We set up two models of gastric bleeding in rats using low-dose aspirin (ASA) and the antiplatelet drug clopidogrel, a P2Y12
receptor antagonist, and examined the effect of antiulcer drugs on gastric bleeding and ulcerogenic responses under such conditions. Under
urethane anesthesia, two catheters were inserted into the rat stomach, one from the esophagus and another through the pylorus via an
incision in the duodenum. In the first model, the stomach was perfused with 25 mM ASA dissolved in 50 mM HCl using an infusion
pump, and gastric bleeding was measured as the hemoglobin concentration in perfusate collected every 15 min. In the second model, the
stomach was perfused with ASA under stimulation of acid secretion by a continuous i.v. infusion of histamine (8 mg/kg/hr). Clopidogrel
(30 mg/kg) was given p.o. 24 h before the ASA perfusion, while antiulcer drugs were given i.d. or i.v. 30 min before. Perfusion of the
stomach with acidified ASA or ASA under histamine-stimulated acid secretion caused minimal bleeding in the stomach with few lesions.
The ulcerogenic and bleeding responses to ASA under these conditions were markedly aggravated by pretreatment with clopidogrel,
which by itself provoked neither bleeding nor damage. Antiulcer drugs, such as prostaglandin E2, irsogladine, rebamipide and teprenone,
reduced the severity of gastric bleeding and damage in response to ASA plus clopidogrel in the presence of both exogenous and endogenous
acid. In contrast, antisecretory drugs such as a proton pump inhibitor and histamine H2 receptor antagonists markedly suppressed the
gastric bleeding and lesion responses to ASA plus clopidogrel under histamine-stimulated acid secretion, but had no effect on the responses
to acidified ASA plus clopidogrel. These results suggest that clopidogrel increases gastric bleeding induced by ASA and that
antiulcer drugs are useful for preventing gastric bleeding caused by the dual antiplatelet therapy.