NOVEL ROLE OF PROSTACYCLIN IN STRESS-INDUCED GASTRIC-MUCOSAL LESION FORMATION IN RATS

We investigated the novel role of prostacyclin (PGI(2)) in gastric muc osal lesion formation induced by stress in rats. Gastric 6-keto-prosta glandin F-1 alpha (6-keto-PGF(1) alpha) levels were significantly incr eased 30 minuates after water-immersion restraint stress (WIR). Subcut aneous indomethacin (IM) (5 mg/kg) inhibited this increase but signifi cantly exacerbated gastric mucosal lesion formation in rats subjected to WIR. Although gastric myeloperoxidase (MPO) activity was not increa sed by WIR, it significantly increased with time after WIR in animals pretreated with IM. NS-398, a selective inhibitor of cyclooxygenase-2, did not inhibit the WIR-induced increase in gastric 6-keto-PGF(1) alp ha. Neither the gastric lesion index nor gastric MPO activity were aff ected in animals pretreated with NS-398 and subjected to WIR. WIR-indu ced mucosal lesion formation was significantly inhibited in animals gi ven iloprost, a stable analog of PGI(2), and in those with nitrogen mu stard-induced leukocytopenia. Iloprost prevented the gastric leukocyte accumulation and exacerbation of gastric mucosal lesions induced by I M in animals subjected to WIR. These IM-induced events also were preve nted in animals subjected to WIR with nitrogen mustard-induced leukocy topenia. These observations implicate leukocytes in the process leadin g to gastric mucosal lesions induced by WIR. The increase in WIR-induc ed gastric PGI(2) synthesis, mainly mediated by cyclooxygenase-1, appe ars important in preventing lesion formation, not only by maintaining gastric mucosal blood flow but also by inhibitin`g leukocyte activatio n.