Histamine modulation of human neutrophil oxidative metabolism, locomotion, degranulation, and membrane potential changes

Previous reports have suggested that histamine modulates neutrophil chemotaxis, but this has not been observed by all laboratories. We have re-addressed this controversial point and demonstrate that histamine and H1- and H2-receptor-specific agonists cause limited inhibition of chemotaxis while stimulating chemokinesis. Furthermore, using the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe) as a stimulus, we demonstrate that histamine and H1/H2 agonists inhibit f-met-leu-phe-stimulated changes in membrane potential (monitored with the cyanine dye dipentyloxacarbocyanine), superoxide anion production (cytochrome c reduction), hydrogen peroxide formation (scopoletin fluorescence), and degranulation of granule contents (lysozyme and beta-glucuronidase) in a dose-dependent manner but have no effect on neutrophil functions stimulated by the secretagogues phorbol myristate acetate or A23187. All inhibitory effects of histamine and the H1/H2 agonists are reversed in a competitive manner by the H2 antagonist cimetidine. In addition, structure-activity studies using H1 and H2 receptor agonists and antagonists indicate that a single site with specificity for both H1 and H2 analogue structures modulates the various f-met-leu-phe-stimulated functions studied. Kinetic studies demonstrate that the inhibitory effects of histamine on neutrophil function are only observed when histamine is added before f-met-leu-phe and that inhibition occurs within 10 to 20 sec of histamine addition, does not persist after its removal, and is reversed by addition of cimetidine 10 to 20 sec before stimulation with f-met-leu-phe. Although the inhibitory effects of histamine are exerted early in the sequence of PMN activation by f-met-leu-phe, histamine does not affect the binding or internalization of f-met-leu-3H]phe. The ability of histamine to modify the variety of neutrophil responses demonstrated in this report suggests an important and direct role for histamine in the regulation of inflammatory reactions in acute allergic settings or other disease states in which histamine release may occur.