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 gas tric damage but the mechanism of this damage has not been fully explai ned. This study was designed the determine whether topical application with NH4OH at low concentration or the generation of the NH4OH in gas tric lumen by the hydrolysis of urea in the presence of urease can ind uce adaptive cytoprotection. Single insult of NH4OH alone in various c oncentrations (15-500 mM) caused the mucosal damage starting at 30 mM and reaching at 250 mM the value similar to that obtained with 100% et hanol and being accompanied by the fall in gastric blood now 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 microscop ic damage of surface epithelium, but then insulted by a high concentra tion (250 mM) of NH4OH, the extent of mucosal damage was greatly atten uated as compared to that caused by NH4OH alone. This ''adaptive'' cyt oprotection, 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 deac tivation of sensory nerves. The combined topical pretreatment with ure a (2%) and urease (100 U) to generate NH4OH in the stomach, also signi ficantly reduced the severity of gastric lesions induced by 100% ethan ol and this was also accompanied by a significant rise in the gastric blood flow. The protective and hyperemic effects of urea and urease we re significantly attenuated by the pretreatment with indomethacin or s uppression of NO-synthase by L-NAME. The functional ablation of sensor y nerves by the pretreatment with capsaicin also reversed, in part, th e protective effect of the combination of urea plus urease and abolish ed completely the mucosal hyperemia accompanying this protection. We c onclude that 1) NH4OH alone at higher concentrations damages the gastr ic mucosa but when applied at lower concentration corresponding to tha t in the stomach of Hp-infected patients, or generated by the urea in the presence of urease, NH4OH acts like ''mild irritant'' to induce ad aptive cytoprotection, 2) this adaptive cytoprotection is mediated, in part, by endogenous PG, sensory nerves and arginine-NO-dependent path way.