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Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.

McN-4130 is an experimental compound having antiarrhythmic and antifibrillatory activity in several animal models. In anesthetized, open-chest pigs subjected to total occlusion and subsequent reperfusion of the left anterior descending coronary artery, McN-4130 dose-dependently (2.5-10.0 mg/kg i.v.) protected against fibrillation and death. Mean arterial pressure was not significantly affected, but heart rate was dose-dependently reduced. In anesthetized normal dogs, McN-4130 increased ventricular fibrillation threshold for up to 45 min. This increase in fibrillation threshold was associated with concurrent increases in ventricular conduction time and ventricular effective refractory period. In conscious dogs subjected to occlusion of the left anterior descending coronary artery 24 h previously, McN-4130, 2.5 and 5.0 mg/kg i.v., significantly reduced the rate of ventricular arrhythmias for up to 45 min. McN-4130 was more effective and had a longer duration of action than comparable doses of lidocaine and disopyramide. McN-4130 was orally effective in this model at 10 mg/kg. These results indicate that McN-4130, a structurally unique experimental antiarrhythmic compound, may be useful as a ventricular antiarrhythmic agent with antifibrillatory properties.