The influence of chlorhexidine on superoxide generation by induced human neutrophils

Chlorhexidine directly stimulates the generation of superoxide anion (O 2 ) by neutrophils at nontoxic concentrations of the drug (less than 0.01%). The kinetics of drug‐induced O 2 generation simulated that of receptor‐mediated FMLP induction of O 2 , but not that of PMA‐induced synthesis. Nontoxic concentrations of chlorhexidine inhibited FMLP‐induced generation of O 2 if the neutrophils were pretreated with chlorhexidine or if chlorhexidine and FMLP were added simultaneously. Cells activated first by FMLP were unaffected by chlorhexidine. These data support the concept that chlorhexidine interferes with the binding of FMLP to its receptor. Chlorhexidine inhibited both the velocity and the duration of FMLP‐induced O 2 synthesis. In contrast, chlorhexidine promoted PMA‐induced O 2 generation irrespective of the sequence of addition of chlorhexidine and PMA. Chlorhexidine decreased the lag interval between PMA induction and O 2 synthesis, and increased the velocity of synthesis, which leads us to propose that chlorhexidine increases PMA penetrance of neutrophils. Since neither nonionic detergents nor polycationic polymers separately minic the effect of chlorhexidine treatment, it appears that more than surfactant or charge effects are involved. The interrelation between the positive charge and the hydrophobic domain of chlorhexidine plays a role in the drug‐neutrophil interaction which directly stimulates O 2 generation, and which modulates neutrophil responsiveness to FMLP and to PMA.