ABSTRACT
BACKGROUND: Persistent myocardial ischemia post-myocardial infarction can lead to fatal ventricular arrhythmias such as ventricular tachycardia and fibrillation, both of which carry high mortality rates. Dexmedetomidine (Dex) is a highly selective α2-agonist used in surgery for congenital cardiac disease because of its antiarrhythmic properties. Dex has previously been reported to prevent or terminate various arrhythmias. The purpose of the present study was to determine the anti-arrhythmic properties of Dex in the context of ischemic cardiomyopathy (ICM) after myocardial infarction. METHODS AND RESULTS: We randomly allocated 48 rats with ICM, created by persistent ligation of the left anterior descending artery for 4 weeks, into six groups: Sham (n = 8), Sham + BML (n = 8), ICM (n = 8), ICM + BML (n = 8), ICM + Dex (n = 8), and ICM + Dex + BML (n = 8). Treatments started after ICM was confirmed (the day after echocardiographic measurement) and continued for 4 weeks (inject intraperitoneally, daily). Dex inhibited the generation of collagens, cytokines, and other inflammatory mediators in rats with ICM via the suppression of NF-κB activation and increased the distribution of connexin 43 (Cx43) via phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Dex reduced the occurrence of spontaneous ventricular arrhythmias (ventricular premature beat or ventricular tachycardia), decreased the inducibility quotient of ventricular arrhythmias induced by PES, and partly improved cardiac contraction. The AMPK antagonist BML-275 dihydrochloride (BML) partly weakened the cardioprotective effect of Dex. CONCLUSION: Dex conferred anti-arrhythmic effects in the context of ICM via upregulation of Cx43 and suppression of inflammation and fibrosis. The anti-arrhythmic and anti-inflammatory properties of Dex may be mediated by phosphorylation of AMPK and subsequent suppression of NF-κB activation.
ABSTRACT
BACKGROUND: With chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti-inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7-nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM). METHODS AND RESULTS: Left anterior descending artery of adult male Sprague-Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti-inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF-κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti-inflammatory, anti-fibrosis, and anti-arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration-induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF-κB activation in lipopolysaccharide-stimulated RAW264.7 cells, and α-bungarotoxin (an α7-nAChR selective antagonist) partly inhibited the nicotine-treatment effect. In addition, 4-week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia. CONCLUSIONS: Eliciting the cholinergic anti-inflammatory pathway exerts anti-arrhythmogenic effects against ICM-induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM-induced ventricular arrhythmia by eliciting the cholinergic anti-inflammatory pathway.
