INHIBITION BY FENAMATES OF CALCIUM INFLUX AND PROLIFERATION OF HUMAN-LYMPHOCYTES

1 Flufenamic and tolfenamic acids have recently been shown to inhibit receptor-mediated calcium influx in human neutrophils. The present wor k was designed to study the effects of these two nonsteroidal anti-inf lammatory drugs on human peripheral blood lymphocyte activation. 2 Per ipheral blood mononuclear cells (PBMNCs; containing 90% lymphocytes) w ere stimulated by mitogen concanavalin A (Con A) or by a combination o f an inhibitor of microsomal Ca2+-adenosine triphosphatase thapsigargi n (TG) and phorbol myristate acetate (PMA). The effects of the two fen amates on cell proliferation were compared with respective changes in calcium metabolism. 3 Flufenamic and tolfenamic acids (10-100 mu M) in hibited both Con A and TG+PMA-induced [H-3]- thymidine incorporation i n a dose-dependent manner. At the same concentration range, the two fe namates inhibited the increase in intracellular free calcium concentra tion induced by Con A or TG+PMA. This effect was due to inhibition of calcium influx whereas calcium release from intracellular stores remai ned unaltered. 4 The inhibition of divalent cation influx was confirme d by showing that fenamates inhibited TG+PMA-induced Mn2+ influx. 5 Th e inhibitory effects of fenamates on PBMNC proliferation and Ca2+ infl ux were qualitatively similar with those of SK&F 96365, an earlier kno wn inhibitor of receptor-mediated calcium entry. Ketoprofen, a chemica lly different prostaglandin synthetase inhibitor did not show similar suppressive effects on PBMNCs. 6 The data suggest that flufenamic and tolfenamic acids suppress proliferation of human peripheral blood lymp hocytes by a mechanism which involves inhibition of Ca2+ influx and is not related to inhibition of prostanoid synthesis.