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可溶性鸟苷酸环化酶刺激剂利奥西呱可降低肝硬化大鼠的纤维化和门静脉压力。

The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats.

机构信息

Division of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Vienna Hepatic Hemodynamic Laboratory, Vienna, Austria.

出版信息

Sci Rep. 2018 Jun 19;8(1):9372. doi: 10.1038/s41598-018-27656-y.

DOI:10.1038/s41598-018-27656-y
PMID:29921982
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6008436/
Abstract

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

摘要

在肝硬化患者中，门静脉高压（PHT）会降低生存率，但治疗选择有限。PHT 中肝内血管收缩功能障碍的一个主要原因是一氧化氮信号转导功能障碍。可溶性鸟苷酸环化酶（sGC）是一氧化氮的受体，可被 riociguat 刺激。Riociguat 已被批准用于肺动脉高压，但尚未在肝硬化中进行研究。在这项研究中，我们评估了 riociguat 对胆汁淤积（胆管结扎，BDL）和毒性（四氯化碳，CCl4）大鼠模型中 PHT 和肝纤维化的影响。在肝硬化肝脏中，sGC 表达上调。在 BDL 大鼠中，riociguat 降低了肝纤维化并降低了门静脉压力，而不影响全身血液动力学。在 BDL 疾病的早期阶段，riociguat 减少了胆管增殖，改善了窦状血管功能障碍并抑制了血管生成。在晚期 BDL 中，riociguat 表现出抗炎作用。在 CCl4 大鼠中，riociguat 的治疗效果不那么明显，仅限于早期疾病阶段。同样，在患有胆汁淤积性肝硬化和 PHT 的患者中，硝酸盐（诱导 sGC 活性）降低门静脉压力的效果比患有非胆汁淤积性病因的患者更有效。我们还发现接受 riociguat 治疗的肺动脉高压患者的转氨酶有所改善。我们的研究结果支持在患有肝硬化 PHT 的患者中开发 sGC 刺激剂的临床应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/535bf610120e/41598_2018_27656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/a35eef62769b/41598_2018_27656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/80418ba9be51/41598_2018_27656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/a90e48425d59/41598_2018_27656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/3ced1ca6cedc/41598_2018_27656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/85a9547fe6a3/41598_2018_27656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/535bf610120e/41598_2018_27656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/a35eef62769b/41598_2018_27656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/80418ba9be51/41598_2018_27656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/a90e48425d59/41598_2018_27656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/3ced1ca6cedc/41598_2018_27656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/85a9547fe6a3/41598_2018_27656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5ac/6008436/535bf610120e/41598_2018_27656_Fig6_HTML.jpg

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