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.
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb-kyoto-phu.ac.jp
Koji
K
Takeuchi
Tohru
T
Miyazawa
Masahiro
M
Matsumoto
Yujiro
Y
Hayashi
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