Cariporide and KB-R9032, new Na-H exchange (NHE) subtype 1 inhibitors, have antiarrhythmic effects on canine coronary ischemia and reperfusion induced arrhythmias, which might be induced by intracellular Ca overload following myocardial ischemia. These favorable antiarrhythmic effects on coronary ischemia and reperfusion occurred without changes in the blood pressure, heart rate and ECG parameters. Such antiarrhythmic and antifibrillatory effects were specific for myocardial ischemia related arrhythmias, namely they did not show such antiarrhythmic effects on digitalis or adrenaline induced arrhythmias, the mechanisms of which are also thought to be due to intracellular Ca overload. A new selective Na/Ca exchange inhibitor, KBR7943, was proved to be a reverse mode inhibitor, but failed to show antiarrhythmic effects on the canine coronary ischemia and reperfusion induced arrhythmias.
Using two-stage coronary ligation-, digitalis- and epinephrine-induced canine ventricular arrhythmia models, we examined whether a new positive inotropic agent, NKH477, 6-(3-dimethylaminopropionyl)forskolin hydrochloride, a water-soluble derivative of forskolin, had deleterious effects on arrhythmias. NKH477 increased heart rate (HR) and decreased blood pressure (BP) in dogs with all the arrhythmia models. Unexpectedly, NKH477 suppressed digitalis- and epinephrine-induced arrhythmias, but did not suppress two-stage coronary ligation arrhythmia or aggravate it. These results indicate that NKH477, unlike other new positive inotropic agents such as amrinone, milrinone, sulmazole and vesnarinone, did not worsen these arrhythmias; thus, NKH477 may be a useful positive inotropic agent with little arrhythmogenic effect.
Antiarrhythmic effects of (+)-cibenzoline and (-)-cibenzoline were examined using two canine ventricular arrhythmia models. Digitalis arrhythmia, which is suppressed by Na channel blockers, was induced by intermittent intravenous (i.v.) injection of ouabain in pentobarbital-anesthetized dogs. Adrenaline arrhythmia, which is suppressed by Ca channel blockers, was induced by adrenaline infusion in halothane-anesthetized dogs. Ten and 5 mg/kg i.v. (+)-cibenzoline suppressed digitalis-and adrenaline-induced arrhythmias, respectively. The minimum effective plasma concentrations of (+)-cibenzoline for digitalis- and adrenaline-induced arrhythmias were 1.4 ± 0.4 and 2.0 ± 0.6 μg/ml, respectively (mean ± SD, n = 6). A lower dose of 1 mg/kg i.v. of (-)-cibenzoline suppressed the digitalis-induced arrhythmia, whereas 5 mg/kg i.v. was needed to suppress adrenaline-induced arrhythmias. The minimum effective plasma concentrations of (-)-cibenzoline for digitalis-and adrenaline-induced arrhythmia were 0.06 ± 0.04 and 0.7 ± 0.1 μg/ml, respectively (mean ± SD, n = 6). The stronger antiarrhythmic effect of (-)-cibenzoline indicates that (-)-isomer may have an effect nearly 5–20 times stronger in suppressing Na channels, but effects of both drugs on Ca channels may be almost equipotent.
