Dose-finding study with nimodipine: A selective central nervous system calcium channel blocker on aminophylline induced seizure models in rats

Nimodipine, a dihydropyridine derivative central nervous system (CNS) selective calcium channel blocker was studied at four different dosage schedules in five different models of seizures in rats. At a dose of 5 mg/kg, i.p. with pretreatment time of 15 min, nimodipine significantly antagonized aminophylline (175 and 200 mg/kg, i.p.), electroshock (150 mA for 0.2 s), pentylenetetrazole (60 and 75 mg/kg, i.p.), aminophylline (100 mg/kg i.p.) + electroshock (66mA for 0.2 s), and aminophylline (100 mg/kg, i.p.) + pentylenetetrazole (40 mg/kg, i.p.) induced seizures in rats. No hemodynamic alteration was observed with this dose of nimodipine. However, 2 mg/kg, i.p. (pretreatment time of 15 min and 30 min) and 5 mg/kg, i.p. (pretreatment time of 30 min) doses of nimodipine failed to demonstrate any significant anticonvulsant effect. The study highlighted the critical role of calcium ion flux into the neurons for the genesis of seizure activity to aminophylline, electroshock, and pentylenetetrazole in rats. Furthermore, the critical dose requirement for nimodipine could be explained on the basis of its short half-life and shorter duration of protection against seizures. Therefore, nimodipine may be tried clinically as an anticonvulsant in patients who are on aminophylline because of bronchial asthma or chronic obstructive pulmonary disease, when such patients have concomitant epilepsy or other seizure prone neurological deficits or are scheduled to undergo electroshock therapy. (C) 1998 Elsevier Science Inc.