Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats
Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats
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DOI：
10.1038/sj.bjp.0706331
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发表时间：
2005-10-01
影响因子：
7.3
通讯作者：
Lee, SS
中科院分区：
文献类型：
--
作者：
Gaskari, SA;Liu, HQ;Lee, SS
1肝硬化患者的心脏收缩力在基线时是正常的，但对刺激反应迟钝，这种现象被称为"硬化性心肌病"。其发病机制尚不清楚。内源性大麻素是血管活性的，但以前没有被检查在心脏病。因此，我们的目的是系统地澄清内源性大麻素的发病机制中可能发挥的作用。2肝硬化诱导的Sprague-道利大鼠胆管结扎;对照组进行假手术。术后4周，研究了离体左心室乳头肌收缩性。3在存在和不存在CB-1拮抗剂AM 251（1 μ M）的情况下，构建β-肾上腺素能激动剂异丙肾上腺素的剂量-反应曲线。肝硬化肌肉对异丙肾上腺素的反应减弱，AM251可完全恢复。4对花生四烯酸的剂量-反应曲线，在Western印迹和逆转录-聚合酶链反应实验中，CB-1和CB-2蛋白和mRNA表达在肝硬化和假手术肌肉之间没有显著差异。5在肝硬化和正常肌肉中进行力-频率关系研究。在较高的频率，anandamide再摄取阻滞剂（VDM11和AM404）显着增强肌肉松弛的痉挛肌肉，但不是在控制。这种作用被AM251和百日咳毒素完全阻断，而河豚毒素部分逆转了它。6总之，这些结果表明，内源性大麻素的局部（神经元）产生增加的致病作用，由Gi蛋白依赖性CB-1反应途径介导。心动过速应激诱导的内源性大麻素释放增加可能有助于解释为什么收缩性在基线时是正常的，但随着应激而减弱。
1 Cardiac contractility in cirrhosis is normal at baseline but hyporesponsive to stimuli, a phenomenon known as ` cirrhotic cardiomyopathy'. The pathogenesis remains unclear. Endocannabinoids are vasoactive, but have not previously been examined in the cirrhotic heart. We therefore aimed to systematically clarify a possible role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy.2 Cirrhosis was induced in Sprague - Dawley rats by bile duct ligation; controls underwent a sham operation. At 4 weeks after operation, isolated left ventricular papillary muscle contractility was studied.3 Dose - response curve for a beta- adrenergic agonist isoproterenol was constructed in the presence and absence of a CB- 1 antagonist AM251 ( 1 mu M). Cirrhotic muscles had a blunted response to isoproterenol, which was completely restored by AM251.4 Dose- response curves to anandamide, and CB- 1 and CB- 2 protein and mRNAexpression in Western blot and reverse transcriptase - polymerase chain reaction experiments were not significantly different between cirrhotic and sham muscles.5 Force - frequency relationship studies were performed in cirrhotic and normal muscles. At higher frequencies, anandamide reuptake blockers ( VDM11 and AM404) significantly enhanced muscle relaxation in cirrhotic muscles, but not in controls. This effect was completely blocked by AM251 and pertussis toxin, whereas tetrodotoxin partially reversed it.6 Taken together, these results indicate a pathogenic role for increased local ( neuronal) production of endocannabinoids, mediated by a Gi- protein- dependent CB- 1- responsive pathway in cirrhotic cardiomyopathy. The increased tachycardia- stress- induced release of endocannabinoids may help explain why contractility is normal at baseline but attenuated with stress.