Inhibitory effects of various drugs on phorbol myristate acetate and n-formyl methionyl leucyl phenylalanine induced O2- production in polymorphonuclear leukocytes

Abstract

To clarify the mechanisms of O2- formation by polymorphonuclear leukocytes (PMNs), the effects of clinically employed drugs on PMNs were investigated by measuring changes in membrane potential and rates of O2- production. These variables were effectively diminished with antihistaminic agents, adrenergic beta-antagonists, and antiarrhythmic drugs when guinea pig peritoneal PMNs were stimulated by either phorbol myristate acetate (PMA) or n-formyl-methionyl-leucyl-phenylalanine (FMLP). The order of potency of the inhibitory effects of these chemicals on the PMA-induced O2- formation was as follows: azelastine (IC50 = 4.1 microM) less than clemastine less than dl-propranolol less than chlorpheniramine maleate less than dichlorisoproterenol less than quinidine less than diphenhydramine less than indomethacin (IC50 greater than 400 microM). Similar phenomena were observed when FMLP was employed instead of PMA, but the FMLP-stimulated O2- production was effectively inhibited by indomethacin. Changes in membrane potential, using the cyanin dye method, also indicated that most of these drugs cancelled functional changes of plasma membrane of PMNs. From these observations, it was demonstrated that changes in membrane potential by the stimuli were essential for the initiation of O2- generation from plasma membrane of PMNs, although the initiation mechanisms were not identical for the two stimuli.