POTENTIATION OF DIURETIC EFFECTS OF METHYL XANTHINES AND PYRIMIDINES BY CARBONIC ANHYDRASE INHIBITORS

¹ Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida

Administration of theophylline, caffeine, aminoisometridine or aminometridine to dogs caused a urinary electrolyte excretion pattern which was characterized by quantitative pre-dominance of Na⁺ and Cl^- with smaller amounts of K⁺ and virtually no HCO₃^- in acid urine. Following simultaneous intravenous injection of any of these with acetazolamide, Cl^-, HCO₃^- and Na⁺ excretion rates were increased greatly above the sum of separate effects of each agent, but the effects on K⁺ output were generally additive. Theophylline was also potentiated by other general carbonic anhydrase inhibitors, methazolamide and ethoxzolamide. At one dose combination of acetazolamide and theophylline there was a consistent drop in inulin clearance averaging 13%. Glomerular filtration rate was not measured at other doses or with other drugs.

Theophylline was not potentiated by CL 13,850, an analogue of acetazolamide which is devoid of carbonic anhydra. se inhibitory activity.

Another analogue, CL 11,366, which at doses studied is an inhibitor of renal but not erythrocytic carbonic anhydrase (nor presumably that of other sites), gave results similar to theophylline-acetazolamide combination indicating renal site of potentiation.

Potentiation effects observed were considered to be a function of increased intracellular pH of renal tubules due to carbonic anhydrase inhibition favoring the activity of methyl xanthines and pyrimidines.