Flufenamic and tolfenamic acids inhibit calcium influx in human polymorphonuclear leukocytes
Kankaanranta, H.; Moilanen, E.
Molecular Pharmacology 47(5): 1006-1013
1995
ISSN/ISBN: 0026-895X PMID: 7746266 Document Number: 444055
Fenamates, a subgroup of nonsteroidal anti-inflammatory drugs, inhibit several functions of human polymorphonuclear leukocytes (PMNs) in vitro, 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 Ca-2+ metabolism in human PMNs. The two fenamates inhibited the increases in intracellular free calcium concentration induced 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 influx, as evidenced by measurement of Mn-2+ influx and the influx of radioactive calcium. In addition, the actions of flufenamic and tolfenamic acids were similar to those of an experimental blocker of nonselective cation channels (SK and F 96365). The two other control compounds, an antagonist of voltage-dependent calcium channels (nifedipine) and an inhibitor of prostanoid synthesis (ketoprofen), were ineffective. In conclusion, inhibition of calcium influx in PMNs is introduced as a novel prostanoid-independent mode of action of two nonsteroidal anti-inflammatory drugs with fenamate structure, flufenamic and tolfenamic acids, which could explain their earlier documented inhibitory effects on PMN functions.