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  • Title: Synergistic inhibition of complement induced granulocyte margination by BW755C and calcium channel blockers.
    Author: Issekutz AC, Rochon Y, Ripley M.
    Journal: Int J Immunopharmacol; 1985; 7(6):791-800. PubMed ID: 3000960.
    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.
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