title: Synergistic inhibition of complement induced granulocyte margination by BW755C and calcium channel blockers.
abstract: Intravenous infusion of granulocyte (PMNL) chemotactic factors including C5ades Arg present in zymosan activated plasma (ZAP), induces granulocytopenia due to PMNL margination. Since some PMNL responses are dependent on Ca++ ions and lipoxygenation of arachidonic acid, we evaluated the effects of a lipoxygenase (and cyclooxygenase) inhibitor, BW755C and Ca++ channel blocking agents, verapamil and nifedipine, on chemotactic factor induced granulocytopenia and margination in rabbits. BW755C (20 mg/kg i.v.) treatment significantly attenuated ZAP induced granulocytopenia. Verapamil or nifedipine alone were without effect. However, combined treatment with BW755C and verapamil or nifedipine (250 micrograms/kg) completely prevented ZAP-induced granulocytopenia. Ibuprofen, a cyclooxygenase inhibitor, was without effect either by itself or in combination with the calcium channel blockers. In striking contrast to the effect on ZAP-induced granulocytopenia, BW755C plus verapamil or nifedipine had virtually no effect on f-met-leu-phe, platelet activating factor or leukotriene B4 induced granulocytopenia. PMNL aggregation in vitro in response to all of the above chemotactic factors was inhibited by BW775C to similar degrees (56-75%) and was not influenced by simultaneous treatment with verapamil. We conclude that: (a) inhibitors of the lipoxygenase pathway may synergize with Ca++ channel blocking agents in inhibiting PMNL responses to complement derived chemotactic factors in vivo; (b) that in vivo PMNL margination to other chemotactic factors may be less dependent on endogenous lipoxygenation and/or Ca++ fluxes; and (c) there is a poor correlation between pharmacological inhibition of PMNL aggregation in vitro and PMNL margination in vivo in this system.
mesh_terms: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000380:Agranulocytosis / Q000209:etiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002449:Cell Aggregation / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D003165:Complement System Proteins / Q000502:physiology*; D005260:Female; D006098:Granulocytes / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002630:Chemotactic Factors; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011720:Pyrazoles; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003165:Complement System Proteins; D014700:Verapamil; D002118:Calcium