GASTRIC-MUCOSAL PROTECTION BY YM638, A NOVEL LEUKOTRIENE D-4 RECEPTOR ANTAGONIST, IN RATS

YM638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid) is a novel leukotriene D-4 receptor antagonist. We investigated the involvement of the leukotriene D-4 receptor blocking activity of YM638 in the gastric mucosal protection of this drug in rats. YM638 significantly prevented gastric lesion formation induced by water-immersion restraint stress, indomethacin, absolute ethanol, 0.7 N HCl and the combination of 0.2 N HCl and hemorrhagic shock, with ED(50) values of 26.4, 4.1, 4.7, 35.4 and 8.0 mg/kg p.o., respectively. Cetraxate and sofalcone showed inhibitory effects on most of these gastric lesions, but the inhibitory effects of these compounds were much weaker than those of YM638. In contrast, YM638 had no effect on gastric acid secretion and gastric lesion formation in pylorus-ligated rats, or on duodenal lesion formation in cysteamine-administered rats. YM638 competitively antagonized leukotriene D-4-induced contraction of the isolated stomach, with a pA(2) value of 7.63 +/- 0.18. In anesthetized rats, intravenous YM638 inhibited leukotriene D-4-induced aggravation of gastric lesions caused by HCl, and leukotriene D-4 and HCl-induced reduction of the potential difference. In addition, oral YM638 significantly increased gastric mucosal blood flow and prevented ethanol-induced increase in gastric vascular permeability. Endogenous prostaglandins, sulfhydryls and nitric oxides were not involved in this inhibitory effect on absolute ethanol-induced gastric lesion, YM638 did not react with the stable free radical 1,1-diphenyl-2-picrylhydrazyl in vitro, indicating that YM638 does not have potential as free radical scavenger. These results suggest that the preventive effect of YM638 on gastric lesions is attributable not only to its leukotriene D-4 receptor blocking activity but also to the activation of gastric mucosal defensive mechanisms such as mucosal blood flow and vascular permeability.