Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart

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• 作者：Mauricio Ibacache^a ; ^b ; Gina Sanchez^b ; ^c ; ^{gisanchez@med.uchile.cl} ; Zully Pedrozo^b ; Felipe Galvez^b ; ^c ; Claudio Humeres^b ; ^c ; Ghislaine Echevarria^a ; Juan Duaso^b ; ^c ; Mario Hassi^b ; ^c ; Lorena Garcia^b ; Guillermo Dí ; az-Araya^b ; Sergio Lavandero^b ; ^c ; ^d ; ^{slavander@uchile.cl}
• 关键词：AAR ; area at risk ; ADCA ; anterior descendent coronary artery ; Akt ; protein kinase B ; CPP ; coronary perfusion pressure ; DEX ; dexmedetomidine ; EGF ; epidermal growth factor ; Erk1/2 ; extracellular signal-regulated kinase 1/2 ; eNOS ; endothelial nitric oxide sy
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：April, 2012
• 卷：1822
• 期：4
• 页码：537-545
• 文件大小：1304 K

摘要

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an 伪₂-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The 伪₂-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of 伪₂-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of 伪₂-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac 伪₂-adrenergic receptor stimulation.