Key result
Nicorandil at 1 mM significantly increased the isoproterenol-induced cAMP-dependent Cl− current by 23.1% in guinea-pig ventricular cells, likely via increased intracellular cGMP.
Nicorandil enhances the cAMP-dependent Cl- current in guinea-pig cardiomyocytes via an increase in intracellular cGMP, though this occurs at supratherapeutic concentrations.
Supratherapeutic nicorandil effects in guinea-pig myocytes should not change practice; leaves open cGMP-Cl− current interactions for human investigation.
In guinea-pig cardiomyocytes, a cAMP-dependent Cl(-) current (I(Cl,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,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,cAMP) in isolated guinea-pig ventricular cells using patch clamp techniques. Nicorandil in concentrations higher than 300 microM enhanced the I(Cl,cAMP) preactivated by 0.1 microM isoproterenol. The isoproterenol-induced I(Cl,cAMP) was inhibited by 100 microM glibenclamide, but not by 100 microM pinacidil. SNAP (S-nitroso-N-acetyl-D,L-penicillamine, 10 microM), a nitric oxide (NO) donor, similarly enhanced the isoproterenol-induced I(Cl,cAMP). However, SG-86, a denitrated metabolite possessing K(+ )channel-opening action, failed to enhance the Cl(-) current. When the I(Cl,cAMP) was activated by 3-isobutyl-1-methylxanthine (IBMX, 30 microM), either nicorandil or SNAP failed to enhance the isoproterenol-induced I(Cl,cAMP). Thus, nicorandil enhances I(Cl,cAMP) in guinea-pig cardiomyocytes through an increase in intracellular cGMP, although direct modulation of I(Cl,cAMP) by NO cannot be completely excluded.
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Nishimura et al. (2010) studied this question. Nicorandil vs. Isoproterenol alone was evaluated on Increase in isoproterenol-induced ICl,cAMP at +80 mV (p=<0.05). Nicorandil at 1 mM significantly increased the isoproterenol-induced cAMP-dependent Cl− current by 23.1% in guinea-pig ventricular cells, likely via increased intracellular cGMP.
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