THE ANTICONVULSANT ACTION OF INHIBITORS OF CARBONIC ANHYDRASE: SITE AND MODE OF ACTION IN RATS AND MICE

¹ Department of Experimental Pharmacology, Lederle Laboratories Division, American Cyanamid Co., Pearl River, New York

The concentrations of inhibitor in brain, red cells and plasma were measured enzymatically 5 min after i.v. administration of the carbonic anhydrase inhibitors 2-ben-zenesulfonamido-1,3,4-thiadiazole-5-sulfonamide (CL 11,366) and methazolamide to rats, and after 15 min and 2 hr to mice. Carbonic anhydrase inhibition in brain and red cells was calculated. Measurements were also made of the pH of venous blood and of plasma acidlabile CO₂. Pvco₂ and bicarbonate concentration were derived by use of the Henderson-Hasselbalch equation. Inhibition of carbonic anhydrase in erythrocytes appeared to be causally related to the anticonvulsant action of these two agents in rats. In mice, CL 11,366 appeared to act by inhibition of carbonic anhydrase in red cells and methazolamide primarily by inhibition of the enzyme in brain, although a contribution by red cell carbonic anhydrase cannot be excluded by the data. By effects on Pvco₂, inhibition of carbonic anhydrase in red cells calculated on the basis of concentration of inhibitor in cells or unbound in plasma does not appear to be a valid measurement of enzyme inhibition in vivo. On the basis of the results of this study, it was generalized that carbonic anhydrase inhibitors as a class cause anticonvulsant action in rats by inhibition of red cell carbonic anhydrase. In mice, the enzyme in brain, in red cells or at both sites may be involved, the determinants being potency and comparative ease of entry into brain and red cells. In both animals, renal carbonic anhydrase does not appear to be primarily involved.