ENHANCEMENT OF THE ANTICONVULSANT ACTION OF INHIBITORS OF CARBONIC ANHYDRASE IN NEPHRECTOMIZED MICE: MODE OF ACTION

¹ Department of Experimental Pharmacology, Lederle Laboratories, Pearl River, New York

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.