Gastric mucosal damage and adaptive protection by ammonia and ammonium ion in rats.
Helicobacter pylori (Hp) is considered as the major pathogen in Hp-associated gastritis but the mechanism of its action has not been fully explained. We investigated both the damaging and protective effects of intragastric (i.g.) application of ammonia (NH4OH) and ammonium ion (NH4Cl), the major products of Hp-derived urease, on the rat stomach with intact and capsaicin-deactivated sensory nerves or suppressed prostaglandin (PG) and nitric oxide (NO) synthesis. NH4OH given i.g. resulted in a concentration-dependent mucosal damage starting at 30 mM and reaching maximum at 250 mM (pH 11), the extent of damage being similar to that obtained with 100% ethanol. NaOH solution (1 mM) at pH 11 given i.g. did not affect mucosal integrity. The damage caused by NH4OH was accompanied by the fall in gastric blood flow (GBF) reaching at 250 mM NH4OH about 30% of the vehicle control value. The NH4OH-induced gastric damage was augmented by capsaicin-induced deactivation of sensory nerves, the suppression of nitric oxide (NO) synthase with L-NAME or the decrease of i.g. acidity by ranitidine. The pretreatment with scavengers of reactive oxidants significantly reduced the area of NH4OH-induced gastric lesions. When the mucosa was first exposed to a low 15-mM concentration of NH4OH and then insulted with large 250 mM NH4OH or with 100% ethanol, the lesion area was markedly reduced as compared to that obtained with 250 mM NH4OH or 100% ethanol alone. This adaptive protection by 'mild' concentration of NH4OH against strong irritants (250 mM NH4OH or 100% ethanol) was reversed, in part, by pretreatment with L-NAME and indomethacin. NH4Cl (60-500 mM) given i.g. alone failed to affect the mucosal integrity but when applied before 100% ethanol it produced a concentration-dependent fall in the mucosal damage by these irritants. We conclude that; (1) ammonia at higher concentrations damages the gastric mucosa, while ammonium ion exerts the protective activity; (2) the ammonia-induced gastric damage may involve the formation of reactive oxidants; (3) ammonia at lower concentration acts like a mild irritant via the activation of sensory nerves, NO-arginine pathway and PG.
Konturek
S J
SJ
Institute of Physiology and Pathomorphology, Jagiellonian University School of Medicine, Krakow, Poland.
Konturek
P C
PC
Brzozowski
T
T
Stachura
J
J
Zembala
M
M
D000222:Adaptation, Physiological; D000493:Allopurinol / Q000494:pharmacology; D000641:Ammonia / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D003714:Denervation; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005756:Gastritis / Q000209:etiology / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism; D008163:Luminescent Measurements; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005609:Free Radicals; D000643:Ammonium Chloride; D000493:Allopurinol; D000641:Ammonia; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D015232:Dinoprostone; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester; D004121:Dimethyl Sulfoxide