Since endogenous
vasopressin has been reported to be an aggressor in the gastric mucosa and a
vasoconstrictor in the gastric circulation, we investigated the gastric cytoprotective effects of
OPC-21268, a newly developed, nonpeptide, orally active vasopressin-1 receptor antagonist, on
ethanol-induced gastric injury in rats. The rats were treated with
OPC-21268 or placebo 2 hr before
ethanol administration, and the gastric mucosa was evaluated macroscopically for
ulcer damage, and histologically for gastric mucosal injury. Gastric mucosal blood flow, erythrocyte volume, and erythrocyte velocity were also measured in groups given saline,
ethanol alone, and
ethanol after
OPC-21268. To investigate the role of systemic or locally secreted
vasopressin, we measured plasma and tissue (gastric mucosa)
vasopressin concentrations after
ethanol or vehicle administration. Prophylactic
OPC-21268 treatment improved the
gastric ulcer score in a dose-dependent manner, and histological examination demonstrated that the
drug significantly ameliorated the gastric injury induced by
ethanol. The hemodynamic values obtained in the OPC-21268-treated and
ethanol-treated group were similar to those in the saline control group, but values were significantly (P < 0.05) higher for gastric mucosal blood flow and erythrocyte velocity and lower for erythrocyte volume compared to the group given
ethanol alone. Plasma
vasopressin 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 in gastric tissue
vasopressin level (P < 0.05) compared to the control group. These results suggested that
OPC-21268 relieved congestive
hyperemia in the gastric mucosa and ameliorated the mucosal injury caused by
ethanol, probably as a result of inhibition of
vasopressin-mediated actions on the stomach. The
vasopressin involved was probably generated locally in the gastric mucosa after
ethanol administration.