Modulation of three types of K+ currents in canine coronary artery smooth muscle cells by NS-004, or 1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone.

The effects of the cardioprotective, vasorelaxant agent NS-004 [1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone] on K+ currents of freshly isolated canine coronary artery smooth muscle cells were examined using the suction pipette method. The Ca(++)-sensitive K+ current (IK, Ca) was isolated by using a holding potential of 0 mV and 5 mM ATP in the internal perfusate. The voltage-dependent delayed rectifier K+ current (IK, DR) was recorded at potentials below 20 mV in internal solution containing 5 mM ATP. The ATP-sensitive K+ current (IK, ATP) was induced by removing ATP in the pipette solution and was measured at potentials negative to -30 mV where IK, Ca and IK, DR were absent. External application of NS-004 activated IK, Ca, which, at 80 mV, was increased from 0.28 +/- 0.03 to 1.1 +/- 0.2, to 3.2 +/- 1.0, to 5.6 +/- 1.6 and to 8.5 +/- 1.6 nA, respectively, by 12.5, 25, 50 and 100 microM NS-004. Structurally related flufenamic, niflumic and mefenamic acids, at 100 microM, also enhanced IK, Ca. The order of potency for IK, Ca activation was NS-004 >> flufenamic = niflumic > mefenamic. In contrast, NS-004 blocked IK, DR, beginning at 2 microM with 50% inhibition at 22 microM. NS-004 also inhibited IK, ATP with a Ki value of 2.4 microM and a Hill coefficient of 1.3 in 0 mM intracellular ATP. These results demonstrate that NS-004 is a more potent activator of IK, Ca than the fenamates and that it is also a relatively potent blocker of IK, DR and IK, ATP in canine coronary artery smooth muscle cells.