Fenamates stimulate BKCa channel activity in the human osteoblast-like MG-63 cells

Background: The fenamates, a family of nonsteroidal antiinflammatory drugs that are derivatives of N-phenylanthranilic acid, are the inhibitors of cyc lo-oxygenase. The ionic mechanism of actions of these compounds in osteobla sts is not well understood. Methods: The effects of the fenamates on ionic currents were investigated i n 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+ o utward currents (I-K). The niflumic acid-stimulated I-K was reversed by sub sequent application of iberiotoxin or paxilline, yet not by that of glibenc lamide or apamin. In the inside-out configuration, niflumic acid (30 mu mol /L) added to the bath did not modify single-channel conductance but increas ed the activity of large-conductance Ca2(+)-activated K+ (BKCa) channels. T he EC50 values for niflumic acid- and meclofenamic acid-induced channel act ivity were 22 and 24 mu mol/L, respectively. Niflumic acid (30 mu mol/L) an d meclofenamic acid (30 mu mol/L) shifted the activation curve of BKCa chan nels to less positive membrane potentials. Membrane stretch potentiated nif lumic acid-stimulated channel activity. The rank order of potency for the a ctivation of BKCa channels in these cells was niflumic acid = meclofenamic acid > tolfenamic acid > flufenamic acid > nimesulide. Evans blue and nordi hydroguaiaretic acid increased channel activity; however, indomethacin, pir oxicam, 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 prostaglan din pathway. The activation of the BKCa channel may hyperpolarize the osteo blast, thereby modulating osteoblastic function.