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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.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Yamanaka H,Hayashi Y,Iwasaki M,Kamibayashi T,Yamatodani A,Mashimo T

doi

10.1016/j.ejphar.2010.08.035

subject

Has Abstract

pub_date

2010-11-25 00:00:00

pages

155-60

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(10)00839-3

journal_volume

647

pub_type

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Activation of phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide are needed for the antiarrhythmic effect of centrally administered rilmenidine.