Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201801, China.
Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Clin Res Hepatol Gastroenterol. 2024 Oct;48(8):102448. doi: 10.1016/j.clinre.2024.102448. Epub 2024 Aug 17.
Vascular hyporeactivity increases with the incidence of obstructive jaundice (OJ). Evidence suggests that OJ activates the farnesoid X receptor (FXR) as well as the large-conductance Ca-activated K (BK or MaxiK) channel. This study was designed to explore the role of the FXR in vascular hyporesponsiveness induced by cholestasis.
The OJ model rats were constructed by bile duct ligation (BDL) and treated with an FXR agonist or antagonist. Vasoconstriction of the mesenteric arteries (MAs) was assessed in vitro. Whole-cell patch clamp recordings were used to investigate BK channel function. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect mRNA and protein levels.
A significant increase in vascular tone and responsiveness to norepinephrine (NE) was observed after the MaxiK channel blocker (IbTX) was administered. This effect was pronounced in BDL animals and can be mimicked by the FXR agonist GW4064 and inhibited by the FXR antagonist Z-guggulsterone (Z-Gu). GW4064 has a similar effect as cholestasis in promoting MaxiK currents in isolated arterial smooth muscle cells (ASMCs), while Z-Gu blunted this effect. The mRNA and protein expression of FXR and MaxiK-β1, but not MaxiK-α, were significantly increased in the BDL group in comparison to the sham. Furthermore, activation or inhibition of FXR promoted or inhibited the mRNA and protein expression of the MaxiK-β1 subunit, respectively.
Activation of FXR enhances the capability of the MaxiK channel to regulate vascular tone and leads to vascular hyporesponsiveness in the MAs of BDL rats, which may be mediated by the nonparallel upregulation of MaxiK-α and MaxiK-β1 subunit expression.
血管低反应性随着阻塞性黄疸（OJ）的发生率而增加。有证据表明，OJ 会激活法尼醇 X 受体（FXR）以及大电导钙激活钾（BK 或 MaxiK）通道。本研究旨在探讨 FXR 在胆汁淤积引起的血管低反应性中的作用。
通过胆管结扎（BDL）构建 OJ 模型大鼠，并给予 FXR 激动剂或拮抗剂进行治疗。在体外评估肠系膜动脉（MAs）的血管收缩。使用全细胞膜片钳记录来研究 BK 通道功能。实时定量聚合酶链反应（RT-qPCR）和 Western blot 用于检测 mRNA 和蛋白水平。
在给予 MaxiK 通道阻滞剂（IbTX）后，观察到血管张力和对去甲肾上腺素（NE）的反应性显著增加。在 BDL 动物中，这种作用更为明显，并且可以被 FXR 激动剂 GW4064 模拟，被 FXR 拮抗剂 Z-金雀花素（Z-Gu）抑制。GW4064 具有与胆汁淤积相似的作用，可促进分离的动脉平滑肌细胞（ASMCs）中的 MaxiK 电流，而 Z-Gu 则减弱了这种作用。与假手术组相比，BDL 组 FXR 和 MaxiK-β1 的 mRNA 和蛋白表达显著增加，但 MaxiK-α 则没有。此外，FXR 的激活或抑制分别促进或抑制了 MaxiK-β1 亚基的 mRNA 和蛋白表达。
FXR 的激活增强了 MaxiK 通道调节血管张力的能力，导致 BDL 大鼠 MAs 的血管低反应性，这可能是通过 MaxiK-α 和 MaxiK-β1 亚基表达的非平行上调介导的。
