FLUFENAMIC AND TOLFENAMIC ACIDS INHIBIT CALCIUM INFLUX IN HUMAN POLYMORPHONUCLEAR LEUKOCYTES

Fenamates, a subgroup of nonsteroidal anti-inflammatory drugs, inhibit several functions of human polymorphonuclear leukocytes (PMNs) in vit ro, by a thus far unknown mechanism. To determine the mechanism behind this action, we studied the effects of two fenamates (flufenamic and tolfenamic acids) on Ca2+ metabolism in human PMNs. The two fenamates inhibited the increases in intracellular free calcium concentration in duced by either the chemotactic peptide N-formyl-L-methionyl-L-leucyl- L-phenylalanine or the calcium ionophore A23187 in fura-2-labeled PMNs . This inhibition was concluded to be due to blocking of the cation in flux, as evidenced by measurement of Mn2+ influx and the influx of rad ioactive calcium. In addition, the actions of flufenamic and tolfenami c acids were similar to those of an experimental blocker of nonselecti ve cation channels (SK&F 96365). The two other control compounds, an a ntagonist of voltage-dependent calcium channels (nifedipine) and an in hibitor of prostanoid synthesis (ketoprofen), were ineffective. In con clusion, inhibition of calcium influx in PMNs is introduced as a novel prostanoid-independent mode of action of two nonsteroidal anti-inflam matory drugs with fenamate structure, flufenamic and tolfenamic acids, which could explain their earlier documented inhibitory effects on PM N functions.