Modulation of rabbit aortic Ca(2+)-activated K+ channels by pinacidil, cromakalim, and glibenclamide.
Rabbit aortic smooth muscle microsomes were isolated and large-conductance Ca(2+)-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) > NH4+ (0.14) >> Na+, Cs+ (< 0.05). Application of pinacidil or cromakalim (0.05-10 microM) shifted the probability of opening (Po)-voltage relationship in the hyperpolarizing direction. The concentrations of pinacidil and cromakalim required to increase Po 50% of the maximum value at -40 mV were 0.96 +/- 0.04 and 0.52 +/- 0.03 microM, respectively. Neither pinacidil nor cromakalim altered the voltage sensitivity of the channel (11-13 mV/e-fold change in Po). Kinetic analysis of data at -40 mV demonstrated that pinacidil (1 microM) 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 microM) had no effect on Po of BK channels. However, glibenclamide reversed the pinacidil- or cromakalim-stimulated increase in Po of BK channels. These data suggest that both cromakalim and pinacidil increased the probability of opening of single rabbit aortic large-conductance Ca(2+)-activated K+ channels and that this channel modulation may contribute to the vasorelaxant properties of these drugs.
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Florida 33101.
G H
GH
Gelband
J R
JR
McCullough
D000818:Animals; D001011:Aorta / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D002412:Cations; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D008051:Lipid Bilayers; D008564:Membrane Potentials / Q000187:drug effects; D008861:Microsomes / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D002412:Cations; D006146:Guanidines; D008051:Lipid Bilayers; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D020110:Pinacidil; D005905:Glyburide; D002118:Calcium