Interactions between ACE inhibitors and classical antiepileptic drugs in the mouse maximal electroshock seizures

This study evaluated the effect of two angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, commonly used antihypertensive drugs, on the protective efficacy of the classical antiepileptics - carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB). For this purpose, we used the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with ACE inhibitors and antiepileptic drugs in the passive avoidance task and chimney test were assessed. All drugs were administered intraperitoneally. Neither enalapril (10, 20 and 30 mg/kg) nor cilazapril (5, 10 and 20mg/kg) affected the threshold for electroconvulsions. Enalapril (30 mg/kg) but not cilazapril (20mg/kg), enhanced the protective action of VPA, decreasing its ED(50) value from 249.5 to 164.9 mg/kg (p<0.01). Free plasma (non-protein-bound) and total brain concentrations of VPA were not significantly influenced by enalapril. Therefore, the observed interaction could be pharmacodynamic in nature. The combinations of ACE inhibitors with other antiepileptics (CBZ, PHT, and PB) were ineffective in that their ED(50) values against MES were not significantly changed. Enalapril and cilazapril remained ineffective as regards memory retention in the passive avoidance task or motor performance in the chimney test. The current study suggests that there are no negative interactions between the studied ACE inhibitors and classical antiepileptic drugs. Enalapril was even documented to enhance the anticonvulsant activity of VPA.