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

YM638 ylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid) is a novel leukotriene D-4 receptor antagonist. We investigated the in volvement of the leukotriene D-4 receptor blocking activity of YM638 i n the gastric mucosal protection of this drug in rats. YM638 significa ntly prevented gastric lesion formation induced by water-immersion res traint stress, indomethacin, absolute ethanol, 0.7 N HCl and the combi nation 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 sofalc one showed inhibitory effects on most of these gastric lesions, but th e 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 lesi on formation in cysteamine-administered rats. YM638 competitively anta gonized leukotriene D-4-induced contraction of the isolated stomach, w ith 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 p otential difference. In addition, oral YM638 significantly increased g astric mucosal blood flow and prevented ethanol-induced increase in ga stric vascular permeability. Endogenous prostaglandins, sulfhydryls an d nitric oxides were not involved in this inhibitory effect on absolut e ethanol-induced gastric lesion, YM638 did not react with the stable free radical 1,1-diphenyl-2-picrylhydrazyl in vitro, indicating that Y M638 does not have potential as free radical scavenger. These results suggest that the preventive effect of YM638 on gastric lesions is attr ibutable not only to its leukotriene D-4 receptor blocking activity bu t also to the activation of gastric mucosal defensive mechanisms such as mucosal blood flow and vascular permeability.