Intracellular acidification and ADP enhance nicorandil induction of ATP sensitive potassium channel current in cardiomyocytes.
OBJECTIVE
Potassium channel openers target ATP sensitive potassium (KATP) channels, and might be beneficial in the treatment of ischaemic cardiac conditions. Ischaemia is associated with an increase in the concentrations of intracellular nucleoside diphosphates and protons, two regulators of KATP channels. Since it is largely unknown whether these factors modulate the action of potassium channel openers, the aim of this study was to define the effects of ADP and intracellular acidification on KATP channel activation by nicorandil, a potassium channel opener currently in clinical use.


METHODS
To measure ionic currents, the whole cell patch clamp technique was employed in guinea pig single ventricular myocytes. Induction of KATP channel current by pinacidil, a potassium channel opener chemically unrelated to nicorandil, was used for comparison.


RESULTS
Nicorandil (300 microM) and pinacidil (100 microM) induced a time independent K+ current, which was inhibited by glibenclamide (6 microM), a selective blocker of KATP channels. ADP in the pipette solution was required for the nicorandil induced activation of KATP channels when the pH of the pipette solution was 7.2. In the absence of ADP, lowering the pH of the pipette solution to 6.5 was necessary for nicorandil to induce KATP channel current. For pinacidil to induce KATP channel current neither the addition of intracellular ADP nor acidification was required.


CONCLUSIONS
Nicorandil may activate KATP channel current more effectively in conditions associated with a change in intracellular proton and ADP concentrations such as cardiac ischaemia.
Jahangir
A
A
Mayo Clinic, Rochester, MN 55905.
Terzic
A
A
Kurachi
Y
Y
D000200:Action Potentials / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; 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; D009536:Niacinamide; D020108:Nicorandil; D000244:Adenosine Diphosphate; D020110:Pinacidil; D000255:Adenosine Triphosphate