Anticonvulsant Properties of Calcium Channel Blockers in Mice: N‐Methyl‐D‐, L‐Aspartate‐ and Bay K 8644‐Induced Convulsions are Potently Blocked by the Dihydropyridines

Summary: Ten calcium channel blockers were evaluated in mice after intraperitoneal (i.p.) administration for prevention of seizures induced by various convulsants. The dihydropyridines (class II calcium antagonists, i.e., nisoldipine, nitrendipine, nicardipine, nifedipine, and nimodipine) selectively prevented seizures elicited by administration of pentylenetetrazol (PTZ), N ‐methyl‐D, L‐ aspartate (NMDLA) and the dihydropyridine calcium channel agonist BAY K 8644. With regard to prevention of NMDLA‐induced seizures and the subsequent mortality, these compounds were similar in potency to the noncompetitive NMD A receptor antagonist MK801. Unlike MK801 (IC 50 = 0.014 μ M ), the dihydropyridines did not inhibit in vitro binding of MK801 to synaptic membrane fractions prepared from rat cerebrohippocampal tissue. The dihydropyridines did not influence seizures elicited by maximal electroshock (MES). Flunarizine (diphenyl‐alkylamine, class IV) was selectively active in the MES test, considerably less potent against NMDLA‐induced convulsions/mortality, exhibited weak noncompetitive NMD A antagonism in vitro (IC 50 = 28 μ M ), and was inactive in the PTZ and BAY K 8644 testing paradigms. Diltiazem, a class III benzothiazepine, possessed relatively weak broad spectra of activity against MES, PTZ, NMDLA, and BAY K 8644 test situations. It was inactive in vitro as a noncompetitive NMDA antagonist. The class I compound verapamil (phenylalkylamine) displayed only moderate inhibition of NMDLA‐evoked seizures/ mortality. Prenylamine (class V) was moderately active against convulsions produced by MES and NMDLA while retaining a degree (IC 50 =16 μ M ) of noncompetitive NMDA antagonism. Lidoflazine (class VI) was inactive in all tests. The Ca 2+ channel blockers and MK801 were inconsistent in their ability to prevent bicuculline (BlC)‐elicited convulsions. Inhibition of these seizures by 40–50% was rare; usually higher doses were less effective or led to appearance of side effects. The reference agent, MK801, worsened the convulsions and subsequent catatonia after administration of BAY K 8644. The data show unexpected action(s) of dihydropyridines with NMDA receptor‐mediated mechanisms and suggest thrée possibilities: (a) prevention of presynaptic/Ca 2+ regulated release of excitatory amino acid, (b) direct depolarization by NMDA of dihydropyridine‐regulated Ca 2+ channels, and (c) coupled/indirect regulation of dihydropyridinesensitive channels after NMDA receptor activation.