Vanneste Gwen, Van Nassauw Luc, Kalfin Reni, Van Colen Inge, Elinck Ellen, Van Crombruggen Koen, Timmermans Jean-Pierre, Lefebvre Romain A
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
Surgery. 2008 Sep;144(3):410-26. doi: 10.1016/j.surg.2008.05.011.
In animal models of postoperative ileus (POI), inflammation of the intestine plays an important role in the pathogenesis of POI. Changes in alpha(2)-adrenoceptors and nitrergic regulation have been proposed to be implicated. The aim of our study was to investigate the presynaptic alpha(2)-receptor-mediated control of cholinergic nerve activity, the nitrergic nerve activity, and the possible role of soluble guanylate cyclase (sGC) during the inflammatory phase of POI.
Ileus was induced by anesthesia and manipulation of the rat jejunum. Rats were treated with the sGC inhibitors methylene blue or ODQ; nonoperated animals served as controls. After 24 h, plasma and jejunal tissue were collected for biochemical assays, nitric oxide synthase-1 (NOS-1)-immunohistochemistry, acetylcholine (Ach)-release experiments, and muscle tension experiments.
In all operated animal groups, myeloperoxidase activity was significantly increased, which indicates initiation of an inflammatory response. The alpha(2)-adrenoceptor agonist UK14,304 reduced electrically induced Ach-release similarly in operated and nonoperated animals. In strips of operated animals, electrically induced nitrergic relaxations were decreased, whereas relaxations induced by exogenous nitric oxide (NO) remained unchanged compared with control. The number of myenteric neurons and the percentage of NOS-1-positive neurons were not influenced. Plasmatic cyclic guanosine monophosphate (cGMP) levels were decreased in all operated groups, whereas jejunal cGMP levels were unchanged compared with nonoperated controls; treatment with sGC inhibitors did not reduce plasmatic cGMP levels.
This study demonstrates that presynaptic alpha(2)-receptor mediated control of intestinal cholinergic nerve activity is unchanged during manipulation-induced inflammation. However, this inflammation induces impaired nitrergic neurotransmission related to decreased NOS-1 activity in the nitrergic nerves.
在术后肠梗阻（POI）动物模型中，肠道炎症在POI发病机制中起重要作用。有人提出α（2）-肾上腺素能受体和一氧化氮能调节的变化与之有关。我们研究的目的是调查在POI炎症期，突触前α（2）-受体介导的胆碱能神经活动控制、一氧化氮能神经活动以及可溶性鸟苷酸环化酶（sGC）的可能作用。
通过麻醉和操作大鼠空肠诱导肠梗阻。大鼠用sGC抑制剂亚甲蓝或ODQ治疗；未手术的动物作为对照。24小时后，收集血浆和空肠组织进行生化测定、一氧化氮合酶-1（NOS-1）免疫组织化学、乙酰胆碱（Ach）释放实验和肌肉张力实验。
在所有手术动物组中，髓过氧化物酶活性显著增加，这表明炎症反应开始。α（2）-肾上腺素能受体激动剂UK14,304在手术和未手术动物中同样降低电诱导的Ach释放。在手术动物的肠条中，电诱导的一氧化氮能舒张降低，而与对照相比，外源性一氧化氮（NO）诱导的舒张保持不变。肌间神经元数量和NOS-1阳性神经元百分比不受影响。所有手术组血浆环磷酸鸟苷（cGMP）水平降低，而与未手术对照相比空肠cGMP水平不变；用sGC抑制剂治疗未降低血浆cGMP水平。
本研究表明，在操作诱导的炎症期间，突触前α（2）-受体介导的肠道胆碱能神经活动控制未改变。然而，这种炎症导致与一氧化氮能神经中NOS-1活性降低相关的一氧化氮能神经传递受损。
