MODULATION OF RABBIT AORTIC CA2+-ACTIVATED K+ CHANNELS BY PINACIDIL, CROMAKALIM, AND GLIBENCLAMIDE

Rabbit aortic smooth muscle microsomes were isolated and large-conductance Ca2+-activated K+ (BK) channels incorporated into planar lipid bilayers. The selectivity sequence and relative permeability ratios for monovalent cations was K+ (1.0) > Rb+ (0.68) > NH+ (0.14) >> Na+, Cs+ (<0.05). Application of pinacidil or cromakalim (0.05-10 muM) shifted the probability of opening (P(o))-voltage relationship in the hyperpolarizing direction. The concentrations of pinacidil and cromakalim required to increase P(o) 50% of the maximum value at -40 mV were 0.96 +/- 0.04 and 0.52 +/- 0.03 muM, respectively. Neither pinacidil nor cromakalim altered the voltage sensitivity of the channel (11-13 mV/e-fold change in P(o)). Kinetic analysis of data at -40 mV demonstrated that pinacidil (1 muM) decreased the length of time the channel dwelled in its long-closed state by 50% from 173 +/- 50 to 86 +/- 19 ms. No significant change was observed for the open time constant (20 ms). Glibenclamide (10 muM) had no effect on P(o) of BK channels. However, glibenclamide reversed the pinacidil- or cromakalim-stimulated increase in P(o) of BK channels. These data suggest that both cromakalim and pinacidil increased the probability of opening of single rabbit aortic large-conductance Ca2+-activated K+ channels and that this channel modulation may contribute to the vasorelaxant properties of these drugs.