title: Role of endothelin-converting enzyme-1 in the suppression of constitutive nitric oxide synthase in rat gastric mucosal injury by indomethacin.
abstract: BACKGROUND
  Disturbances in nitric oxide generation and the release of a vasoactive peptide, endothelin-1 (ET-1), are well recognized early events in pathogenesis of NSAID-induced gastropathy. In this study using phosphoramidon, a potent inhibitor of endothelin-converting enzyme-1 (ECE-1), we investigated the influence of ET-1 on the expression of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2) during gastric mucosal injury caused by indomethacin.
  
  
  METHODS
  The experiments were conducted with groups of rats pretreated intragastrically with phosphoramidon (10, 20, and 40 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 4 h later and their mucosal tissue subjected to macroscopic damage assessment and biochemical measurements.
  
  
  RESULTS
  In the absence of phosphoramidon, indomethacin caused extensive multiple hemorrhagic lesions of glandular mucosa, accompanied by a 29.9-fold increase in epithelial cell apoptosis, a 13.3-fold increase in NOS-2 and a 5.5-fold decline in the activity of cNOS, while the mucosal expression of ECE-1 activity increased 4-fold and the level of ET-1 showed a 4.8-fold increase. Pretreatment with phosphoramidon produced dose-dependent reduction in the extent of mucosal damage caused by indomethacin, accompanied by a significant recovery in the expression of cNOS, and a marked decline in ECE-1, epithelial cell apoptosis and the mucosal level of ET-1. Phosphoramidon, however, had no effect on the indomethacin-induced increase in the mucosal expression of NOS-2.
  
  
  CONCLUSIONS
  The results suggest that suppression of ET-1 generation counters the mucosal drop in cNOS and the extent of gastric mucosal damage caused by indomethacin, but has no effect on the mucosal responses associated with up-regulation of NOS-2 expression. Hence, only cNOS plays a role in the protection of gastric mucosa against damage by NSAIDs.
authors.affiliation: Research Center, University of Medicine and Dentistry of New Jersey, Newark, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Slomiany
authors.forename: A
authors.initials: A
authors.lastname: Slomiany
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072396:Endothelin-Converting Enzymes; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006020:Glycopeptides / Q000494:pharmacology; D007213:Indomethacin / Q000633:toxicity*; D008666:Metalloendopeptidases; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006020:Glycopeptides; D011480:Protease Inhibitors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon; D007213:Indomethacin