Effect of a novel histamine H2 receptor antagonist, IT-066, on acute gastric injury induced by ischemia-reperfusion in rats, and its antioxidative properties.

The effect of a novel histamine H2 receptor antagonist IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-++ +butenylamino]- 3-cyclobutene-1,2-dione hydrochloride), on acute gastric mucosal injury induced by ischemia-reperfusion was investigated from the standpoint of oxygen radical-mediated lipid peroxidation in rats. Ischemia-reperfusion injury was produced in the rat stomach by applying a small vascular clamp to the celiac artery for 30 min and subsequent removal of the clamp for 60 min. The decrease in gastric mucosal blood flow was not influenced by treatment with IT-066. The antiulcer activity of IT-066 was demonstrated in this injury after intragastric ingestion as well as after intravenous injection. IT-066 significantly inhibited this injury in the presence of exogenous HCl. The mucosal protection by IT-066 was not reversed by pretreatment with indomethacin or nitric oxide synthase inhibitor. The increase in lipid peroxides in the gastric mucosa after ischemia-reperfusion was significantly inhibited by the intragastric treatment with IT-066 at doses of 1.0 and 3.0 mg/kg. The total area of erosions closely paralleled the accumulation of lipid peroxide with a significant correlation. A spin trapping method using 5,5-dimethyl-1-pyrroline-N-oxide showed that IT-066 scavenged superoxide radical and hydroxyl radical generated by the hypoxanthine-xanthine oxidase system and the hydrogen peroxide-ferrous iron system, respectively. IT-066 also significantly inhibited the in vitro increase of lipid peroxide in the gastric mucosal homogenates induced by a free radical initiator. These results suggest that the protective effect of IT-066 against ischemia/reperfusion-induced gastric mucosal injury may result in part from its antioxidative properties.