title: Chlorpromazine inhibits neutrophil chemotaxis beyond the chemotactic receptor-ligand interaction.
abstract: Phenothiazines depress Ca++-dependent neutrophil functions, perhaps by binding to calmodulin or perturbing membrane structure through hydrophobic interactions. We examined effects of chlorpromazine (CPZ) on the human polymorphonuclear neutrophil (PMN) chemotactic-oligopeptide receptor and PMN membrane fluidity. CPZ had a reversible, biphasic effect on PMN motility in the Boyden chamber (slight depression at 5 microM, enhancement at 10 microM, and dose-dependent inhibition at higher concentrations). Order of potency for inhibition of motility (trifluoperazine greater than CPZ greater than promethazine) was identical to that for both inhibition of superoxide (O-2) release and binding to calmodulin. CPZ nonspecifically altered the binding affinity of chemotactic fMet-Leu-[3H]Phe. As assessed with two spin-probes, PMN membrane fluidity was unaltered at CPZ concentrations that depressed PMN receptor-mediated chemotaxis and O-2 release. The data suggest that CPZ nonspecifically alters receptor affinity and depresses chemotaxis and O-2 release independently, without altering bulk membrane fluidity. We speculate that unidentified "post-receptor changes" at a common translocation step for functions tested account for the observed inhibition.
mesh_terms: D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D002746:Chlorpromazine / Q000494:pharmacology*; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
chemical_list: D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D013481:Superoxides; D014268:Trifluoperazine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002746:Chlorpromazine