Invited Symposium: Arachidonic Acid Metabolites, Other Inflammatory Mediators and Intestinal Ion Transport
The isoprostanes are novel prostaglandin (PG)-like compounds formed in vivo by the free-radical catalyzed peroxidation of arachidonic acid, and synthesized independent of the cyclooxygenase (Morrow and Roberts, 1997). In contrast to their PG isomere, they differ by the cis orientation of their side-chains. Recent studies have suggested an involvement of PG subtype E (EP) receptors (Elmhurst et al., 1997), although an "unique" isoprostane receptor might be involved additionally. The biological effects of the isoprostanes have been documented on several test systems though information on their gastrointestinal effects are sparse. Earlier work suggested that the isoprostanes had effects both on the canine colonic epithelium, and the muscularis mucosae. The pig jejunum responded to 8-iso-PGE2, one of the isoprostanes (Unmack et al., 1998). We will discuss the potential implications of isoprostanes in physiological, pathophysiological and pharmacological studies.
Materials and Methods
The experiments were performed on stripped porcine jejunum sheets, obtained from female pigs, with outer muscle layers and myenteric plexus removed, and mounted in Ussing chambers. Bicarbonate Ringer's solutions were applied mucosally and serosally. All solutions contained 1.4 µM indomethacin to suppress the endogenous synthesis of prostanoids. The tissues were short-circuited with transepithelial potential differences of 0 mV by an automatic voltage clamp setup, and the short-circuit currents (ISC) were measured. All components were added to the serosal side.
The isoprostane, 8-iso-PGE2, elicited concentration-dependent increases in ISC, suggesting that the porcine jejunum epithelium possessed receptors for the isoprostane. Cross-desensitization experiments with the analog, PGE2, suggested additionally that the stimulant effects involve a prostanoid EP receptor. Pretreatment of the tissue with the thromboxane A2 (TP) receptor agonist, U46619, did not alter the response to a subsequent addition of 8-iso-PGE2.
Discussion and Conclusion
We have demonstrated that the isoprostanes have effects on the porcine, and the canine gastrointestinal system. It has been an open question, whether the isoprostanes interact with an "unique" receptor or with an EP receptor. Our preliminary studies suggest that an EP receptor is involved in the effect of 8-iso-PGE2 in the porcine jejunum, whereas, both prostanoid TP and EP receptors are involved in the canine colon. If an "unique" isoprostane receptor exists it might from a physiological point of view be speculated why, as these products are thought to be injurious, in that they might be mediators of oxidant injury (Morrow and Roberts, 1996; 1997). Thus, the level of isoprostanes have been suggested to be an index of lipid peroxidation (Morrow and Roberts, 1997). An involvement of the isoprostanes in the pathogenesis of selected gastrointestinal disorders might be likely. Prostanoids are known to be generated in response to inflammatory insults, and for instance, elevated levels of PGE2 have been measured intraluminally in the porcine small intestine following exposure to Salmonella or cholera toxin (Grøndahl et al., 1998). It might be interesting to investigate whether the invasion of Salmonella into the intestinal epithelium, or intestinal exposure to enterotoxins, induces lipid peroxidation, and synthesis of isoprostanes. In addition to this, it would be attractive to explore a possible involvement of isoprostanes in gastrointestinal disorders, besides their electrophysiological effects in the intestine. Nonetheless, a more precise biological role of the isoprostanes remains unclear despite the fact that they can be detected in virtually every animal and human biological fluid, and tissue that have been analysed so far (Morrow and Roberts, 1997).
AcknowledgementM.A. Unmack gratefully acknowledges the support of The Else and Mogens Wedell-Wedellsborg Foundation, The King Christian IX and Queen Louise Anniversary Foundation, The Dagmar Marshall Foundation, The Ingeborg Roikjer Foundation, Landed Proprietor Viktor A. Goldschmidt Foundation (Dept. B), The Novo Nordisk Foundation, and The Carlsberg Foundation (RVAU). P.K. Rangachari was supported by MRC Canada.
| Discussion Board | Previous Page | Your Symposium |
|Unmack, Martin Andreas; Skadhauge, Erik; Rangachari, Patangi K.; (1998). Effects of Prostanoids and Isoprostanes on the Porcine Small Intestine. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/rangacharipharm/unmack0591/index.html|
|© 1998 Author(s) Hold Copyright|