Aims

The uremic toxin indoxyl sulfate (IS) was reported to be the cause of cardiovascular disease associated with chronic kidney disease. Therefore, we evaluated the direct influences of IS on vascular function, focusing on the superoxide anion (O₂⁻) and nitric oxide (NO)/soluble guanylate cyclase (sGC) pathways.

Main methods

Isolated rat thoracic aortas with and without vascular endothelium were incubated with IS for 4 h in a physiological solution. In some experiments, several inhibitors were treated 30 min before the addition of IS. O₂⁻ production was measured by the chemiluminescence method, and the vascular reactivity to different vasorelaxants was examined using organ chamber technique.

Key findings

1) Experiments using endothelium-intact vascular rings: IS significantly increased O₂⁻ production. The increase was suppressed by addition of the NADPH oxidase inhibitor apocynin, the antioxidant ascorbic acid and the aryl hydrocarbon receptor (AhR) inhibitor CH223191. Furthermore, IS attenuated the acetylcholine (ACh)-induced vasorelaxantion, which was suppressed by addition of the above drugs. 2) Experiments using endothelium-denuded vascular rings: IS significantly increased O₂⁻ production and also attenuated sodium nitroprusside (SNP)-induced vasorelaxation. These influences of IS were normalized only by ascorbic acid addition. On the other hand, IS did not affect the vasorelaxation by the sGC stimulator BAY 41-2272.

Significance

This study suggested that IS causes O₂⁻ production in vascular tissues, thereby attenuating ACh- and SNP-induced vasorelaxation, probably through NO inactivation. Furthermore, it is reasonable to consider that IS-promoted O₂⁻ production in the presence of vascular endothelium is through binding to AhR and the activation of NADPH oxidase.

中文翻译：

---

硫酸吲哚酚通过芳烃受体-NADPH氧化酶途径诱导ROS的产生并使血管组织中的NO失活

目的

据报道，尿毒症毒素吲哚酚硫酸盐（IS）是与慢性肾脏疾病相关的心血管疾病的病因。因此，我们评估了直接影响对血管功能是，着眼于超氧阴离子（O ₂ ^- ）和一氧化氮（NO）/可溶性鸟苷酸环化酶（sGC的）途径。

主要方法

将分离的有或没有血管内皮的大鼠胸主动脉与IS在生理溶液中孵育4小时。在某些实验中，在加入IS前30分钟对几种抑制剂进行了处理。ö ₂ ^-产量通过化学发光法测定，并使用器官腔技术检测了血管反应性，以不同vasorelaxants。

主要发现

1）利用内皮完整血管环实验：IS显著增加ö ₂ ^-生产。通过添加NADPH氧化酶抑制剂Apocynin，抗氧化剂抗坏血酸和芳烃受体（AhR）抑制剂CH223191抑制了这种增加。此外，IS减弱了乙酰胆碱（ACh）诱导的血管舒张作用，其通过添加上述药物被抑制。2）采用内皮剥蚀血管环实验：IS显著增加ö ₂ ^-生产和也衰减硝普钠（SNP）诱导的血管舒张。IS的这些影响仅通过添加抗坏血酸来归一化。另一方面，IS不会影响sGC刺激物BAY 41-2272的血管舒张作用。

意义

这项研究表明，IS导致Ø ₂ ^-血管组织生产，从而减弱ACH-和SNP诱导血管舒张，可能是通过NO失活。此外，它是合理的考虑IS-促进ö ₂ ^-生产血管内皮的存在是通过结合的AhR和NADPH氧化酶的激活。