GASTRIC-MOTILITY AND MUCOSAL ULCEROGENIC RESPONSES INDUCED BY PROKINETIC DRUGS IN RATS UNDER PROSTAGLANDIN-DEFICIENT CONDITIONS

The present study was performed to examine whether gastric prokinetic drugs may induce damage in the rat stomach under normal and prostaglan din (PG)-deficient conditions. Male SD rats fasted for 18 hr were admi nistered subcutaneously with three different prokinetic drugs such as metoclopramide (3-60 mg/kg), ondansetron (0.3-3 mg/kg), and cisapride (3-30 mg/kg). Half the number of these animals were pretreated with in domethacin (5 mg/kg) subcutaneously for induction of PG deficiency in the stomach. Administration of these drugs increased gastric motor act ivity ia a dose-dependent manner and expedited gastric emptying at low er doses than those affecting gastric motility; the potency of the hyp ermotility effect was in the following order: metoclopramide = ondanse tron > cisapride. None of these drugs alone caused gross damage in the stomach, although whitish rough areas were observed in the gastric mu cosa along the folds. In the rats pretreated with indomethacin, howeve r, both metoclopramide and ondansetron provoked multiple hemorrhagic l esions in the gastric mucosa. Indomethacin at this dose showed over 90 % inhibition of cyclooxygenase activity without causing any damage in the stomach, and this PG-deficient effect was not affected by coadmini stration with the prokinetic drugs. The mucosal ulcerogenic responses induced by metoclopramide in the presence of indomethacin were signifi cantly inhibited by prior administration of atropine (1 mg/kg) or PGE( 2) (300 mu g/kg) at doses that inhibited gastric hypermotility induced by metoclopramide. These results suggest that: (1) gastric prokinetic drugs induce damage in rat stomachs under PG-deficient conditions at the doses that enhance gastric motility and emptying but not at the do ses that expedite gastric emptying only, and (2) gastric hypermotility has the potential to cause gross damage in the stomach, supporting th e importance of gastric motility as a pathogenic element of gastric le sions.