Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

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• 作者：Jaime A. Riquelme^a ; Francisco Westermeier^a ; Andrew R. Hall^b ; José ; Miguel Vicencio^b ; Zully Pedrozo^a ; ^c ; Mauricio Ibacache^d ; Bá ; rbara Fuenzalida^e ; Luis Sobrevia^e ; ^f ; ^g ; Sean M. Davidson^b ; Derek M. Yellon^b ; Gina Sá ; nchez^c ; ^{gisanchez@med.uchile.cl" class="auth_mail" title="E-mail the corresponding author} ; Sergio Lavandero^a ; ^c ; ^h ; ^{slavander@uchile.cl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PTIO ; (9S ; 10R ; 12R)-2 ; 3 ; 9 ; 10 ; 11 ; 12-hexahydro-10-methoxy-2 ; 9-dimethyl-1-oxo- ; 12epoxy 1Hdiindolo [1 ; 2 ; 3-fg ; 3&prime ; 2&prime ; 1&prime ; -kl] pyrrolo[3 ; 4-i] [1 ; 6] benzodiazocine-10-carboxylic acid ; methyl ester KT58232phenyl-4 ; 4 ; 5 ; 5-tetramethylimidazoline-1-oxyl 3-oxide ; L-NAME ; L-NG-nitroarginine methyl ester ; Dex ; Dexmedetomidine ; TTC ; triphenyltetrazolium chloride ; IR ; Ischemia-Reperfusion ; sIR ; simulated ischemia-reperfusion ; eNOS ; endothelial nitric oxide synthase ; nNOS ; neuronal nitric oxide synt
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：103
• 期：Complete
• 页码：318-327
• 全文大小：1808 K

文摘

The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10 nM) for 25 min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120 min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.