Abstract

Carbonic anhydrase inhibitors including acetazolamide usually elicit physiological responses at various sites in the body without discrimination by dose. These responses, particularly those related to erythrocytic enzyme inhibition, tend to complicate study of any single system. A compound related to acetazolamide, 2-benzene-sulfonamido-1,3,4-thiadiazole-5-sulfonamide (CL 11,366), was found to have properties which make possible a separation of renal from erythrocytic and other effects. Acetazolamide and CL 11,366 were given intravenously to dogs over a wide range of dose. Studies were made of inhibitor distribution and physiological responses in kidney, red blood cells and certain other tisssues.

Acetazolamide at the lowest dose which gives maximal renal HCO₃^- output (10 mg/kg) gave acute respiratory changes including hyperventilation and a fall in alveolar CO₂ tension. This is a dose known to be associated with other responses such as an acute rise in cerebrospinal fluid pressure, decreases in cerebrospinal fluid flow and intraocular pressure, and inhibition of postfeeding gastric acid secretion. By contrast, CL 11,366 was not accompanied by respiratory or the other responses over a range of dose which gave a full renal response (0.3 to 3 mg/kg). Effective erythrocytic enzyme inhibition with respiratory changes occurred at 10 mg/kg.

Elimination of acute respiratory effects during maximal renal carbonic anhydrase inhibition by CL 11,366 is related to 1) partial exclusion of inhibitor from red cells by high plasma binding, ionization and rapid plasma decay, and 2) concentration of inhibitor in kidney by active secretion. Acute respiratory changes were demonstrated to be related to inhibition of erythrocytic carbonic anhydrase (greater than 0.995) independent of the renal HCO₃^- loss.

The results indicate that selective renal carbonic anhydrase inhibition without acute effects on respiration can be obtained by the use of appropriate doses of CL 11,366.