Effect of phenothiazines on protein kinase C- and calcium-dependent activation of peritoneal macrophages.

The effects of some phenothiazines (promethazine, PMZ; chlorpromazine, CPZ; levomepromazine, LVPZ; thioridazine, TRDZ; trifluoperazine, TFPZ) on the activation and viability of rat peritoneal macrophages were investigated. The macrophage activation was estimated by measuring of luminol-dependent chemiluminescence, induced by phorbol-12-myristate-13-acetate (PMA) (a protein kinase C activator) or calcium ionophore A23187. The viability of macrophages was determined using ATP bioluminescence as a criterion of cell viability. It was observed that all drugs, in concentrations higher than 1 micromol/L, markedly decreased the chemiluminescent index of PMA-activated or A23187-activated macrophages. The inhibitory effect was dose-dependent. It was better expressed in the case of CPZ, followed by TFPZ and TRDZ, and less expressed in the case of PMZ and LVPZ. The suppression of chemiluminescence of PMA-/A23187-activated macrophages by phenothiazines was not a result of their cytotoxic effect. Moreover, it was found that all drugs dose-dependently enhanced the viability of macrophages, estimated by ATP production. The inhibitory effects of phenothiazines on the chemiluminescence of PMA-/A23187-activated macrophages were greater than their ability to decrease KO2-induced chemiluminescence as a result of interaction with superoxide radicals. It may be supposed that the inhibitory effect of phenothiazines on PMA-/A23187-induced chemiluminescence of macrophages is a result not only of interaction between drugs and superoxide radicals, generated during the "oxidative burst" of activated cells. Presumably the drugs have an immunomodulating effect on rat peritoneal macrophages.