COX Inhibitors and Intestinal Transport
Wallace K. MacNaughton
Contact Person: Wallace K. MacNaughton (firstname.lastname@example.org)
Prostaglandins (PG) are mediators of numerous physiological and pathophysiological processes and are produced from arachidonic acid through the activity of two isoforms of cyclo-oxygenase (COX). COX-1 is constitutively expressed; COX-2 is induced in inflammation. PGE2 stimulates chloride and water secretion in the intestine and acts as the final mediator of many secretagogues. However, the isoform of COX responsible for PGE2 synthesis in the intestinal has not been described. According to current dogma, PGE2 synthesis in uninflamed intestine occurs via COX-1, whereas PGE2 synthesis in inflamed gut may be dependent upon both COX-1 and COX-2. However, our preliminary evidence from the mouse shows that normal, uninflamed colon constitutively expresses both COX-1 and COX-2 mRNA, suggesting that COX inhibitors of varying selectivity for a given COX isoform may differentially affect secretion. In electrolyte transport studies conducted in vitro, we have shown that the PG-dependent secretory responses to bradykinin and arachidonic acid are inhibited by piroxicam, a non-selective inhibitor of both COX isoforms. Interestingly, in normal tissue, the secretory response to these PG-dependent secretagogues is partially inhibited by COX-2 selective inhibitors such as SC58125 and NS-398, at concentrations which do not affect COX-1 activity. These data challenge the dogma that physiological PG-dependent secretion is exclusively COX-1 dependent, and suggest that selective COX-2 inhibitors may alter normal secretory processes.
Presentation Number SAmacnaughton0399