title: Nicorandil improves electrical remodelling, leading to the prevention of electrically induced ventricular tachyarrhythmia in a mouse model of desmin-related cardiomyopathy.
abstract: 1. Transgenic (TG) mice overexpressing an arg120gly missense mutation in heat shock protein B5 (HSPB5; i.e. R120G TG mice) exhibit desmin-related cardiomyopathy. Recently, the cardioprotective effect of nicorandil has been shown to prolong the survival of R120G TG mice. However, whether the TG mice exhibit ventricular arrhythmias and whether nicorandil can inhibit these arrhythmias remain unknown. In the present study we examined the effects of chronic nicorandil administration on ventricular electrical remodelling and arrhythmias in R120G TG mice. 2. Mice were administered nicorandil (15 mg/kg per day) or vehicle (water) orally from 5 to 30 weeks of age. Electrocardiograms (ECG) and optical action potentials were recorded from R120G TG mouse hearts. In addition, the expression of ventricular connexin 43 and the cardiac Na(+) channel Nav1.5 was examined in TG mice. 3. All ECG parameters tested were prolonged in R120G TG compared with non-transgenic (NTG) mice. Nicorandil improved the prolonged P, PQ and QRS intervals in R120G TG mice. Interestingly, impulse conduction slowing and increases in the expression of total and phosphorylated connexin 43 and Nav1.5 were observed in ventricles from R120G TG compared with NTG mice. Nicorandil improved ventricular impulse conduction slowing and normalized the increased protein expression levels of total and phosphorylated connexin 43, but not of Nav1.5, in R120G TG mouse hearts. Electrical rapid pacing at the ventricle induced ventricular tachyarrhythmias (VT) in six of eight R120G TG mouse hearts, but not in any of the eight nicorandil-treated R120G TG mouse hearts (P < 0.05). 4. These findings demonstrate that nicorandil inhibits cardiac electrical remodelling and that the prevention of VT by nicorandil is associated with normalization of connexin 43 expression in this model.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Iwate Medical University School of Pharmaceutical Sciences, Shiwa-gun, Iwate, Japan; Department of Pharmacology, Iwate Medical University School of Medicine, Shiwa-gun, Iwate, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Matsushita
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Irie
authors.forename: Eiichi
authors.initials: E
authors.lastname: Taira
mesh_terms: D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000503:physiopathology*; D018031:Connexin 43 / Q000096:biosynthesis; D003893:Desmin / Q000502:physiology*; D004452:Echocardiography; D004558:Electric Stimulation; D004562:Electrocardiography; D055724:Electrophysiological Phenomena / Q000187:drug effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000096:biosynthesis; D020108:Nicorandil / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D003893:Desmin; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D020108:Nicorandil
keywords: Nav1.5; connexin 43; desmin-related cardiomyopathy; heat shock protein B5; nicorandil; ventricular tachyarrhythmia