Effects of dilazep on arachidonic acid metabolism by neutrophils and platelet/neutrophil interactions.
The effect of dilazep (tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanolbis(3,4, 5-trimethoxy-benzoate)dihydrochloride monohydrate, Comelian), a coronary and cerebral vasodilator and an anti-platelet agent, on endogenous and exogenous arachidonic acid (AA) metabolism by human neutrophils and platelet/neutrophil interactions was studied in vitro. Neutrophils preincubated with dilazep (up to 300 mumol/l) were incubated with the Ca ionophore A23187 in the absence or presence of AA. Platelet/neutrophil mixtures preincubated with dilazep (up to 100 mumol/l) were incubated with thrombin plus N-formylmethionylleucylphenylalanine (FMLP), FMLP plus AA, and platelet-activating factor (PAF) plus AA. AA metabolites including leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE) and 5S,12S-dihydroxyeicosatetraenoic acid (5S,12S-DiHETE) were analyzed and quantitated by reversed-phase high-performance liquid chromatography. The formation of LTB4 and 5-HETE from endogenous AA by neutrophils was inhibited by dilazep, whereas their production from exogenous AA was enhanced. LTB4 synthesis from endogenous AA by platelet/neutrophil interactions was inhibited by dilazep, while 5S,12S-DiHETE production was increased. The production of 5-lipoxygenase metabolites from exogenous AA by these interactions was increased by this drug. Thus, dilazep inhibits endogenous AA metabolism by neutrophils and by platelet/neutrophil interactions, whereas it stimulates exogenous AA metabolism by these blood cells and their interactions.
Okuma
M
M
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Kanaji
K
K
Ushikubi
F
F
Ishibashi
T
T
Uchino
H
H
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D004109:Dilazep / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000097:blood; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*
D001095:Arachidonic Acids; D001381:Azepines; D016718:Arachidonic Acid; D007770:L-Lactate Dehydrogenase; D004109:Dilazep