Study of indomethacin-induced gastric mucosal damage
Study of indomethacin-induced gastric mucosal damage
Gastrointestinal side effects are among the most commonly encountered problems of NSAID's. A number of investigations into the pathogenesis of NSAID-induced gatric damage have indicated the underlying mechanism may be due to drug-induced reduction in endogenous prostaglandin biosynthesis. There are numerous methodological problems encountered when measuring prostaglandins which may explain why there is equivocal evidence for a correlation between the ulcerogenic and prostaglandin inhibitory capacity of NSAID's in animals. This thesis attempts to further define the role that prostaglandins have in pathogenesis of ulceration and the relationship of prostaglandin inhibition to tissue and plasma concentrations of NSAID's. Reproducible methods for measuring prostaglandin generation from rat gastric and duodenal mucosa were developed. In gastric tissue my studies defined that preparation of tissue at 0oC rather than at room temperature resulted in considerably less non-specific preparation-induced prostaglandin generation. Removal of gastric mucosal tissue using a technique involving blistering by injecting Kreb's buffer between the mucosal and muscle layers, produced preparations that had a different prostaglandin synthesising profile to scraped tissue. Unlike scraped tissue the `blistered' preparation synthesised less PGE2 in the presence of indomethacin. Scraped duodenum caused little preparation-induced PGE2 synthesis relative to that produced in a short term incubation. Gastric fundus, antrum and duodenum synthesised differing amounts of PGE2. Differences in inhibitory potency of indomethacin was also seen between scraped duodenal mucosa and fundic mucosal discs, with a lower IC50 concentration of indomethacin for duodenal mucosa tissue. Three variations in feeding conditions were shown to alter both the siting and severity of indomethacin-induced gastric damage in the rat. The siting of indomethacin-induced damage in fasted rats was mainly confined to the fundic mucosa, whereas in animals fasted for 24 hours and fed one hour prior to drug administration gastric damage was mainly confined to the antral mucosa. In continuously fed animals indomethacin-induced minor damage in both the antrum and fundus. Alteration in feeding conditions did not cause any consistent change in antral or fundic mucosal PGE2 synthesis. In indomethacin treated animals fundic and antral mucosal synthesis was decreased by 80% and the extent of this did not significantly differ among feeding groups or between animals of the same feeding group during the study period. Under the experimental conditions used in this study feeding conditions seem to alter both the severity and location of indomethacin induced damage by a prostaglandin independent mechanism.
University of Southampton
1991
Martin, Steven William
(1991)
Study of indomethacin-induced gastric mucosal damage.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Gastrointestinal side effects are among the most commonly encountered problems of NSAID's. A number of investigations into the pathogenesis of NSAID-induced gatric damage have indicated the underlying mechanism may be due to drug-induced reduction in endogenous prostaglandin biosynthesis. There are numerous methodological problems encountered when measuring prostaglandins which may explain why there is equivocal evidence for a correlation between the ulcerogenic and prostaglandin inhibitory capacity of NSAID's in animals. This thesis attempts to further define the role that prostaglandins have in pathogenesis of ulceration and the relationship of prostaglandin inhibition to tissue and plasma concentrations of NSAID's. Reproducible methods for measuring prostaglandin generation from rat gastric and duodenal mucosa were developed. In gastric tissue my studies defined that preparation of tissue at 0oC rather than at room temperature resulted in considerably less non-specific preparation-induced prostaglandin generation. Removal of gastric mucosal tissue using a technique involving blistering by injecting Kreb's buffer between the mucosal and muscle layers, produced preparations that had a different prostaglandin synthesising profile to scraped tissue. Unlike scraped tissue the `blistered' preparation synthesised less PGE2 in the presence of indomethacin. Scraped duodenum caused little preparation-induced PGE2 synthesis relative to that produced in a short term incubation. Gastric fundus, antrum and duodenum synthesised differing amounts of PGE2. Differences in inhibitory potency of indomethacin was also seen between scraped duodenal mucosa and fundic mucosal discs, with a lower IC50 concentration of indomethacin for duodenal mucosa tissue. Three variations in feeding conditions were shown to alter both the siting and severity of indomethacin-induced gastric damage in the rat. The siting of indomethacin-induced damage in fasted rats was mainly confined to the fundic mucosa, whereas in animals fasted for 24 hours and fed one hour prior to drug administration gastric damage was mainly confined to the antral mucosa. In continuously fed animals indomethacin-induced minor damage in both the antrum and fundus. Alteration in feeding conditions did not cause any consistent change in antral or fundic mucosal PGE2 synthesis. In indomethacin treated animals fundic and antral mucosal synthesis was decreased by 80% and the extent of this did not significantly differ among feeding groups or between animals of the same feeding group during the study period. Under the experimental conditions used in this study feeding conditions seem to alter both the severity and location of indomethacin induced damage by a prostaglandin independent mechanism.
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Published date: 1991
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Local EPrints ID: 460559
URI: http://eprints.soton.ac.uk/id/eprint/460559
PURE UUID: 1498ce22-05d1-4a9b-abc0-d9ca7897a316
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Date deposited: 04 Jul 2022 18:24
Last modified: 04 Jul 2022 18:24
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Author:
Steven William Martin
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