Both selective COX-1 and COX-2 inhibitors aggravate gastric damage induced in rats by 2-deoxy-D-glucose. relation to gastric hypermotility and COX-2 expression.
OBJECTIVE
2-deoxy-D-glucose (2DG), despite causing gastric hypermotility via vagal stimulation, does not by itself induce damage in the stomach but produces gross lesions under prostaglandin (PG) deficiency induced by non-ulcerogenic dose of indomethacin. In this study, we examined the roles PG and cyclo-oxygenase (COX) isozymes play in the gastric ulcerogenic effect of 2DG in the rat stomach under PG deficiency caused by indomethacin.


METHODS
The animals were given 2DG i.v. (200 mg/kg as a bolus injection followed by an infusion at 100 mg/kg), and the mucosa was examined for lesions 8 h later. SC-560 or/and rofecoxib was given p.o. 1 h before 2DG treatment.


RESULTS
2DG alone caused slight damage in the stomach despite causing acid hypersecretion and hypermotility. Neither SC-560 nor rofecoxib alone caused any damage in the stomach, yet these agents significantly aggravated 2DG-induced gastric lesions; the severity of damage was much greater when SC-560 was given together with 2DG. SC-560, but not rofecoxib, enhanced both acid secretion and gastric motility in response to 2DG, with a decrease in mucosal PGE2 content. Expression of COX-2 was up-regulated in the stomach as early as 2 h after 2DG treatment, and the PGE2 content was increased when determined 6 h later, in a COX-2-dependent/rofecoxib-sensitive manner. Both the expression of COX-2 and gastric hypermotility during 2DG treatment were inhibited by prior administration of atropine but not omeprazole, although 2DG-induced gastric lesions were prevented by both agents.


CONCLUSIONS
These results suggest that potentiation by indomethacin of 2DG-induced gastric lesions is related to inhibition of both COX-1 and COX-2, and that 2DG up-regulates COX-2 in the gastric mucosa, the event occurring in association with gastric hypermotility and contributing to suppression of later extension of the damage.
Takeuchi
Koji
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb-kyoto-phu.ac.jp
Miyazawa
Tohru
T
Matsumoto
Masahiro
M
Hayashi
Yujiro
Y
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D003847:Deoxyglucose / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000633:toxicity*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000494:pharmacology* / Q000633:toxicity*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D011720:Pyrazoles; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D003847:Deoxyglucose; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin