ROLE OF ENDOGENOUS ENDOTHELIN IN PATHOGENESIS OF ETHANOL-INDUCED GASTRIC-MUCOSAL INJURY IN RATS

The major objective of this study was to elucidate the role of endogen ous endothelin (ET)-1, a potent vasoconstrictor peptide, in the pathog enesis of ethanol (EtOH)-induced gastric mucosal injury. Two series of experiments were performed in anesthetized rats. First, we examined t he time course of relationships among changes in ET-1 concentrations i n gastric mucosal and portal plasma, gastric mucosal hemodynamics, and mucosal damage produced by EtOH. Intragastric EtOH stimulated release of endogenous ET-1 in gastric mucosal tissue. Plasma ET-1 concentrati ons in the portal vein also increased after intragastric EtOH administ ration. ET-1 concentrations in gastric mucosal tissue and portal plasm a increased significantly before gastric mucosal hemorrhagic damage oc curred. Moreover, 30 min after EtOH administration there were signific ant correlations between gastric mucosal ET-1 concentrations and both area of gastric hemorrhagic damage as well as concentration of EtOH ad ministered intragastrically. After intragastric EtOH administration, i ncrease in gastric mucosal hemoglobin concentration and decrease in ga stric mucosal hemoglobin oxygen saturation, estimated using reflectanc e spectrophotometry, occurred within 2.5 min and continued throughout the experiments. The time course of microcirculatory changes correlate d closely with increases in gastric mucosal ET-1 and portal plasma ET- 1 concentrations after intragastric EtOH administration. Gastric micro circulatory disturbances induced by EtOH were associated with signific ant decreases in gastric mucosal ATP content. Second, we examined whet her pretreatment with anti-ET-1 antibody protected against EtOH-induce d mucosal injury by improving mucosal microcirculation. Pretreatment w ith anti-ET-1 antibody microscopically and macroscopically reduced gas tric mucosal hemorrhagic damage induced by EtOH and significantly redu ced EtOH-induced gastric microcirculatory disturbances and decreases i n gastric mucosal ATP. We concluded that changes in endogenous ET-1 in duced by EtOH play a critical role in pathogenesis of EtOH-induced gas tric mucosal injury through impairment of mucosal microcirculation.