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Cyclo-oxygenase isozymes in mucosal ulcergenic and functional responses following barrier disruption in rat stomachs
T Hirata1, H Ukawa, H Yamakuni
1Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
Abstract:
1. We examined the effects of selective and nonselective cyclo-oxygenase (COX) inhibitors on various functional changes in the rat stomach induced by topical application of taurocholate (TC) and investigated the preferential role of COX isozymes in these responses. 2. Rat stomachs mounted in ex vivo chambers were perfused with 50 mM HCl and transmucosal potential difference (p.d.), mucosal blood flow (GMBF), luminal acid loss and luminal levels of prostaglandin E2 (PGE2) were measured before, during and after exposure to 20 mM TC. 3. Mucosal application of TC in control rats caused a reduction in p.d., followed by an increase of luminal acid loss and GMBF, and produced only minimal damage in the mucosa 2 h later. Pretreatment with indomethacin (10 mg kg[-1], s.c.), a nonselective COX-1 and COX-2 inhibitor, attenuated the gastric hyperaemic response caused by TC without affecting p.d. and acid loss, resulting in haemorrhagic lesions in the mucosa. In contrast, selective COX-2 inhibitors, such as NS-398 and nimesulide (10 mg kg[-1], s.c.), had no effect on any of the responses induced by TC and did not cause gross damage in the mucosa. 4. Luminal PGE2 levels were markedly increased during and after exposure to TC and this response was significantly inhibited by indomethacin but not by either NS-398 or nimesulide. The expression of COX-1-mRNA was consistently detected in the gastric mucosa before and after TC treatment, while a faint expression of COX-2-mRNA was detected only 2 h after TC treatment. 5. Both NS-398 and nimesulide significantly suppressed carrageenan-induced rat paw oedema, similar to indomethacin. 6. These results confirmed a mediator role for prostaglandins in the gastric hyperaemic response following TC-induced barrier disruption, and suggest that COX-1 but not COX-2 is a key enzyme in maintaining 'housekeeping' functions in the gastric mucosa under both normal and adverse conditions.
Insights
Nonselective cyclo-oxygenase (COX) inhibitors like indomethacin protect the stomach lining from taurocholate damage by preserving prostaglandin E2 levels, unlike selective COX-2 inhibitors. This highlights COX-1
Area of Science:
- Gastroenterology
- Pharmacology
- Biochemistry
Background:
- Taurocholate (TC) induces gastric mucosal damage.
- Cyclo-oxygenase (COX) enzymes play a role in prostaglandin synthesis and gastric function.
- Understanding the roles of COX-1 and COX-2 isozymes in gastric protection is crucial.
Purpose of the Study:
- To investigate the effects of selective and nonselective COX inhibitors on functional changes in the rat stomach induced by taurocholate.
- To determine the preferential role of COX isozymes in mediating these gastric responses.
Main Methods:
- Ex vivo perfusion of rat stomachs with HCl and TC.
- Measurement of transmucosal potential difference, mucosal blood flow, acid loss, and prostaglandin E2 levels.
- Assessment of mucosal damage and COX-1/COX-2 mRNA expression.
Main Results:
- TC induced gastric hyperemic response, increased luminal acid loss, and PGE2 levels, with minimal damage.
- Indomethacin (nonselective COX inhibitor) attenuated hyperemic response but increased lesions, while selective COX-2 inhibitors had no effect.
- Luminal PGE2 increase was inhibited by indomethacin but not selective COX-2 inhibitors; COX-1 mRNA was constitutive, COX-2 mRNA was induced post-TC exposure.
Conclusions:
- Prostaglandins mediate the gastric hyperemic response to TC-induced barrier disruption.
- COX-1, not COX-2, is essential for maintaining gastric mucosal 'housekeeping' functions under normal and adverse conditions.