘nonischemic’ ventricular fibrillation thresholds, and was minimally effective in reducing the decrease in ‘ischemic’ fibrillation thresholds when administered in cumulative intravenous doses of 5.0–20.0 mg/kg. In conscious dogs in the subacute phase of anterior myocardial infarction, the administration of a cumulative 10.0–40.0 mg/kg sulphinpyrazone failed to alter the mode of induction, rate or morphology of ventricular tachyarrhythmias initiated by programmed ventricular stimulation. These data suggest that neither sulphinpyrazone nor its sulfide metabolite possess primary electrophysiologic properties which might contribute directly to significant antiarrhythmic or antifibrillatory activity.