PHARMACOLOGICAL PROPERTIES OF ATP-SENSITIVE K+ CHANNELS IN MAMMALIAN SKELETAL-MUSCLE CELLS

The patch-clamp technique (single-channel recordings) was used to study the effects of glibenclamide and some channel openers on the K(ATP) channel in mouse skeletal muscle. In outside/out membrane patches, glibenclamide reversibly inhibited K(ATP) channel activity in a dose-dependent manner with an apparent K(i) of 190 nM. In inside/out membrane patches, RP 61419 increased K(ATP) channel activity both in the absence and in the presence of internal ATP while other K+ channel openers such as nicorandil and cromakalim required the presence of internal ATP to evoke channel activation. The half-maximal activity effect for cromakalim, with 0.5 mM ATP at the cytoplasmic face, was observed at about 220 muM. Pinacidil was unable to activate the K(ATP) channel in the absence of internal ATP and could even reduce channel opening in situations where activity was high in the control. In the presence of internal Mg2+, activation by pinacidil occurred when ATP or low and weakly activating concentrations of ADP were present at the cytoplasmic side. Pinacidil activation could also be observed in the presence of ATP or ADP when Mg2+ was absent from the internal solution. The mechanism of action of pinacidil is discussed in terms of interactions between the different nucleotide regulatory sites and the K+ channel opener binding site of the K(ATP) channel. Half-maximum activation of the K(ATP) Channel in the presence of 0.5 mM ATP at the cytoplasmic face was observed at 125 muM pinacidil.