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

• Published in: Biochimica et biophysica acta Vol. 1822; no. 4; pp. 537 - 545
• Main Authors: Ibacache, Mauricio, Sanchez, Gina, Pedrozo, Zully, Galvez, Felipe, Humeres, Claudio, Echevarria, Ghislaine, Duaso, Juan, Hassi, Mario, Garcia, Lorena, Díaz-Araya, Guillermo, Lavandero, Sergio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2012
• Subjects: Alpha2-adrenergic receptor; Anesthesia; Animals; Dexmedetomidine; Dexmedetomidine - pharmacology; Male; Myocardial infarction; Myocardial ischemia; Myocardial Ischemia - enzymology; Myocardial Ischemia - prevention & control; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury - prevention & control; Myocardial infarction; Ser; CPP; eNOS; LVSP; Myocardial ischemia; HR; LV; dP/dtmin; I/R; LY; LVEDP; PI3K; Anesthesia; ADCA; Thr; Erk1/2; dP/dtmax; EGF; Akt; Tyr; Alpha2-adrenergic receptor; AAR; YOH; LVDP; DEX; Dexmedetomidine; MAP
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2011.12.013

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α2-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 30min of regional ischemia followed by 120min of reperfusion with dexmedetomidine before ischemia. The α2-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 α2-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 α2-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 α2-adrenergic receptor stimulation. ► Dexmedetomidine activates Erk 1/2, Akt and eNOS in rat cardiac tissue. ► Dexmedetomidine reduces myocardial infarction size in models of regional I/R injury. ► Dexmedetomidine improves ventricular function recovery in a model of I/R injury. ► All these effects are mediated by cardiomycyte α2-adrenergic receptor stimulation.