Antithrombin prevents stress-induced gastric mucosal injury by increasing the gastric prostacyclin level in rats

The interaction of antithrombin (AT) with cell surface glycosaminoglycans h as been shown to promote the endothelial release of prostacyclin (PGI(2)). Because PGI(2) plays an important role in gastric cytoprotection, we examin ed whether AT prevents water-immersion restraint stress (WIR)-induced gastr ic mucosal injury in rats by promoting the endothelial release of PGI(2). I ntravenous administration of AT (250 U/kg) prevented WIR-induced gastric mu cosal injury in rats. Gastric levels of 6-keto-prostaglandin F-1 alpha, a s table metabolite of PGI(2), were significantly increased 0.5 and 1 hour aft er WIR in animals administered AT compared with control animals. The effect s induced by AT in animals subjected to WIR were not observed in animals th at were administered DEGR-Xa, a selective inhibitor of thrombin generation, or Trp(49)-modified AT, which lacks affinity for heparin. In animals subje cted to WIR gastric mucosal blood flow was significantly reduced with a sim ultaneous increase in gastric mucosal microvascular permeability. Activated neutrophils have been implicated in the WIR-induced reduction of gastric m ucosal blood flow by increasing microvascular permeability. Although AT pre vented the reduction of gastric mucosal blood flow and the increase in gast ric mucosal microvascular permeability in animals subjected to WIR, neither DEGR-Xa nor Trp49-modified AT had any effect. Pretreatment of animals with indomethacin completely inhibited the protective effects of AT against WIR -induced gastric mucosal injury and the AT-induced increase in post-WIR gas tric 6-keto-prostaglandin F-1 alpha levels. These results strongly suggest that AT prevents stress-induced gastric mucosal injury by increasing the ga stric levels of PGI(2) through the interaction of AT with cell-surface glyc osaminoglycans, thus increasing gastric mucosal blood flow both by vasodila tion and by inhibiting neutrophil activation.