Multiple effects of mefenamic acid on K + currents in smooth muscle cells from pig proximal urethra

The effects of mefenamic acid on both membrane potential and K + currents in pig urethral myocytes were investigated using patch‐clamp techniques (conventional whole‐cell, cell‐attached, outside‐out and inside‐out configuration). In the current‐clamp mode, mefenamic acid caused a concentration‐dependent hyperpolarization, which was inhibited by preapplication of 1 μ M glibenclamide. In the voltage‐clamp mode, mefenamic acid induced an outward current that was blocked by glibenclamide even in the presence of iberiotoxin (IbTX, 300 n M ) at −50 mV. ATP‐sensitive K + channels (K ATP channels) could be activated in the same patch by mefenamic acid and levcromakalim, with the same unitary amplitude and the similar opening gating at −50 mV in cell‐attached configuration. In outside‐out recording, external application of mefenamic acid activated intracellular Ca 2+ ‐activated IbTX‐sensitive large‐conductance K + channels (BK Ca channels). Mefenamic acid (30 μ M ) activated spontaneous transient outward currents (STOCs). In contrast, mefenamic acid (100 μ M ) increased sustained outward currents, diminishing the activity of STOCs. Over the whole voltage range, mefenamic acid caused opposite effects on the membrane currents in the absence and presence of 5 μ M glibenclamide. In the presence of 10 m M 4‐aminopyridine (4‐AP), mefenamic acid only increased the outward currents. These results indicate that mefenamic acid increases the channel activities of two distinct types of K + channels (i.e. BK Ca channels and K ATP channels) and decreased 4‐AP‐sensitive K + channels in pig urethral myocytes.British Journal of Pharmacology (2003) 140 , 1341–1350. doi: 10.1038/sj.bjp.0705524