Fenamates stimulate BKCa channel osteoblast-like MG-63 cells activity in the human.
BACKGROUND
The fenamates, a family of nonsteroidal anti-inflammatory drugs that are derivatives of N-phenylanthranilic acid, are the inhibitors of cyclo-oxygenase. The ionic mechanism of actions of these compounds in osteoblasts is not well understood.


METHODS
The effects of the fenamates on ionic currents were investigated in a human osteoblast-like cell line (MG-63) with the aid of the whole-cell and inside-out configurations of the patch-clamp technique.


RESULTS
In MG-63 cells, niflumic acid and meclofenamic acid increased K+ outward currents (IK). The niflumic acid-stimulated IK was reversed by subsequent application of iberiotoxin or paxilline, yet not by that of glibenclamide or apamin. In the inside-out configuration, niflumic acid (30 micromol/L) added to the bath did not modify single-channel conductance but increased the activity of large-conductance Ca2+-activated K+ (BKCa) channels. The EC50 values for niflumic acid- and meclofenamic acid-induced channel activity were 22 and 24 micromol/L, respectively. Niflumic acid (30 micromol/L) and meclofenamic acid (30 micromol/L) shifted the activation curve of BKCa channels to less positive membrane potentials. Membrane stretch potentiated niflumic acid-stimulated channel activity. The rank order of potency for the activation of BKCa channels in these cells was niflumic acid = meclofenamic acid > tolfenamic acid > flufenamic acid > nimesulide. Evans blue and nordihydroguaiaretic acid increased channel activity; however, indomethacin, piroxicam, and NS-398 had no effect on it.


CONCLUSIONS
The fenamates can stimulate BKCa channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway. The activation of the BKCa channel may hyperpolarize the osteoblast, thereby modulating osteoblastic function.
Wu
S N
SN
Department of Medical Education and Research, Kaohsiung-Veterans General Hospital, Kaohsiung City, Taiwan, ROC. snwu@isca.vghks.gov.tw
Jan
C R
CR
Chiang
H T
HT
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D008469:Meclofenamic Acid / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009544:Niflumic Acid / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020746:Calcium Channels, L-Type; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D008469:Meclofenamic Acid; D009544:Niflumic Acid; D005905:Glyburide