Isoproterenol-induced gastric mucosal protection from bile acid. Role of endogenous prostaglandins.
Topical isoproterenol is a potent protective agent against bile acid-induced gastric mucosal injury in hypotensive and normotensive rats. This study was undertaken to ascertain what role endogenous prostaglandins and gastric mucosal blood flow play in isoproterenol-induced protection. Accordingly, anesthetized, fasted rats were given the cyclooxygenase inhibitor, indomethacin (5 mg/kg subcutaneously), 30 min prior to topical pretreatment with 3 ml of intragastric saline, isoproterenol (3 microM), or 16,16-dimethyl prostaglandin E2 (3 microM) for 15 min. Gastric injury was induced with topical 5 mM acidified taurocholate and damage assessed by measuring net transmucosal ion fluxes, the appearance of DNA into the gastric lumen, and histology of the gastric epithelium. In a separate set of experiments, the effects of topical isoproterenol on gastric mucosal blood flow (laser Doppler flowmetry) and luminal PGE2 concentrations (125I radioimmunoassay) were examined. Pretreatment with topical isoproterenol or 16,16-dimethyl prostaglandin E2 significantly decreased bile acid-induced net luminal ion fluxes and DNA accumulation, suggesting mucosal protection. The protective effect of isoproterenol, but not 16,16-dimethyl prostaglandin E2, was negated by indomethacin (corroborated by histology). Further, isoproterenol did not significantly alter gastric mucosal blood flow, but did augment luminal PGE2 concentrations, an effect also abolished by indomethacin. Thus, isoproterenol appears to protect the gastric mucosa from the damaging effects of bile acid through a mechanism that requires the synthesis and release of cytoprotective endogenous prostaglandins.
Mercer
D W
DW
Reichle Research Laboratory, Department of Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA.
Merchant
N B
NB
Ritchie
W P
WP
Dempsey
D T
DT
D015064:16,16-Dimethylprostaglandin E2 / Q000032:analysis / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001647:Bile Acids and Salts / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects
D001647:Bile Acids and Salts; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D007545:Isoproterenol; D015064:16,16-Dimethylprostaglandin E2; D007213:Indomethacin