NEW PHARMACOLOGY ASPECTS RELATED TO CARBONIC ANHYDRASE

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A five-fold program has been developed in which the central theme is the enzyme carbonic anhydrase (C.A.), its chemistry, inhibition, and role in certain organ systems, presently unknown. The continuity between biochemical and physiological events is stressed. We plan to study the following: I. The role of carbonic anhydrase in muscle, uterus, ova, and secretion of endolymph. This introduces also fundamental questions about the physiology of these organs. Particularly, in muscle we shall study CO2 output after inhibition of the enzyme; in uterus the implantation evironment; in ova the dispersion of the corona radiata; in endolymph the rate and character of secretion. II. We shall study the role of CO2 in neutral secretions (NaCl) and whether there can be renal H+ output independent of the CO2 system. III. New sulfonamide inhibitors combining lipid and water solubility will be developed. Studies of drug-enzyme kinetics will be pursued, with attention ot "uncompetitive" inhibition, and differences between the three C.A. isozymes. IV. We wish to characterize mitochondrial C.A., and also the enzyme in brain myelin, with respect to Kcat, Km, and susceptibility to inhibition by the sulfonamides. V. We plan to study gas exchange and acid-base balance in sub-order of Amphibia, the plethodonts, which lack both lungs and gills, and respire entirely through the skin. They are also the only adult vertebrates that lack red cell C.A.