Comparison of prostaglandin and cimetidine in protection of isolated gastric glands against indomethacin injury.
Prostaglandins can protect the in vivo gastric mucosa against necrosis produced by a variety noxious agents. Cimetidine has also been shown to have protective properties in humans and in some models of experimental injury. Whether prostaglandins or cimetidine may protect gastric mucosal cells directly in the absence of systemic factors remains controversial. In the present study, the potential protective actions of prostaglandin and cimetidine against indomethacin injury were assessed in isolated rat gastric glands. Gastric glands were pre-incubated in oxygenated medium with either placebo, 16,16 dimethyl prostaglandin E(2) (dm PGE(2)) or cimetidine and incubated at 37 degrees C in medium containing 0.5 mg/ml of indomethacin for 2, 4 and 6 hrs. Cell injury and protection was assessed by the Fast Green exclusion test (viability test), leakage of lactate dehydrogenase (LDH) into the medium, and by scanning and transmission electron microscopy. In addition, the generation of PGE(2) by the gland cells was determined using RIA assay. Indomethacin by itself significantly reduced the viability of gastric glands, increased LDH release into the medium and produced prominent ultrastructural damage. In contrast to cimetidine, co-incubation of gastric glands with dm PGE(2) added to indomethacin, significantly reduced indomethacin-induced injury, increased the number of viable cells, reduced LDH leakage and diminished the extent of ultrastructural damage. The dose of indomethacin (5 microg/ml) which significantly inhibited the generation of PGE(2) (up to 90% inhibition) had no effect on cell viability nor LDH release. We conclude that 1) exogenous PGE2 exerts a potent protective activity in vitro which is independent on neural, vascular and hormonal factors; 2) inhibition of endogenous PGs may not the primary mechanism in the deleterious action of indomethacin against damage to gastric glandular cells and 3) indomethacin can exert a direct cytotoxic effect on the mucosal cells in gastric glands.
Brzozowski
T
T
Gastroenterology Section, VA Medical Center, Long Beach, University of California, Irvine, CA, USA.
Tarnawski
A
A
Hollander
D
D
Sekhon
S
S
Krause
W J
WJ
Gergely
H
H
D015064:16,16-Dimethylprostaglandin E2 / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000648:ultrastructure; D066298:In Vitro Techniques; D007213:Indomethacin / Q000008:administration & dosage / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D002927:Cimetidine; D007770:L-Lactate Dehydrogenase; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D007213:Indomethacin