Effects of Nicorandil on the cAMP-Dependent Cl- Current in Guinea-Pig Ventricular Cells

In guinea-pig cardiomyocytes, a cAMP-dependent Cl- current (I-Cl,I-cAMP) flows through a cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which belongs to a family of the ATP-binding cassette (ABC) proteins. Although several K+-channel openers and sulfonylurea ATP-sensitive K+ (K-ATP)-channel blockers reportedly inhibit I-Cl,I-cAMP, effects of nicorandil on the Cl- current have not been evaluated. This study was conducted to examine the effects of nicorandil on I-Cl,I-cAMP in isolated guinea-pig ventricular cells using patch clamp techniques. Nicorandil in concentrations higher than 300 mu M enhanced the I-Cl,I-cAMP preactivated by 0.1 mu M isoproterenol. The isoproterenol-induced I-Cl,I-cAMP was inhibited by 100 mu M glibenclamide, but not by 100 mu M pinacidil. SNAP (S-nitroso-N-acetyl-D,L-penicillamine, 10 mu M), a nitric oxide (NO) donor, similarly enhanced the isoproterenol-induced I-Cl,I-cAMP. However, SG-86, a denitrated metabolite possessing K+ channel-opening action, failed to enhance the Cl- current. When the I-Cl,I-cAMP was activated by 3-isobutyl-1-methylxanthine (IBMX, 30 mu M), either nicorandil or SNAP failed to enhance the isoproterenol-induced I-Cl,I-cAMP. Thus, nicorandil enhances I-Cl,I-cAMP in guinea-pig cardiomyocytes through an increase in intracellular cGMP, although direct modulation of I-Cl,I-cAMP by NO cannot be completely excluded.