Inhibition of pinacidil induced IK(ATP) in heart by changes in extracellular pH.
OBJECTIVE
The aim was to determine whether extracellular protons influence the activation of ATP sensitive potassium channels (KATP) in heart by the drug pinacidil.


METHODS
Single channel and whole cell currents were measured in enzymatically dispersed guinea pig ventricular myocytes with patch clamp procedures. ATP sensitive potassium channel activity was induced by pinacidil in whole cell experiments and either by lowering cytoplasmic ATP or pinacidil in membrane patch experiments.


RESULTS
Extracellular acidification inhibited and extracellular alkalisation potentiated ATP sensitive potassium channel currents (IK(ATP)) induced by pinacidil under whole cell conditions. In membrane patches, IK(ATP) induced by low cytoplasmic ATP (1 mM) was not sensitive to changes in extracellular pH, but IK(ATP) induced by cytoplasmic application of pinacidil was inhibited by extracellular acidification.


CONCLUSIONS
Interactions between protons and pinacidil drug molecules underlie the pH dependent changes in IK(ATP) induced by pinacidil. Based on the kinetics of pH dependent changes in pinacidil induced channel activity in inside-out membrane patches, our data suggest that the important inhibitory site of action of this drug is located on the extracellular side of the cell membrane.
Kwok
W M
WM
Department of Physiology, University of Rochester Medical Center, NY 14624.
Kass
R S
RS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D005110:Extracellular Space / Q000502:physiology*; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011522:Protons; D014665:Vasodilator Agents / Q000494:pharmacology*
D006146:Guanidines; D015221:Potassium Channels; D011522:Protons; D014665:Vasodilator Agents; D020110:Pinacidil