Ma Z, Zhang Y, Huet P M, Lee S S
Liver Unit, Faculty of Medicine, The University of Calgary, Alberta, Canada.
J Hepatol. 1999 Mar;30(3):485-91. doi: 10.1016/s0168-8278(99)80109-3.
BACKGROUND/AIMS: Attenuated cardiac function has been reported in cirrhosis as well as in jaundice, but the mechanisms remain unclear. This study aimed to explore the differential effects of jaundice and cirrhosis on the heart.
Three rat models of cirrhosis were studied: chronic bile duct ligation, bile duct ligation followed by choledochojejunostomy to relieve jaundice, and a less jaundiced model induced by thioacetamide administration. Controls underwent a sham operation. Cardiac function was assessed by measuring isolated ventricular papillary muscle contractility. Cardiac beta-adrenergic receptor signaling was studied by measuring cAMP production stimulated at the receptor, G-protein, and adenylyl cyclase levels in the signaling pathway, using isoproterenol, aluminum fluoride and forskolin, respectively.
Serum bilirubin and bile salt levels were markedly elevated in the bile duct-ligated group, moderately increased in the thioacetamide rats, and normal in the choledochojejunostomy and sham-operated controls. Papillary muscle contractile force after maximal beta-adrenergic receptor stimulation was decreased to a similar extent in all three cirrhotic models. In the bile duct-ligated and thioacetamide-induced cirrhotic rats, production of cAMP by all three drugs was significantly attenuated. However, the cAMP production in the choledochojejunostomy group was blunted only with isoproterenol and fluoride, and remained intact with forskolin stimulation.
These results demonstrate that cirrhosis per se impairs cardiac function by attenuating the portion of the beta-adrenergic receptor signaling pathway upstream of adenylyl cyclase. Furthermore, significant jaundice and/or cholemia can inhibit adenylyl cyclase, which may contribute to blunted cardiac contractility in jaundiced patients.
背景/目的：已有报道称肝硬化以及黄疸患者存在心脏功能减弱的情况，但其机制尚不清楚。本研究旨在探讨黄疸和肝硬化对心脏的不同影响。
研究了三种肝硬化大鼠模型：慢性胆管结扎、胆管结扎后行胆总管空肠吻合术以缓解黄疸，以及通过给予硫代乙酰胺诱导的轻度黄疸模型。对照组进行假手术。通过测量离体心室乳头肌收缩力评估心脏功能。分别使用异丙肾上腺素、氟化铝和福斯高林，通过测量信号通路中受体、G蛋白和腺苷酸环化酶水平刺激产生的环磷酸腺苷（cAMP），研究心脏β-肾上腺素能受体信号传导。
胆管结扎组血清胆红素和胆汁盐水平显著升高，硫代乙酰胺大鼠组中度升高，胆总管空肠吻合术组和假手术对照组正常。在所有三种肝硬化模型中，最大β-肾上腺素能受体刺激后乳头肌收缩力均有相似程度的降低。在胆管结扎和硫代乙酰胺诱导的肝硬化大鼠中，三种药物产生的cAMP均显著减少。然而，胆总管空肠吻合术组仅在异丙肾上腺素和氟化物刺激下cAMP产生受到抑制，在福斯高林刺激下仍保持完整。
这些结果表明，肝硬化本身通过减弱腺苷酸环化酶上游的β-肾上腺素能受体信号通路部分来损害心脏功能。此外，显著的黄疸和/或胆血症可抑制腺苷酸环化酶，这可能导致黄疸患者心脏收缩力减弱。
