Ca2+-dependent production of reactive oxygen metabolites by human neutrophils in response to fluorinated propranolol analogues

Fluorinated analogues of propranolol, namely trifluoroethyl propranolol (F3 ), pentafluoropropyl propranolol CF5, and heptafluorobutyl propranolol (F7) , were found to induce reactive oxygen metabolite (ROM) production in human neutrophils in a dose-dependent manner. Preincubation of neutrophils with the calcium chelator BAPTA-AM or the tyrosine kinase inhibitor genistein in hibited this ROM production. Direct measurements of intracellular calcium r evealed that these analogues caused a transient increase in intracellular c alcium. In addition, these fluorinated analogues of propranolol caused a tr ansient increase in actin polymerization. The effects of these compounds we re found to be dependent upon the degree of fluorination of the parent comp ound. Propranolol, on the other hand, had no direct effect on ROM, calcium, or actin polymerization when added alone to neutrophils, although it did m odify responses of cells to various stimuli. Whereas ROM production induced by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was enhan ced in a dose-dependent manner, the response to the particulate stimulus, l atex beads, was abolished. (C) 2001 Elsevier Science Inc. All rights reserv ed.