Protective Effect of a Vasopressin-1 Selective Antagonist, OPC-21268, Against Ethanol-Induced Damage of The rat Gastric Wall

Since endogenous vasopressin has been reportedto be an aggressor in the gastric mucosa and avasoconstrictor in the gastric circulation, weinvestigated the gastric cytoprotective effects ofOPC-21268, a newly developed, nonpeptide, orally activevasopressin-1 receptor antagonist, on ethanol-inducedgastric injury in rats. The rats were treated withOPC-21268 or placebo 2 hr before ethanol administration, and the gastric mucosa was evaluatedmacroscopically for ulcer damage, and histologically forgastric mucosal injury. Gastric mucosal blood flow,erythrocyte volume, and erythrocyte velocity were alsomeasured in groups given saline, ethanol alone, andethanol after OPC-21268. To investigate The role ofsystemic or locally secreted vasopressin, we measuredplasma and tissue (gastric mucosa) vasopressinconcentrations after ethanol or vehicle administration.Prophylactic OPC-21268 treatment improved the gastriculcer score in a dose-dependent manner, and histologicalexamination demonstrated that the drug significantly ameliorated the gastric injury induced byethanol. The hemodynamic values obtained in theOPC-21268-treated and ethanol-treated group weResimilarto those in the saline control group, but values weresignificantly (P < 0.05) higher for gastric mucosal bloodflow and erythrocyte velocity and lower for erythrocytevolume compared to the group given ethanol alone. Plasmavasopressin concentrations were not significantly different in the control group and at 15, 30,and 60 min after administration of ethanol. However,ethanol administration caused a threefold increase ingastric tissue vasopressin level (P < 0.05) compared to the control group. These results suggestedthat OPC-21268 relieved congestive hyperemia in thegastric mucosa and ameliorated the mucosal injury causedby ethanol, probably as a result of inhibition of vasopressin-mediated actions on the stomach.The vasopressin involved was probably generated locallyin the gastric mucosa after ethanoladministration.