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 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 Ca2+ 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 Mn2+ 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&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.
Kankaanranta
H
H
Medical School, University of Tampere, Finland.
Moilanen
E
E
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005439:Flufenamic Acid / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D007660:Ketoprofen / Q000494:pharmacology; D008345:Manganese / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D007093:Imidazoles; D062367:ortho-Aminobenzoates; C059537:3',5-dichlorodiphenylamine-2-carboxylic acid; D000001:Calcimycin; C009500:tolfenamic acid; D008345:Manganese; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005439:Flufenamic Acid; D007660:Ketoprofen; D004159:Diphenylamine; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; D002118:Calcium