S N Wu1, C R Jan, H T Chiang. 1. Department of Medical Education and Research, Kaohsiung-Veterans General Hospital, Kaohsiung City, Taiwan, ROC. snwu@isca.vghks.gov.tw
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 (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.
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.
Authors: Aaron G Blankenship; Aaron M Hamby; Alana Firl; Shri Vyas; Stephan Maxeiner; Klaus Willecke; Marla B Feller Journal: J Neurosci Date: 2011-07-06 Impact factor: 6.167