Inhibition of the neutrophil oxidative burst and degranulation by phenothiazines

Trifluoperazine inhibits superoxide production and O₂ uptake by guinea pig neutrophils incubated with arachidonic acid, N-formylmethionylphenylalanine, digitonin or ionophore A23187, with IC₅₀ values of 7–37uM. Since this inhibition is produced by concentrations of trifluoperazine which inhibit interaction of calmodulin with proteins, we examined the effects of two other phenothiazines which interact less effectively with calmodulin. Chlorpromazine, promethazine and trifluoperazine all inhibit N-formylmethionylphenylalanine-stimulated superoxide production with similar efficiency. Furthermore, degranulation stimulated by A23187 or N-formylmethionylphenylalanine is inhibited similarly by all three phenothiazines with IC₅₀ values of 18–45 uM. These results are consistent with the suggestion that phenothiazines may inhibit neutrophil function as a result of non-specific interactions with the cells' membranes rather than by specific interaction with calmodulin.