Jaue D N, Ma Z, Lee S S
Liver Unit, University of Calgary, Alberta, Canada.
Hepatology. 1997 Jun;25(6):1361-5. doi: 10.1002/hep.510250610.
The pathogenesis of cirrhotic cardiomyopathy remains unclear. Because ventricular contractility is dependent on the interplay of stimulatory beta-adrenergic and inhibitory muscarinic receptors, we aimed to examine a possible role of muscarinic M2 receptor overactivity in a rat model of cirrhotic cardiomyopathy. Cirrhosis was induced by bile duct ligation (BDL), while controls underwent sham operations. Contractile responses to the muscarinic agonist carbachol were measured in situ in the autonomic-denervated pithed rat and in vitro in isolated ventricular papillary muscles. Ventricular sarcolemmal plasma membranes were isolated by sucrose density gradients, and muscarinic receptor characteristics were studied using 1-[N-methyl-3H]scopolamine (NMS). Membrane adenylyl cyclase activity was tested by a protein binding assay. Maximum first time derivative of peak ventricular systolic pressure (+dP/dt) for sham-operated and cirrhotic rats at baseline was 3,599 +/- 296 versus 1,226 +/- 63 mm Hg/sec (P < .01). Maximum first time derivative of ventricular diastolic relaxation (-dP/dt) for sham and cirrhotic rats at basal levels was -3,040 +/- 235 versus -864 +/- 59 (P < .01). The +dP/dt(max), and -dP/dt(max) responses to carbachol were blunted in the cirrhotic rats. The cirrhotic papillary muscles showed significantly less inhibition to incremental doses of carbachol than control rat muscles. Likewise, isoproterenol-stimulated membrane adenylyl cyclase activity was significantly less inhibited by carbachol doses in the cirrhotic rats. Membrane M2 receptor density and binding affinity in cirrhotic rat hearts were similar to controls. We conclude that muscarinic responsiveness was blunted in cirrhotic hearts, but this was not caused by receptor down-regulation, suggesting changes in postreceptor factors. These changes in muscarinic function are likely compensatory, and M2 receptor overactivity is not involved in the genesis of cirrhotic cardiomyopathy.
肝硬化性心肌病的发病机制尚不清楚。由于心室收缩力取决于刺激性β-肾上腺素能受体和抑制性毒蕈碱受体的相互作用，我们旨在研究毒蕈碱M2受体活性过高在肝硬化性心肌病大鼠模型中的可能作用。通过胆管结扎（BDL）诱导肝硬化，而对照组进行假手术。在自主神经去神经的脊髓麻醉大鼠中对毒蕈碱激动剂卡巴胆碱的收缩反应进行原位测量，并在离体心室乳头肌中进行体外测量。通过蔗糖密度梯度分离心室肌膜质膜，并使用1-[N-甲基-3H]东莨菪碱（NMS）研究毒蕈碱受体特征。通过蛋白质结合试验测试膜腺苷酸环化酶活性。假手术组和肝硬化大鼠在基线时心室收缩压峰值的最大首次时间导数（+dP/dt）分别为3599±296和1226±63 mmHg/秒（P<.01）。假手术组和肝硬化大鼠在基础水平时心室舒张期松弛的最大首次时间导数（-dP/dt）分别为-3040±235和-864±59（P<.01）。肝硬化大鼠对卡巴胆碱的+dP/dt（max）和-dP/dt（max）反应减弱。肝硬化乳头肌对递增剂量卡巴胆碱的抑制作用明显小于对照大鼠肌肉。同样，肝硬化大鼠中卡巴胆碱剂量对异丙肾上腺素刺激的膜腺苷酸环化酶活性的抑制作用明显较小。肝硬化大鼠心脏中的膜M2受体密度和结合亲和力与对照组相似。我们得出结论，肝硬化心脏中毒蕈碱反应性减弱，但这不是由受体下调引起的，提示受体后因素发生了变化。毒蕈碱功能的这些变化可能是代偿性的，并且M2受体活性过高不参与肝硬化性心肌病的发生。
