INTRACELLULAR ACIDIFICATION AND ADP ENHANCE NICORANDIL INDUCTION OF ATP-SENSITIVE POTASSIUM CHANNEL CURRENT IN CARDIOMYOCYTES

Objective: Potassium channel openers target ATP sensitive potassium (K-ATP) 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 K-ATP 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 K-ATP 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 K-ATP channel current by pinacidil, a potassium channel opener chemically unrelated to nicorandil, was used for comparison. Results: Nicorandil (300 mu M) and pinacidil (100 mu M) induced a time independent K+ current, which was inhibited by glibenclamide (6 mu M), a selective blocker of K-ATP channels. ADP in the pipette solution was required for the nicorandil induced activation of K-ATP 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 K-ATP channel current. For pinacidil to induce K-ATP channel current neither the addition of intracellular ADP nor acidification was required. Conclusions: Nicorandil may activate K-ATP channel current more effectively in conditions associated with a change in intracellular proton and ADP concentrations such as cardiac ischaemia.