BOSENTAN, A NOVEL SYNTHETIC MIXED-TYPE ENDOTHELIN RECEPTOR ANTAGONIST, ATTENUATES ACUTE GASTRIC-MUCOSAL LESIONS INDUCED BY INDOMETHACIN ANDHCL IN THE RAT - ROLE OF ENDOGENOUS ENDOTHELIN-1

Endothelin-1 has been reported to be responsible for gastric mucosal d amage in various experimental models. We evaluated the role of endogen ous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2 N HCl intragastrically. G astric mucosal damage, gastric endogenous endothelin-1, and gastric mu cosal hemodynamics were measured. The effects of bosentan, a mixed end othelin receptor antagonist, on gastric mucosal integrity and hemodyna mics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20 min, gastric mucosal blood flow began to decrease signi ficantly at 25 min, and gastric damage occupied 52.2% of the total gla ndular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosentan (5, 10, 30, and 60 mg/kg) significantly at tenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the init ial decrease of blood flow and, even at 135 min, improved blood flow a nd hemoglobin oxygen saturation significantly. We suggest that indomet hacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. End ogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.