Effects of pinacidil on K+ channels in human coronary artery vascular smooth muscle cells.
We investigated pinacidil-activated K+ currents in vascular smooth muscle cells (VSMC) from human coronary arteries with the patch-clamp method. In 19 of 54 VSMC, pinacidil (1 and 20 microM) induced a large, nonrectifying, outward current [IK(ATP)] and increased voltage-dependent outward K+ currents [IK(Ca)] positive to voltages of -25 mV. The pinacidil-induced (1 microM) IK(ATP) was blocked by glibenclamide (3 microM) but was not affected by iberiotoxin (100-300 nM). Pinacidil activated up to 150 functionally active ATP-dependent K+ channels (KATP channels) per cell with a single-channel conductance of approximately 17 pS at physiological membrane potentials (between -80 and -30 mV) and K+ gradients (6 mM/130 mM). In 26 of 54 VSMC, on the other hand, pinacidil (1-20 microM) failed to induce IK(ATP) but increased IK(Ca). This current was completely blocked by iberiotoxin (100-300 nM) and tetraethylammonium (1 mM) but not by glibenclamide (3 microM). The single-channel conductance of the channel underlying IK(Ca) was approximately 150 +/- 16 pS between -10 and +30 mV, consistent with large-conductance, maxi Ca(2+)-activated, K+ channels (BKCa channels). We conclude that pinacidil is a nonselective K+ channel opener targeting KATP and BKCa channels. Furthermore, the conductance of KATP channels in human coronary arteries is likely to be small under physiological conditions.
Bychkov
R
R
Franz Volhard Clinic, Virchow University Hospitals, Berlin, Germany.
Gollasch
M
M
Ried
C
C
Luft
F C
FC
Haller
H
H
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D004553:Electric Conductivity; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D012604:Scorpion Venoms / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D006146:Guanidines; D010455:Peptides; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012604:Scorpion Venoms; D014665:Vasodilator Agents; C064719:iberiotoxin; D020110:Pinacidil; D005905:Glyburide