Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model

Abstract

Sympathetic nerve activity has arrhythmogenic potential for ventricular arrhythmias associated with structural heart diseases. However, a sufficient amount of beta-blockers occasionally cannot be prescribed in some patients. An experimental study was performed to clarify the therapeutic effects of bepridil, a multiple ionic current inhibitor that does not affect beta-adrenergic receptors, for premature beats occurring during enhanced sympathetic nerve activity. Cardio-sympathetic nerve activity was augmented via stellate-ganglion (SG) stimulation in a canine model (n = 8), and the arrhythmogenic potential and anti-arrhythmic effects of bepridil (2 and 4 mg/kg intravenously) were assessed. For safe use, vagal-stimulation-induced slow HR and programmed electrical stimulation were applied to evaluate possible pro-arrhythmic effects of the drug. Heart rate variability (HRV) indexes were used to estimate cardio-autonomic nerve activity. Either side of the SG-stimulation increased BP and HR. Premature beats were induced in 10/16 SGstimulations and it was more frequent in left (8/8) rather than right stimulation (2/8). Following 2 mg/kg drug administration, premature beats were still inducible in 8/16 stimulations (7/8 in left and 1/8 in right), but burden of the premature beats decreased from 87.1 ± 46.8 to 62.1 ± 42.6 beats. After 4 mg/kg administration, premature beats were inducible in one SG-stimulation. Proarrhythmic effects were not observed in all experiments. Steady-state HRV indexes and percent increases in SG-stimulation-induced BP-elevation and HR-acceleration were similar among the 3 periods (before, 2 and 4 mg/kg of the drug). Bepridil may be an option for ventricular arrhythmias developed during enhanced cardio-sympathetic nerve activity with minimal effect on autonomic nerve responses.