Effects of various drugs on superoxide generation, arachidonic acid release and phospholipase A2 in polymorphonuclear leukocytes.

Abstract

The effects of variety of drugs on metabolic burst and phospholipase A2 in polymorphonuclear leukocytes (PMNs) were investigated. The stimulation of PMNs by n-formyl-methionyl-leucyl-phenylalanine (FMLP) caused arachidonic acid (AA) to be released in the cells concomitantly with the generation of superoxide anion. These variables were effectively diminished with some clinical employed drugs including chlorpromazine, trifluoperazine, azelastine, clemastine and mepacrine at the lower concentration of 20 .mu.M. In contrast, indomethacin and procaine were ineffective even at higher concentration of 100 .mu.M. Subcellular fractionation of PMNs revealed that phospholipase A2 activity was located both in the plasma membrane-rich fraction as well as the granule-microsome-rich fraction, and the potency of inhibition of membrane-bound phospholipase A2 by the above mentioned drugs was: indomethacine (IC50 = 3 .mu.M) < chlorpromazine < azelastine and clemastine (IC50 > 100 .mu.M). The low potency of antipsychotropic drugs and antihistaminic drugs in inhibiting the fractionated phospholipase A2 contrast with the high efficiency with which they inhibit the superoxide generation and the AA release from stimulated PMNs. The AA releases from the PMNs stimulated by FMLP or calcium ionophore (A23187) were almost equally diminished by various drugs at the lower concentration. From these observations, it appeared likely that these drugs might inhibit the metabolic stimulations of PMNs at the site of the Ca2+-dependent activation processes of the enzymes responsible for the AA release and the superoxide generation.