Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP.
We studied the effects of pinacidil (3-50 microM) on the membrane currents of canine ventricular myocytes, using the whole-cell variant of the patch-clamp technique, and the modulation of these effects by intracellular environment, using the pipette perfusion technique. The following observations were obtained: (1) pinacidil induced a dose-dependent outward shift in current at voltages positive to -70 mV; (2) the pinacidil-induced current was largely time-independent at voltages positive to -50 mV and displayed an increase in current fluctuations at more positive voltages, resembling the kinetic properties of current through the ATP-regulated K+ channels; (3) elevating the extracellular potassium concentration [( K+]o) caused a positive shift in the voltage where the pinacidil-induced current crossed the voltage axis and increased the slope conductance of this current; (4) the pinacidil-induced current was reduced by Ba2+ (0.5-1.5 mM) and abolished by intracellular Cs+ (125 mM); (5) glibenclamide reversibly reduced or abolished the pinacidil-induced current; (6) the action of pinacidil was decreased by elevating [ATP] in the pipette solution (from 1 to 10 mM); (7) the action of pinacidil was augmented by adding isoproterenol (1 microM) to the superfusate or adding cAMP (0.1 mM) to the pipette solution; (8) elevating temperature augmented, and accelerated the onset of pinacidil's action; (9) pinacidil reversibly decreased the Ca2(+)-independent transient outward current (Ito1) but augmented the Ca2(+)-dependent transient outward current (Ito2). Based on these observations, we reached the following conclusions: (1) the main effect of pinacidil is to increase an outward current through the ATP-regulated K+ channels; (2) pinacidil's action is modulated by an enzymatic reaction.
Tseng
G N
GN
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Hoffman
B F
BF
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology*; D020110:Pinacidil; D015221:Potassium Channels / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D020110:Pinacidil; D000255:Adenosine Triphosphate; D000242:Cyclic AMP