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ANESTHETIC PHARMACOLOGY

Nicorandil, an Adenosine Triphosphate-Sensitive Potassium Channel Opener, Inhibits Muscarinic Acetylcholine Receptor-Mediated Activation of Extracellular Signal-Regulated Kinases in PC12 Cells

Kazumi Niinomi, MD^*, Yoshiko Banno, PhD, Hiroki Iida, MD, PhD^*, and Shuji Dohi, MD, PhD^*

From the *Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; and Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, Japan.

Address correspondence and reprint requests to: Shuji Dohi, MD, Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Address e-mail to shu-dohi{at}gifu-u.ac.jp.

BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, is reported to have an antinociceptive effect by hyperpolarization through the K⁺ channel. The activation of extracellular signal-regulated kinase (ERK), a family of mitogen-activated protein kinases, plays an important role in synaptic plasticity and noxious stimulation in the dorsal root ganglion, and spinal neurons have been reported to induce its activation. To understand the biological mechanisms of nicorandil, we examined the effects of nicorandil on muscarinic acetylcholine (ACh) receptor-mediated activation of ERK in a neuronal model cell, rat pheochromocytoma PC12 cells.

METHODS: PC12 cells were stimulated with ACh in the presence or absence of nicorandil, and phosphorylation of ERK was examined by a Western blot analysis. We also examined the effects of nicorandil on the ERK activation induced by 4β-phorbol 12-myristate 13-acetate, an activator of protein kinase C, or ionomycin, a calcium ionophore. Intracellular Ca²⁺ increase was visualized in fluo-3-loaded PC12 cells using fluorescence microscopy.

RESULTS: Nicorandil inhibited ACh-induced ERK activation in a concentration-dependent manner. The inhibition was abolished by glibenclamide, an adenosine triphosphate-sensitive potassium channel blocker. Nicorandil suppressed the ERK activation induced by ionomycin but not 4β-phorbol 12-myristate 13-acetate. Pretreatment of PC12 cells with nicorandil reduced the intracellular Ca²⁺ concentration stimulated by ACh.

CONCLUSIONS: Nicorandil inhibits muscarinic activation of the ERK signaling pathway by reducing the intracellular Ca²⁺ concentration.