The anticonvulsant action of the carbonic anhydrase inhibitor methazolamide: possible involvement of a noradrenergic mechanism

WD Gray, CE Rauh - European Journal of Pharmacology, 1974 - Elsevier
WD Gray, CE Rauh
European Journal of Pharmacology, 1974Elsevier
In contrast to previous concepts, the noradrenergic mechanism required for the
anticonvulsant action of inhibitors of carbonic anhydrase in mice is extracerebral on the
basis of the following:(1) the l-aromatic amino acid decarboxylase inhibitor Ro 4-4602/1
abolished the restorative action of d, 1-dopa in reserpine-and phenoxy-benzamine-treated
mice without evidence of significant inhibition of 1-aromatic amino acid decarboxylase in
brain,(2) depletion of extracerebral stores of norepinehrine by the iv administration of 6 …
Abstract
In contrast to previous concepts, the noradrenergic mechanism required for the anticonvulsant action of inhibitors of carbonic anhydrase in mice is extracerebral on the basis of the following: (1) the l-aromatic amino acid decarboxylase inhibitor Ro 4-4602/1 abolished the restorative action of d,1-dopa in reserpine- and phenoxy-benzamine-treated mice without evidence of significant inhibition of 1-aromatic amino acid decarboxylase in brain, (2) depletion of extracerebral stores of norepinehrine by the i.v. administration of 6-hydroxydopamine abolished the anticonvulsant effect of methazolamide, and (3) the anticonvulsant action of the carbonic anhydrase inhibitor in 6-hydroxydopamine-treated mice was restored by the administration of d,1-dopa. The noradrenergic mechanism appears to be of the α-type. Consistent antagonist action was shown by the α-blockers varied in action. The antagonist action of the α-blockers studied appeared to be specifically related to α-adrenergic blockade because (1) potency and duration of antagonist action correspond with potency and duration of α-adrenergic blockade, (2) phenoxybenzamine failed to antagonize the anticonvulsant action of diphenylhydantoin, (3) the anticonvulsant action of methazolamide was not abolished when phenoxybenzamine was given after the carbonic anhydrase inhibitor, (4) d,1-dopa administration reversed the antagonist action of phenoxybenzamine, and (5) the dopamine β-hydroxylase inhibitor U-14624 annulled the reversal of phenoxybenzamine's antagonist action by d,1-dopa. The anticonvusant action of methazolamide in rats was not affected by depletion of cerebral or extracerebral stores of norepinephrine by 6-hydroxydopamine. Anticonvulsant action was abolished by the administration of reserpine to rats injected i.vent. with 6-hydroxydopamine. The data suggest that norepinephrine and serotonin both are involved in the anticonvulsant action of inhibitors of carbonic anhydrase in rats.
Elsevier
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