Breitman D R, Lee S S
Gastroenterology Research Group, University of Calgary, Alberta, Canada.
Hepatology. 1997 Dec;26(6):1380-5. doi: 10.1002/hep.510260601.
Cardiovascular function in cirrhosis is deranged, with indirect evidence of abnormal central cardiovascular regulation. We aimed to elucidate the role of brainstem cardiovascular nuclei in hemodynamic regulation by examining the protein product, Fos, of the immediate-early gene c-fos, in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation (BDL) of 25-days duration, while controls underwent a sham operation. To examine the effects of jaundice per se in the absence of cirrhosis, a third group of 5-day BDL rats was also studied. All rats were anesthetized with pentobarbital, and catheters were inserted to measure baseline blood pressure and heart rate. Separate groups were then subjected to volume manipulation by a hypotensive hemorrhage or isotonic saline infusion, or no challenge. Ninety minutes after the volume manipulation, the animals were killed and the medulla sectioned and stained for Fos by immunohistochemisty. The nucleus tractus solitarius (NTS) of the sham-operated unchallenged rats showed scant Fos immunoreactivity (27.8 +/- 3.3 cells), but both hemorrhage and volume infusion significantly increased Fos staining (86.0 +/- 3.7 and 95.2 +/- 8.5, respectively). In contrast, the unchallenged cirrhotic rats showed markedly increased Fos in the NTS (154.6 +/- 27.0), but neither hemorrhage nor volume infusion significantly changed the amount of Fos staining. Fos staining in the ventrolateral medulla (VLM) followed a similar pattern with low staining in the unchallenged sham rats and increased staining in the other groups, but no differences between the unchallenged and the volume-manipulated cirrhotic groups. The 5-day BDL jaundiced rats showed no baseline increase in Fos staining, nor any significant increase after hemorrhage. These results showing baseline activation of central neuronal regions responsible for blood pressure homeostasis, but completely blunted responsiveness in cirrhotic rats, confirm a central origin of disordered cardiovascular regulation. The presence of jaundice may also contribute to the central cardiovascular hyporesponsiveness.
肝硬化患者的心血管功能紊乱，有间接证据表明其中心血管调节异常。我们旨在通过检测即刻早期基因c-fos的蛋白产物Fos，来阐明肝硬化大鼠脑干心血管核在血流动力学调节中的作用。通过持续25天的慢性胆管结扎（BDL）诱导肝硬化，而对照组进行假手术。为了研究无肝硬化情况下黄疸本身的影响，还研究了第三组结扎5天的BDL大鼠。所有大鼠均用戊巴比妥麻醉，并插入导管测量基线血压和心率。然后将不同组的大鼠分别通过低血压性出血或等渗盐水输注进行容量操作，或不进行刺激。容量操作90分钟后，处死动物，取延髓切片，通过免疫组织化学法对Fos进行染色。假手术未受刺激的大鼠孤束核（NTS）显示Fos免疫反应性较弱（27.8±3.3个细胞），但出血和容量输注均显著增加了Fos染色（分别为86.0±3.7和95.2±8.5）。相比之下，未受刺激的肝硬化大鼠NTS中Fos明显增加（154.6±27.0），但出血和容量输注均未显著改变Fos染色量。延髓腹外侧（VLM）的Fos染色呈现类似模式，未受刺激的假手术大鼠染色较低而其他组染色增加，但未受刺激的肝硬化组与容量操作的肝硬化组之间无差异。结扎5天的BDL黄疸大鼠Fos染色在基线时未增加，出血后也无显著增加。这些结果表明负责血压稳态的中枢神经区域存在基线激活，但肝硬化大鼠的反应性完全减弱，证实了心血管调节紊乱的中枢起源。黄疸的存在也可能导致中枢心血管反应性降低。
