UREA UREASE SYSTEM IN CYTOPROTECTION AGAINST ACUTE MUCOSAL DAMAGE

Ammonia (NH4OH) generated by urease from urea in the Helicobacter pylo ri (Hp)-infected stomach is considered as a one of the major pathogeni c factors in the Hp-associated gastritis but the mechanism of the dele terious action of NH4OH on gastric mucosa has not been fully explained . In this study, the gastric mucosa was exposed to topical NH4OH in va rious concentrations (15-250 mM) (series A) and to NH4OH in a small co ncentration followed by a high concentration (250 mM) of NH4OH (series B) or to the combination of urea and urease to generate NH4OH (series C) followed by 250 mM NH4OH in order to determine the ''mild irritant '' and protective properties of this substance on the mucosa. Administ ration of NH4OH alone resulted in a concentration-dependent mucosal da mage starting at 30 mM and reaching at 250 mM the degree similar to th at obtained with 100% ethanol. The acute mucosal damage by NH4OH was a ccompanied by the fall in gastric blood now reaching nadir at 250 mM N H4OH of about 30% of the normal value. When the mucosa was first expos ed to low concentration of NH4OH (15 mM) and then insulted with its la rger concentration (250 mM), the lesion area was markedly reduced as c ompared to that obtained with 250 mM NH4OH alone and this effect was a ccompanied by a significant rise in the GBF. This adaptive cytoprotect ion by 15 mM NH4OH was reversed, in part, by the pretreatment with ind omethacin to inhibit prostaglandins (PG) or L-NAME to suppress nitric oxide (NO) formation or after capsaicin-induced denervation of sensory nerves. Blockade of endogenous sulfhydryls (SH) by N-ethylmaleimide ( NEM) eliminated this adaptive cytoprotection but the suppression of or nithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, b y alpha-difluoro methylornithine (DFMO) failed to influence the protec tion and accompanying hyperemia afforded by NH4OH in low concentration . The combination of urea (2%) and urease (100 U), which raised the ga stric luminal NH4OH concentration by about 5-folds, also reduced signi ficantly the lesions provoked by 250 mM NH4OH. This protection and acc ompanying hyperemia induced was significantly attenuated by the pretre atment with indomethacin or hydroxyurea, a potent urease inhibitor. Hy droxyurea abolished completely the rise in luminal NH4OH produced by t he combined treatment of urea plus urease. We conclude that 1) NH4OH i n high concentration damages the gastric mucosa but when applied at lo wer concentration or generated in the stomach by urea-urease system, a cts as local mild irritant to induce adaptive cytoprotection that prob ably involves PG, sensory nerves and arginine-NO-pathaway.