title: Activation of phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide are needed for the antiarrhythmic effect of centrally administered rilmenidine.
abstract: Activation of imidazoline receptors in the central nervous system has protective effect on several types of arrhythmias. We demonstrated that centrally administered rilmenidine, a selective imidazoline receptor agonist, prevented adrenaline-induced arrhythmias during halothane anaesthesia. However, detailed myocardial signaling of the antiarrhythmic effect remains to be unexplored. The present study was designed to examine a role of pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide in the antiarrhythmic effect of rilmenidine. Male Sprague-Dawley rats were anaesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of adrenaline was defined as the smallest dose producing 3 or more premature ventricular contractions within 15-s period. Firstly, we confirmed that centrally administered rilmenidine prevented adrenaline-induced arrhythmias during halothane anaesthesia and examined the effect of pertussis toxin, wortmannin (a phosphatidylinositol 3-kinase inhibitor), and nitro-L-arginine methyl ester (L-NAME) (a specific nitric oxide synthesis inhibitors), on the antiarrhythmic effect of rilmenidine. We also performed Western blot analysis to determine phosphorylation of Akt and glycogen synthase kinase 3β, a direct Akt downstream target, following the central administration of rilmenidine. The antiarrhythmic effect of rilmenidine was significantly inhibited by pertussis toxin, wortmannin and L-NAME. Rilmenidine increased Akt and glycogen synthase kinase 3β phosphorylation (28±13% and 32±13%, respectively), and this action was abolished by wortmannin. The present results demonstrated that pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase-Akt-GSK3β signaling pathway and endogenous nitric oxide may play a key role in antiarrhythmic effect of centrally administered rilmenidine.
authors.affiliation: Department of Anesthesiology, Osaka University Medical School, Suita, Osaka, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kamibayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamatodani
authors.forename: Takashi
authors.initials: T
authors.lastname: Mashimo
mesh_terms: D000730:Androstadienes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004837:Epinephrine / Q000008:administration & dosage / Q000494:pharmacology; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D010080:Oxazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077769:Rilmenidine; D015398:Signal Transduction / Q000187:drug effects; D013566:Sympathomimetics / Q000008:administration & dosage / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000889:Anti-Arrhythmia Agents; D004837:Epinephrine; D006221:Halothane; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010080:Oxazoles; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D000077769:Rilmenidine; D013566:Sympathomimetics; D000077191:Wortmannin; C093426:pertussis toxin receptor