The major objective of this study was to elucidate the role of endogenous endothelin (ET)-1, a potent vasoconstrictor peptide, in the pathogenesis of ethanol (EtOH)-induced gastric mucosal injury. Two series of experiments were performed in anesthetized rats. First, we examined the time course of relationships among changes in ET-1 concentrations in 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 concentrations in the portal vein also increased after intragastric EtOH administration. ET-1 concentrations in gastric mucosal tissue and portal plasma increased significantly before gastric mucosal hemorrhagic damage occurred. Moreover, 30 min after EtOH administration there were significant correlations between gastric mucosal ET-1 concentrations and both area of gastric hemorrhagic damage as well as concentration of EtOH administered intragastrically. After intragastric EtOH administration, increase in gastric mucosal hemoglobin concentration and decrease in gastric mucosal hemoglobin oxygen saturation, estimated using reflectance spectrophotometry, occurred within 2.5 min and continued throughout the experiments. The time course of microcirculatory changes correlated closely with increases in gastric mucosal ET-1 and portal plasma ET-1 concentrations after intragastric EtOH administration. Gastric microcirculatory disturbances induced by EtOH were associated with significant decreases in gastric mucosal ATP content. Second, we examined whether pretreatment with anti-ET-1 antibody protected against EtOH-induced mucosal injury by improving mucosal microcirculation. Pretreatment with anti-ET-1 antibody microscopically and macroscopically reduced gastric mucosal hemorrhagic damage induced by EtOH and significantly reduced EtOH-induced gastric microcirculatory disturbances and decreases in gastric mucosal ATP.(ABSTRACT TRUNCATED AT 250 WORDS)