Effects of submucosal administration of endothelin-3 on rat gastric mucosa.

The present study was carried out to examine the effects of submucosal administration of endothelin on gastric mucosal integrity in rats. Injection of endothelin-3 into the submucosal space of the stomach induced gastric mucosal damage dose-dependently and site-specifically. The gastric injury was localized only at the injected site and the mucosal damage was associated with hemorrhage. Macroscopic and microscopic examinations revealed that mucosal injury had developed 15 min after endothelin application. Submucosal injection of either adrenalin or noradrenalin also induced gastric mucosal damage, but produced multiple gastric mucosal lesions; i.e., the macroscopic appearance of endothelin-induced gastric lesions differed from those produced by catecholamines. The endothelin-induced mucosal lesions were significantly inhibited by pretreatment with either atropine, pirenzepine, or ranitidine; or by vagotomy. In addition, NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, significantly enhanced the formation of gastric mucosal lesions. Thus, it appears that nitric oxide synthesis, possibly induced by endothelin, may play a role as an antiulcer mechanism in endothelin-induced gastric mucosal damage. Vagotomy and anti-cholinergic or anti-secretory treatment significantly attenuated the severity of the mucosal lesions, suggesting that vagal cholinergic pathways and acid secretion may influence the development of the gastric mucosal damage induced by endothelin-3. These results suggest that endothelin-3 may play an important role in the development of gastric ulceration; the submucosal application of endothelin-3 in the gastric mucosa may be a useful experimental model for investigating acute gastric mucosal ulceration.