Adaptive cytoprotection by ammonia and urea-urease system in the rat gastric mucosa

Urease and ammonia (NH4OH) have been proposed to be play a major role in the pathogenesis of the the Helicobacter pylori (Hp)-associated gastric damage but the mechanism of this damage has not been fully explained. This study was designed the determine whether topical application with NH4OH at low concentration or the generation of the NH4OH in gastric lumen by the hydrolysis of urea in the presence of urease can induce adaptive cytoprotection. Single insult of NH4OH alone in various concentrations (15-500 mM) caused the mucosal damage starting at 30 mM and reaching at 250 mM the value similar to that obtained with 100% ethanol and being accompanied by the fall in gastric blood flow to about 30% of the normal value. When the mucosa was first exposed to the low concentration (15 mM) of NH4OH, causing by itself only small microscopic damage of surface epithelium, but then insulted by a high concentration (250 mM) of NH4OH, the extent of mucosal damage was greatly attenuated as compared to that caused by NH4OH alone. This "adaptive" cytoprotection, accompanied by the rise in the GBF, was reversed in part, after the pretreatment with indomethacin to inhibit PG-cyclooxygenase, with L-NAME to suppress NO-synthase or with capsaicin to induce deactivation of sensory nerves. The combined topical pretreatment with urea (2%) and urease (100 U) to generate NH4OH in the stomach, also significantly reduced the severity of gastric lesions induced by 100% ethanol and this was also accompanied by a significant rise in the gastric blood flow. The protective and hyperemic effects of urea and urease were significantly attenuated by the pretreatment with indomethacin or suppression of NO-synthase by L-NAME. The functional ablation of sensory nerves by the pretreatment with capsaicin also reversed, in part, the protective effect of the combination of urea plus urease and abolished completely the mucosal hyperemia accompanying this protection. We conclude that 1) NH4OH alone at higher concentrations damages the gastric mucosa but when applied at lower concentration corresponding to that in the stomach of Hp-infected patients, or generated by the urea in the presence of urease, NH4OH acts like "mild irritant" to induce adaptive cytoprotection, 2) this adaptive cytoprotection is mediated, in part, by endogenous PG, sensory nerves and arginine-NO-dependent pathway.