PT  - JOURNAL ARTICLE
AU  - William D. Gray
AU  - Charles E. Rauh
TI  - ENHANCEMENT OF THE ANTICONVULSANT ACTION OF INHIBITORS OF CARBONIC ANHYDRASE IN NEPHRECTOMIZED MICE: MODE OF ACTION
DP  - 1967 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 421--427
VI  - 158
IP  - 3
4099  - http://jpet.aspetjournals.org/content/158/3/421.short
4100  - http://jpet.aspetjournals.org/content/158/3/421.full
SO  - J Pharmacol Exp Ther1967 Dec 01; 158
AB  - In nephrectomized mice the following effects were noted on the anticonvulsant action of CL 11,366 (2-benzenesulfonamide-1,3,4-thiadiazole-5-sulfonamide) and methazolamide, both inhibitors of carbonic anhydrase: 1) an increase in the potency of both agents, 2) prolongation of the effect of CL 11,366 (because of its long duration of action, methazolamide was not studied), 3) retention of the characteristic time-action profile of methazolammde, i.e., delayed occurrence of maximal anticonvulsant effect, and 4) conversion of the time-action profile of CL 11,366 to one similar to that of methazolamide. Decrease in brain excitability caused by nephrectomy was not implicated in the above phenomena. Elevation and persistence of plasma levels of drug primarily accounted for the change in the potency and the duration of the anticonvulsant action of CL 11,366. Acidosis resulting from nephrectomy was the most probable reason for the increased potency of methazolamide and for the time-action profiles of methazolamide and CL 11,366 in nephrectomized mice. The potency-enhancing effect of metabolic acidosis also probably accounts for the 1- to 2-hr delay in the peak anticonvulsant effect of methazolamide in normal mice. The mechanism of action of acidosis is unknown. It is generalized that the kidney may influence the anticonvulsant action of carbonic anhydrase inhibitors by regulation of the plasma concentration of drug and/or by metabolic acidosis produced by the inhibition of renal carbonic anhydrase. © 1967 by The Williams & Wilkins Company