Omeprazole fails to suppress up-regulation of gastric mucosal endothelin-converting enzyme-1 by Helicobacter pylori lipopolysaccharide.
BACKGROUND
Endothelin-1, a key mediator of inflammatory processes, is produced from its biologically inactive precursor, big ET- by the action of endothelin converting enzyme-1(ECE-1). In this study, we applied the animal model of H. pylori lipopolysaccharide-induced gastritis to assess the effect of three different types of antiulcer agents on the gastric mucosal expression of ECE-1 activity.


METHODS
Rats, pretreated twice daily for 3 days with proton pump inhibitor, omeprazole at 40 mg/kg, gastroprotective agent, sulglycotide at 200 mg/kg, H2-receptor antagonist, ebrotidine at 100 mg/kg or the vehicle, were subjected to intragastric application of H. pylori lipopolysaccharide at 50 microg/animal, and after 2, and 4 additional days on the drug or vehicle regimen their mucosal tissue used for histologic and biochemical assessment.


RESULTS
In the absence of antiulcer agents, H. pylori lipopolysaccharide elicited a pattern of mucosal inflammatory responses resembling that of acute gastritis which reached a maximum by the 4th day and were accompanied by a 4.1-fold increase in the mucosal expression of ECE-1 activity and an 8.8-fold enhancement in TNF-alpha. Treatment with sulglycotide led to a 56.7% reduction in the extent of mucosal inflammatory involvement, the mucosal expression of ECE-1 activity fell by a 40.5% and the level of TNF-alpha declined by a 69%. Ebrotidine produced a 50.9% decrease in the extent of mucosal inflammatory involvement, a 33.6% decrease in the expression of ECE-1 activity and a 64.1% decline in TNF-alpha, whereas omeprazole elicited a 37.6% reduction in the extent of mucosal inflammatory involvement and a 29.5% decrease in TNF-alpha, but had no effect on the lipoploysaccharide-induced increase in the mucosal expression of ECE-1 activity.


CONCLUSIONS
The findings implicate up-regulation of ECE-1 in triggering the induction of TNF-alpha and propagation of gastric mucosal inflammatory responses to H. pylori. We also show that omeprazole, in contrast to sulglycotide and ebrotidine, fails to counter the enhancement in the mucosal expression of ECE-1 caused by H. pylori- lipopolysaccharide.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA. slomiabr@umdnj.edu
Piotrowski
J
J
Slomiany
A
A
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005756:Gastritis / Q000139:chemically induced / Q000378:metabolism*; D016480:Helicobacter pylori; D008070:Lipopolysaccharides; D008666:Metalloendopeptidases; D009853:Omeprazole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
D000897:Anti-Ulcer Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D009853:Omeprazole