Effects of ATP-sensitive potassium channel regulators on chloride channels in the sarcoplasmic reticulum vesicles from rabbit skeletal muscle.

The lipid bilayer technique was used to examine the effects of the ATP-sensitive K+ channel inhibitor (glibenclamide) and openers (diazoxide, minoxidil and cromakalim) and Cl- channel activators (GABA and diazepam) on two types of chloride channels in the sarcoplasmic reticulum (SR) from rabbit skeletal muscle. Neither diazepam at 100 microM nor GABA at 150 microM had any significant effect on the conductance and kinetics of the 75 pS small chloride (SCl) channel. Unlike the 150 pS channel, the SCl channel is sensitive to cytoplasmic glibenclamide with Ki approximately 30 microM. Glibenclamide induced reversible decline in the values of current (maximal current amplitude, Imax and average mean current, I') and kinetic parameters (frequency of opening Fo, probability of the channel being open Po and mean open time, To, of the SCl channel. Glibenclamide increased mean closed time, Tc, and was a more potent blocker from the cytoplasmic side (cis) than from the luminal side (trans) of the channel. Diazoxide increased I', Po, and To in the absence of ATP and Mg2+ but it had no effect on Imax and also failed to activate or remove the glibenclamide- and ATP-induced inhibition of the SCl channel. Minoxidil induced a transient increase in I' followed by an inhibition of Imax, whereas cromakalim reduced Po and I' by increasing channel transitions to the closed state and reducing To without affecting Imax. The presence of diazoxide, minoxidil or cromakalim on the cytoplasmic side of the channel did not prevent [ATP]cis or [glibenclamide]cis from blocking the channel. The data suggest that the action(s) of these drugs are not due to their effects on the phosphorylation of the channel protein. The glibenclamide- and cromakalim-induced effects on the SCl channel are mediated via a "flicker" type block mechanism. Modulation of the SCl channel by [diazoxide]cis and [glibenclamide]cis highlights the therapeutic potential of these drugs in regulating the Ca2+-counter current through this channel.