机构：[1]Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People’s Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong, China.[2]Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cardiomyopathy is a common complication associated with increased mortality in sepsis, but lacks specific therapy. Here, using genetic and pharmacological approaches, we explored the therapeutic effect of α2A-adrenergic receptor (AR) blockade on septic cardiomyopathy. CLP-induced septic rats were treated with BRL44408 (α2A-AR antagonist), prazosin (α1-AR antagonist) and/or reserpine. CLP-induced cardiomyopathy, indicated by reduced dP/dt and increased cardiac troponin I phosphorylation, was attenuated by BRL44408, this was associated with reduced cardiac TNF-α and endothelial VCAM-1 expression, cardiomyocyte apoptosis and related signal molecule phosphorylation. BRL44408 increased cardiac norepinephrine (NE) concentration in CLP rats. Pretreatment with reserpine that exhausts cardiac NE without affecting the circulating NE concentration or with prazosin partially abolished the cardioprotection of BRL44408 and reversed its inhibitory effects on myocardial TNF-α, apoptosis and related signal molecule phosphorylation, but not on VCAM-1 expression in septic rats. These effects of BRL44408 were confirmed by α2A-AR gene deletion in septic mice. Furthermore, α2-AR agonist not only enhanced LPS-induced TNF-α and VCAM-1 expression in cardiac endothelial cells that express α2A-AR, but also enhanced LPS-induced cardiac dysfunction in isolated rat hearts. Our data indicate that α2A-AR blockade attenuates septic cardiomyopathy by promoting cardiac NE release that activates myocardial α1-AR and suppressing cardiac endothelial activation.
基金：
This work was supported by grants from the National Natural Science Foundation of China (81170222, 81372028),
the Guangdong Natural Science Foundation (S2011020005408), a Project of the Department of Education of
Guangdong Province (2013KJCX0019), and the Guangzhou Science and Technology Projects (201508020005).
We thank Ms. Yanping Wang for assistance in echocardiographic analysis.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|3 区综合性期刊
小类|3 区综合性期刊
最新[2025]版：
大类|3 区综合性期刊
小类|3 区综合性期刊
第一作者：
第一作者机构：[1]Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People’s Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Xiaohui Yu,Yuan Wang,Duomeng Yang,et al.α2A-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation.[J].Scientific reports.2018,8(1):5478.doi:10.1038/s41598-018-23304-7.
