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Flufenamic and tolfenamic acids inhibit calcium influx in human polymorphonuclear leukocytes
1Medical School, University of Tampere, Finland.
Molecular Pharmacology
|May 1, 1995
Summary
Fenamates, a class of nonsteroidal anti-inflammatory drugs, block calcium influx in human polymorphonuclear leukocytes (PMNs). This novel mechanism, independent of prostanoid synthesis, explains their anti-inflammatory effects.
Area of Science:
- Pharmacology
- Immunology
- Cell Biology
Background:
- Fenamates are nonsteroidal anti-inflammatory drugs (NSAIDs) known to inhibit human polymorphonuclear leukocyte (PMN) functions.
- The precise mechanism underlying fenamate-induced PMN inhibition remains largely unknown.
Purpose of the Study:
- To elucidate the mechanism by which fenamates affect human PMN functions.
- To investigate the impact of flufenamic and tolfenamic acids on calcium (Ca2+) metabolism in human PMNs.
Main Methods:
- Utilized fura-2-labeled human PMNs to measure intracellular free Ca2+ concentrations.
- Assessed cation influx by monitoring manganese (Mn2+) and radioactive calcium (45Ca2+) influx.
- Compared the effects of fenamates with known channel blockers and inhibitors.
Main Results:
- Flufenamic and tolfenamic acids significantly inhibited Ca2+ increases in PMNs induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine and A23187.
- Evidence suggests fenamates block nonselective cation channels, similar to SK&F 96365.
- Nifedipine (calcium channel antagonist) and ketoprofen (prostanoid synthesis inhibitor) did not affect PMN Ca2+ metabolism.
Conclusions:
- Inhibition of calcium influx into PMNs is identified as a novel mechanism of action for fenamates.
- This prostanoid-independent pathway likely explains the previously observed inhibitory effects of flufenamic and tolfenamic acids on PMN functions.