IRRITANT AND PROTECTIVE ACTION OF UREA UREASE AMMONIA IN RAT GASTRIC-MUCOSA - DIFFERENT EFFECTS OF AMMONIA AND AMMONIUM ION

The effects of urea-urease-ammonia on the rat gastric mucosa were exam ined and compared with those of NH4OH and NH4Cl. The mucosal applicati on of urea with urease produced a reduction in potential difference (P D) in a dose-related manner for urea, and a significant drop was obser ved by >0.1% urea in the presence of 100 units urease. Such PD reducti on was also observed when the mucosa was exposed to either NH4OH (>0.0 3%) or NH4Cl (>1%); Delta PD (20 mV) caused by 0.3% NH4OH and 3% NH4Cl was equivalent to that induced by 0.5% urea + urease (100 units). The combined oral administration of urea (similar to 6%) and urease (100 units) did not induce any macroscopic damage in the gastric mucosa. NH 4Cl given orally had no or little effect on the mucosa at any dose lev els even at 10%, while NH4OH given orally caused hemorrhagic lesions i n the mucosa at the dose of >0.3%. In contrast, both urea + urease and NH4Cl given prior to HCl/ethanol protected the gastric mucosa against damage in a dose-related manner, and a significant effect was obtaine d by urea at >0.5% and by NH4Cl at >1%. NH4OH was also effective in re ducing the severity of HCl/ethanol-induced gastric lesions at lower do se (0.3%). The protective effect of urea + urease was attenuated signi ficantly by prior administration of indomethacin or coadministration o f hydroxyurea, while that of NH4Cl or NH4OH was mitigated by indometha cin. These results suggest that the urea-urease-ammonia system in the stomach may be beneficial in normal conditions; ammonia produced by th e hydrolysis of urea yields NH4OH and NH4Cl in the lumen, both of whic h act on the stomach as mild irritant, resulting in adaptive cytoprote ction mediated by endogeneous prostaglandins.