A new model of gastric bleeding induced in rats by aspirin plus clopidogrel under stimulation of acid secretion. Prophylactic effects of antiulcer drugs.

We set up a new model of gastric bleeding induced by the luminal perfusion of aspirin (ASA) in rats pretreated with clopidogrel under conditions where acid secretion is stimulated, and examined the effect of antiulcer drugs on the bleeding. Under urethane anesthesia, acid secretion was stimulated by i.v. infusion of histamine (8 mg/kg/h), and two catheters were inserted into the stomach, one from the esophagus and another from the duodenum. The stomach was perfused with 25 mM ASA at a rate of 0.1 ml/min using an infusion pump, and gastric bleeding was measured as hemoglobin concentration in the perfusate collected every 15 min. Clopidogrel (30 mg/kg) was given orally 24 h before the perfusion. Various antiulcer drugs were given intraduodenally 30 min before the ASA treatment. Perfusion of the stomach with ASA provoked little gastric bleeding or damage even when acid secretion was stimulated. Pretreatment with clopidogrel significantly increased the bleeding and damage caused by ASA. The bleeding and lesions produced by ASA plus clopidogrel were significantly prevented by pretreatment with famotidine and omeprazole. Mucosal protective drugs such as rebamipide, irsogladine and teprenone also prevented gastric bleeding response to ASA/clopidogrel under conditions of acid secretion, although the effect was less pronounced than that of the antisecretory drugs. We conclude that clopidogrel increases gastric bleeding induced by ASA when acid secretion is stimulated. Both antisecretory and mucosal protective drugs are effective in reducing gastric bleeding under such conditions. This model is useful for the screening of drugs that protect against gastric bleeding.