Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil.
Department of Physiology, Institute of Health Sciences, Federal University of Goias, Jatai, Brazil.
Life Sci. 2018 Nov 1;212:168-175. doi: 10.1016/j.lfs.2018.09.051. Epub 2018 Oct 4.
Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation and cirrhotic cardiomyopathy. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include vascular dysregulations.
The present study tested the hypothesis that the systemic vascular hyporesponsiveness in thioacetamide (TAA)-induced liver injury model is dependent on nitric oxide (NO) and cyclooxygenase (COX) derivatives.
Wistar rats were treated with TAA for eight weeks to induce liver injury.
The maximal contractile response in concentration-effect curves to phenylephrine was decreased in aorta from TAA-treated rats, but no differences were found in aorta without endothelium, suggesting an endothelium-dependent mechanism in decreased contractile response. There was no difference in the contractile response with and without L-NAME (N(ω)-nitro-l-arginine methyl ester) in rats with liver injury, showing that the TAA treatment impairs NO synthesis. Pre-incubation of the aorta with indomethacin, a COX-inhibitor, normalized the reduced contractile response to phenylephrine in arteries from TAA group. Also, COX-2 and iNOS (inducible nitric oxide syntase) protein expression was increased in aorta from TAA group compared to control group. Animals submitted to TAA treatment had a reduction in systolic blood pressure. Our findings demonstrated that liver injury induced by TAA caused a decrease in aortic contractile response by a COX-dependent mechanism but not by NO release. Also, it was demonstrated an inflammatory process in the aorta of TAA-treated rats by increased expression of COX-2 and iNOS.
Therefore, there is an essential contribution of COX-2 activation in extra-hepatic vascular dysfunction and inflammation present in cirrhosis induced by TAA.
肝硬化与多种心血管异常相关，包括高动力循环和肝硬化性心肌病。这些心血管变化的发病机制是多因素的，包括血管失调。
本研究检验了以下假设，即在硫代乙酰胺 (TAA) 诱导的肝损伤模型中，全身血管低反应性依赖于一氧化氮 (NO) 和环氧化酶 (COX) 衍生物。
用 TAA 处理 Wistar 大鼠 8 周以诱导肝损伤。
TAA 处理大鼠主动脉对苯肾上腺素的浓度-效应曲线的最大收缩反应降低，但无内皮的主动脉无差异，提示收缩反应降低存在内皮依赖性机制。在肝损伤大鼠中，用和不用 L-NAME（N(ω)-硝基-L-精氨酸甲酯）处理时，收缩反应无差异，表明 TAA 处理损害了 NO 合成。预先孵育 COX 抑制剂吲哚美辛可使 TAA 组动脉对苯肾上腺素的收缩反应正常化。此外，与对照组相比，TAA 组主动脉 COX-2 和 iNOS（诱导型一氧化氮合酶）蛋白表达增加。TAA 处理的动物收缩压降低。我们的发现表明，TAA 诱导的肝损伤通过 COX 依赖机制而不是通过 NO 释放导致主动脉收缩反应降低。此外，TAA 处理大鼠的主动脉中 COX-2 和 iNOS 的表达增加表明存在炎症过程。
因此，在 TAA 诱导的肝硬化中，COX-2 的激活对肝外血管功能障碍和炎症有重要贡献。
