Lautenschläger Ingmar, Frerichs Inéz, Dombrowsky Heike, Sarau Jürgen, Goldmann Torsten, Zitta Karina, Albrecht Martin, Weiler Norbert, Uhlig Stefan
Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
PLoS One. 2015 Mar 20;10(3):e0120802. doi: 10.1371/journal.pone.0120802. eCollection 2015.
Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 μM). The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 μM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments deserves further study.
肠道循环障碍、张力缺乏、水肿和肿胀具有重大临床意义，但相关机制及可能的治疗选择尚未得到充分阐明，部分原因在于全面分析这些情况存在困难。为克服这些局限性，我们建立了一个离体灌注大鼠小肠模型，在此模型中可同时研究所有这些症状。在此，我们利用该模型研究类花生酸、类固醇和奎尼丁在血小板活化因子（PAF）诱导的肠道疾病中的作用。血管内注射PAF（0.5 nmol）可引发血栓素和肽白三烯释放至血管床（峰值浓度分别为35 nM和0.8 nM），并重现肠道衰竭的所有症状：肠系膜血管收缩、液体和大分子从血管向肠腔及淋巴管的转移、肠道水肿形成、肠道蠕动丧失以及半乳糖摄取减少。PAF的所有作用均被PAF受体拮抗剂ABT491（2.5 μM）消除。COX和LOX抑制剂阿司匹林和AA861（500 μM、10 μM）未表现出屏障保护作用，类花生酸拮抗剂SQ29548和MK571（各10 μM）仅适度减轻血管内液体的丢失、向肠腔的再分布以及FITC葡聚糖向肠腔的转移。类固醇地塞米松（10 μM）未表现出屏障保护特性，也未能预防水肿形成。奎尼丁（100 μM）可抑制动脉压升高，稳定所有肠道屏障，减少淋巴生成以及FITC葡聚糖向淋巴的转移。虽然奎尼丁本身会降低蠕动，但它也可避免麻痹，保留肠道功能并预防水肿形成。我们得出结论，奎尼丁对肠道血管收缩、水肿形成和麻痹具有多种保护作用。奎尼丁在肠道疾病治疗中的应用值得进一步研究。
