Influence of platelet activating factor antagonists on the protamine sulphate stimulated release of histamine from peritoneal mast cells of rats in vitro.
The phospholipase (PL)A2 inhibitor p-bromophenacyl bromide (p-BPB), the antagonists of the platelet activating factor (PAF) 3-(4-(2-chlorophenyl)-9-methyl-6H-thieno(3,2-f)-(1,2,4)triazolo(4, 3-a)(1,4)diazepine-2-yl)-1-(4-morpholinyl)-1-propanone (a thieno-triazolo-diazepine, WEB 2086) and terpene-ginkgolide B and the antihistamine with PAF antagonistic qualities 4,9-dihydro-4-(1-methyl-4-piperidinylidene)-10H-benzo[2,5]cyclo hep ta[1,2-b]thiophen-10-one (ketotifen) inhibit in the order p-BPB greater than terpene-ginkgolide B greater than ketotifen greater than WEB 2086 with decreasing activity the protamine sulphate activated histamine release from peritoneal rat mast cells (pRMC) in vitro. All compounds also inhibit the PAF induced aggregation of human platelets. The order of inhibition of the histamine release by these compounds does not agree with the order of their inhibitory activity on PAF induced aggregation of human platelets, indicating that the inhibition of the mast cell degranulation caused by PAF antagonists does not occur via PAF receptors. A generally membrane stabilizing quality of terpene-ginkgolide B and WEB 2086 may be ruled out as the cause of degranulation inhibition because none of the compounds suppresses the cytotoxic, triton X-100 induced release of histamine from pRMC. The mechanism of mast cell degranulation inhibition by PAF antagonists is unclear. An inhibition of PLA2 and/or inhibition of the Ca(2+)-activation are suggested.
Lohde
C
C
Pharmakologische Forschungsgesellschaft Biopharm GmbH, Berlin, Fed. Rep. of Germany.
Bahr
T
T
Labes
D
D
Grupe
R
R
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004224:Diterpenes; D046934:Ginkgolides; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007665:Ketotifen / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D010529:Peritoneal Cavity / Q000166:cytology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011479:Protamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology
D000098:Acetophenones; D001381:Azepines; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011479:Protamines; D014230:Triazoles; C052518:WEB 2086; C045856:ginkgolide B; D010741:Phospholipases A; D054467:Phospholipases A2; C006821:4-bromophenacyl bromide; D007665:Ketotifen