Dexamethasone-induced gastric mucosal damage in the rat: possible role of platelet-activating factor.
1. The aim of the present experiments was to study the possible role of platelet-activating factor (PAF) in mediating gastric mucosal damage induced by dexamethasone in the rat by measuring gastric tissue levels of PAF during dexamethasone-treatment and by investigating the effects of specific PAF receptor antagonists on dexamethasone-induced gastric lesions. PAF-like bioactivity extracted from the rat glandular stomach was determined by a platelet aggregation assay. 2. Dexamethasone treatment (0.4-4 mg kg-1, daily for 1-6 days) produced time- and dose-dependent damage to the glandular mucosa of the stomach as characterized by extensive, uniform hyperaemia with multiple, focal petechiae and erosions. 3. These changes were accompanied by a time-, and dose-dependent increase in PAF content of the glandular stomach. Control rat stomach contained small amounts of PAF (0.14 +/- 0.04 ng per g wet weight), which increased over 40 fold in response to dexamethasone treatment (4 mg kg-1, daily for 6 consecutive days). The presence of PAF-like material in the stomach extract was ascertained by thin-layer chromatography, high performance liquid chromatography and by alkaline hydrolysis. 4. Pretreatment of the animals with one or other of the structurally unrelated PAF receptor antagonists, BN 52021 (10 mg kg-1, i.p.) or BN 50727 (1 mg kg-1, i.p.) significantly reduced dexamethasone-induced gastric damage. In these animals neither petechiae nor erosions were observed. 5. These observations suggest that PAF is a likely endogenous mediator of glucocorticoid-induced gastric mucosal damage in the rat.
Filep
J G
JG
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, P.Q., Canada.
Hermán
F
F
Földes-Filep
E
E
Schneider
F
F
Braquet
P
P
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D003907:Dexamethasone / Q000633:toxicity*; D004224:Diterpenes; D005753:Gastric Mucosa / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled; D058924:Thienopyridines; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D058924:Thienopyridines; D014230:Triazoles; C039351:platelet activating factor receptor; D003907:Dexamethasone; C045856:ginkgolide B; C067429:Setipafant