Fenamates Stimulate BKCa Channel Activity in the Human Osteoblast-Like MG-63 Cells

Abstract

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 (I_K). The niflumic acid-stimulated I_K 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 μmol/L) added to the bath did not modify single-channel conductance but increased the activity of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels. The EC₅₀ values for niflumic acid- and meclofenamic acid-induced channel activity were 22 and 24 μmol/L, respectively. Niflumic acid (30 μmol/L) and meclofenamic acid (30 μmol/L) shifted the activation curve of BK_Ca channels to less positive membrane potentials. Membrane stretch potentiated niflumic acid-stimulated channel activity. The rank order of potency for the activation of BK_Ca 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 BK_Ca channel activity in a manner that seems to be independent of the action of these drugs on the prostaglandin pathway. The activation of the BK_Ca channel may hyperpolarize the osteoblast, thereby modulating osteoblastic function.