心脏咪唑啉受体与alpha2A肾上腺素能受体在右美托咪定加重脓毒症心肌功能障碍中的作用

Myocardial dysfunction is a common complication associated with increased morbidity and mortality in septic patients. Some studies have demonstrated that treatment of septic animals with α2A-adrenergic receptor (α2A-AR) antagonist attenuates myocardial dysfunction and significantly improves survival. According to these findings, we hypothesize that dexmedetomidine (DEX), an α2-AR agonist with sedative and analgesic properties used in the intensive care unit, may aggravate sepsis-induced myocardial dysfunction. Although some studies showed that administration of DEX before or 1 h after sepsis induction reduced the mortality rate and inhibited pro-inflammatory cytokine responses in sepsis, these are different from the clinical setting. In the clinic setting, the patients with severe sepsis and septic shock proceed to the development of one or multiple organ dysfunctions; this condition is similar to that of septic animals 6 h after sepsis induction. However, it is unclear whether administration of DEX 6 h after sepsis induction may affect survival and, particularly, myocardial dysfunction during sepsis. In order to test our hypothesis, we conducted a preliminary experiment and demonstrated that DEX administered 4 h post cecal ligation and puncture increased the mortality rate in rats and DEX treatment also enhanced lipopolysaccharide-induced myocardial dysfunction in isolated rat hearts, but the mechanisms by which DEX aggravated lipopolysaccharide-induced myocardial dysfunction are still unknown. In the present study, we used animal model of sepsis, isolated rat heart, cardiomyocytes, cardiac fibroblasts and endothelial cells to investigate the role of α2A-AR and imidazoline type-1 receptor signaling, cardiac inflammation as well as myocardial calcium regulation and mitochondrial function in the enhancing effects of DEX on sepsis-induced myocardial dysfunction. These investigations will further explain the molecular mechanisms for sepsis-triggered myocardial depression and provide the evidence for reasonable selection of sedative drugs in patients with septic myocardial dysfunction.

心肌功能障碍是脓毒症常见的并发症，与患者死亡密切相关。研究表明，阻断α2A肾上腺素能受体（α2A-AR）能显著减轻脓毒症诱导的心肌功能障碍，降低脓毒症动物的死亡率。因此，右美托咪定（DEX）作为α2-AR激动剂类镇静剂，理论上可能会加重脓毒症心肌功能障碍。尽管有研究显示，复制脓毒症模型前或后1h给予DEX能抑制炎症反应、改善脓毒症动物的生存，但临床上，严重脓毒症或脓毒症休克患者已有器官功能障碍，时间上相当于CLP造模6 h后，那么CLP术后6 h给予DEX对脓毒症动物、特别是心肌功能，有何影响？目前缺乏研究。我们预实验发现DEX确实加重脂多糖诱导的心功能障碍，但机制并不清楚。本研究从心肌细胞、心脏成纤维细胞和血管内皮细胞α2A-AR和咪唑啉Ⅰ型受体、炎症、心肌钙代谢及线粒体功能方面，阐明DEX加重脓毒症心肌功能障碍的机制，对脓毒症心功能障碍患者合理选用镇静剂具有重要的临床指导意义。

心肌功能障碍是脓毒症常见的并发症，与患者死亡密切相关。尽管有研究显示，复制脓毒症模型前或后1h给予右美托咪定（DEX）能抑制炎症反应、改善脓毒症动物的生存，但临床上，脓毒症患者已有器官功能障碍，时间上相当于脓毒症造模6 h后，那么脓毒症发生后6 h给予DEX对脓毒症心肌功能有何影响？目前缺乏研究。我们前期研究发现脓毒症发生后4 h给予DEX确实加重脂多糖诱导的心功能障碍，但机制并不清楚。本研究从心肌细胞、心脏成纤维细胞和血管内皮细胞α2A-肾上腺素能受体(AR)和咪唑啉Ⅰ型受体、炎症、心肌能量代谢方面，阐明DEX加重脓毒症心肌功能障碍的机制。结果发现，脓毒症发生后6h给予DEX会促进脓毒症大鼠死亡。在脓毒症发生后6 h给予DEX处理会加重脓毒症诱发的心功能障碍，促进心脏炎症因子的表达和能量代谢障碍，DEX促进脓毒症心功能障碍不依赖于心脏咪唑啉Ⅰ型受体，主要通过α2A-AR信号途径发挥作用。DEX加重LPS诱导的心肌收缩与舒张功能障碍，促进了心脏血管内皮ICAM-1、VCAM-1和TNF-alpha的表达，敲除α2A-AR可消除右美托咪定的作用；然而，高剂量的DEX显著抑制 LPS 刺激的心脏成纤维细胞产生 TNF-α，但不能影响LPS刺激的心肌细胞释放TNF-α，表明DEX促进脓毒症大鼠心功能障碍主要是通过心脏内皮细胞α2A-AR发挥作用。此外，小胶质细胞可表达α2A-AR，激活该受体可加重脓毒症相关脑病的发病程度。这些结果建议脓毒症患者在脓毒症发生后不宜使用右美托咪定进行镇静，对脓毒症心功能障碍患者合理选用镇静剂具有重要的临床指导意义。