Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil

Summary The antiarrhythmic effects of a new calcium channel blocking agent (SD-3211) and its stereoisomer with additional sodium channel blocking activity (SA3212), were compared with those of a known antiarrhythmic drug (bepridil), using the left coronary artery ligation- and reperfusion-associated arrhythmia models both in isolated rat hearts and in anaesthetized rats.Isolated and perfused rat hearts were subjected to regional ischaemia for 15 min and subsequent reperfusion for 5 min. SD-3211 and SA3212 showed dose-dependently prolongations of the time interval between coronary ligation and first appearance of ventricular premature beats, reductions in the number of total ventricular premature beats during the ligation period and reductions in the incidence of reperfusion-induced ventricular fibrillation. The values of the negative logarithm of IC₅₀ (mol/l) of SD-3211, SA3212 and bepridil were 7.97, 7.41 and 6.64 for the reduction of ventricular premature beats during ligation and 6.43, 7.49 and 6.17 for the reduction of ventricular fibrillation during reperfusion, respectively. In a separate study on force of concentration and coronary flow in perfused heart paced at 340–360 beats/min SD-3211 caused a significant negative inotropic effect between 10^–7 and 10^–6 mol/l. SA3212 at the concentration of < 10^–6 mol/l did not result in any significant change in force of contraction. The coronary flow was increased dose-dependently by SA3212, while it was first increased and then reduced in the presence of higher concentration of SD-3211 (> 10^–7 mol/l). Hearts of aneasthetized rats were also subjected to regional ischaemia for 7 min and subsequent reperfusion. SD-3211, even at the lowest dose tested (25 mg/kg), had a marked protective effect against the ligation-associated arrhythmias. The highest dosage of SA3212 tested (100 mg/kg) also reduced them. SA3212, even at the lowest dosage (25 mg/kg), resulted in a significant reduction of the incidence of reperfusion-induced ventricular fibrillation, while only the highest dosage of SD-3211 (100 mg/kg) reduced it. As for the protective effect against ligation-associated ventricular premature beats SD-3211 is about seven times as potent as bepridil, and for the reduction in the incidence of reperfusion-induced ventricular fibrillation SA3212 is about fourteen times as potent as bepridil. Significant falls in systolic blood pressure and heart rate were observed at the higher doses of SD-3211 (50 and 100 mg/kg).Thus, SD-3211 affords substantial protection against ischaemia-induced ventricular antiarrhythmias partly through the negative inotropic and chronotropic effects, and reduction of afterload. The antiarrhythmic action of SA3212 against reperfusion-induced ventricular fibrillation may be partly explained by depression of automaticity together with a reduction of the inward sodium current.Send offprint requests to M. Fukuchi at the above address