NONSTEROIDAL ANTIINFLAMMATORY DRUGS ACTIVATE CARBONIC-ANHYDRASE BY A DIRECT MECHANISM OF ACTION

Previvous studies by this research team proved that vasodilating prost aglandins (PGs) E(1), E(2) and I-2 inhibit carbonic anhydrase (CA) in vitro and in vivo, which suggested involvement of CA in gastric acid s ecretion inhibition and the increase of gastric mucosa blood flow prod uced by this group of PGs. Relying on these findings, as well as on ou r clinical observations, we studied in vitro and in vivo the effects o f nonsteroidal antiinflammatory drugs (NSAIDs) on CA I and CA II. We a lso followed in vitro the effects on these isozymes of NSAIDs associat ed; to histamine, Ga, PGE, and acetazolamide. The results show that th e NSAIDs used here, which reduce the activity of cyclooxygenase and PG production activated CA I and CA II in a dose-dependent manner by a m echanism of the noncompetitive type, Histamine and Ca added to NSAIDs amplified the activating effect of the latter on CA II. Association of PGE(2) or acetazolamide to NSAIDs reduced NSAID-induced activation of CA I and CA II. Indomethacin abolished the inhibitory effect of aceta zolamide an CA I and CA II. Our data imply that between CA and cycloox ygenase there is an inverse relationship, CA activation being accompan ied by reduction of cyclooxygenase activity, a reduction achieved by t he pH modifications induced by CA activation. In this way, cyclooxygen ase inhibition occurs ''via CA,'' with the pH variations it brings abo ut.