Pinacidil activates the ATP-sensitive K+ channel in inside-out and cell-attached patch membranes of guinea-pig ventricular myocytes.
Patch-clamp techniques were used to study the effects of pinacidil on the adenosine-5'-triphosphate (ATP)-sensitive K+ channel current in guinea-pig ventricular myocytes. In inside-out patches, the ATP-sensitive K+ channel current could be recorded at an internal ATP concentration of 0.5 mM or less and almost complete inhibition was achieved by raising the concentration to 2 mM. Application of pinacidil (10-30 microM) in the presence of 2 mM ATP restored the current, whereas 5 mM ATP antagonized the effect of pinacidil. The conductance of the channel at symmetrical K+ concentrations of 140 mM was 75 pS with a slight inward rectification at voltages positive to + 40 mV. There was no significant change in the conductance after application of pinacidil. In 0.5 mM ATP, at -80 mV, both the distributions of the open time and the life-time of bursts could be fitted by a single exponential. An increase in ATP concentration decreased the mean life-time of bursts, whereas pinacidil increased it with little increase in the mean open time. Closed time distributions of the channel were fitted by at least two exponentials, with a fast and a slow time constant. An increase in ATP concentration markedly increased the slow time constant associated with a decrease in the number of bursts, whereas the effect of pinacidil was opposite to that of increased ATP. These results indicate that pinacidil increases the open-state probability of the ATP-sensitive K+ channel.(ABSTRACT TRUNCATED AT 250 WORDS)
Fan
Z
Z
Department of Cardiovascular Diseases, Tokyo Medical and Dental University, Japan.
Nakayama
K
K
Hiraoka
M
M
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D020110:Pinacidil; D000255:Adenosine Triphosphate