Nimodipine, a
dihydropyridine that interacts with a Ca++ channel-associated binding site, when delivered (30 to 150 micrograms/kg) intra-arterially (ia) to
enflurane-anesthetized cats, produced a dose-dependent suppression of
seizures evoked by
pentylenetetrazol. A comparable suppression was produced by
clonazepam (1 to 30 micrograms/kg, ia).
Phenytoin was maximally effective only at nearly lethal doses (90 mg/kg, ia).
Verapamil, a diphenylalkylamine that interacts with a separate Ca++ channel-associated site, at the maximum nonlethal dose (6 mg/kg, ia) resulted in a mild facilitation of seizure activity. The
drug vehicle used in these studies (50%
polyethylene glycol-400) had no effect when given alone. Regional cerebral blood flow (rCBF) as measured by the clearance of
xenon-133 was markedly elevated immediately after the onset of seizure activity (89 +/- 3 to 168 +/- 4 ml/100 gm/min). Concurrent with their resolution of the seizure activity, both
nimodipine and
clonazepam reduced rCBF to near preseizure levels and preserved the rCBF response to hypercarbia which would otherwise have been abolished following prolonged seizure activity. Moreover, the effect of
nimodipine on rCBF and
seizures occurred without any prominent alterations in mean arterial blood pressure as compared to preseizure levels. These data support the proposition that a
dihydropyridine Ca++ channel binding site may play a role in modulating paroxysmal neuronal activity, and suggest that this class of agents may reflect a novel group of
antiepileptic drugs.