内皮依赖性血管舒张功能受损并非舒尼替尼相关性高血压发生发展的起始因素。

Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension.

作者信息

Thijs Anna M J, van Herpen Carla M L, Verweij Vivienne, Pertijs Jeanne, van den Broek Petra H H, van der Graaf Winette T A, Rongen Gerard A

机构信息

aDepartment of Pharmacology-Toxicology bDepartment of Medical Oncology cDepartment of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.

出版信息

J Hypertens. 2015 Oct;33(10):2075-82. doi: 10.1097/HJH.0000000000000662.

DOI:10.1097/HJH.0000000000000662

PMID:26203967

Abstract

BACKGROUND

Tyrosine kinase inhibitors targeting angiogenesis have become an important part of the treatment of patients with several types of cancer. One of the most reported side effects of vascular endothelial growth factor receptor (VEGFR)-targeted therapies is hypertension. In this study, we hypothesized that the development of hypertension in patients treated with sunitinib, a multitargeted tyrosine kinase inhibitor, is preceded by reduced endothelium-dependent vasodilation. Moreover, we hypothesized that this endothelial dysfunction is a result of impaired nitric oxide release.

METHOD

In a placebo-controlled experiment, we determined vascular responses in isolated mesenteric arteries of rats (n = 26) after 7 days of sunitinib treatment.

RESULTS

Sunitinib reduced endothelium-dependent vasodilation, but not endothelium-independent vasodilation. Moreover, we observed that the difference in endothelium-dependent vasodilation between controls and sunitinib-treated animals disappeared in the presence of N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide antagonist. In patients with metastatic renal cell carcinoma, before and 1 week after start of sunitinib, the endothelium-dependent vasodilator response to intra-arterial acetycholine and the endothelium-independent vasodilator response to intra-arterial sodium nitroprusside was assessed with venous occlusion plethysmography. No changes in forearm blood flow ratios were observed. Mean arterial pressure did significantly increase from 101.9 ± 3.8 to 106.1 ± 2.6 mmHg after 1 week and further to 115.8 (±4.9) mmHg after 2 weeks of treatment.

CONCLUSION

In animals, this study confirms that exposure to high concentrations of sunitinib reduces endothelium-dependent vasodilation by reducing endothelial release of nitric oxide. In humans, however, reduced endothelium-dependent vasodilation does not precede the development of hypertension in patients treated with sunitinib.

摘要

背景

靶向血管生成的酪氨酸激酶抑制剂已成为多种癌症患者治疗的重要组成部分。血管内皮生长因子受体（VEGFR）靶向疗法最常报道的副作用之一是高血压。在本研究中，我们假设，接受多靶点酪氨酸激酶抑制剂舒尼替尼治疗的患者出现高血压之前，会先出现内皮依赖性血管舒张功能降低。此外，我们假设这种内皮功能障碍是一氧化氮释放受损的结果。

方法

在一项安慰剂对照实验中，我们测定了舒尼替尼治疗7天后大鼠（n = 26）离体肠系膜动脉的血管反应。

结果

舒尼替尼降低了内皮依赖性血管舒张，但未降低非内皮依赖性血管舒张。此外，我们观察到，在一氧化氮拮抗剂N-硝基-L-精氨酸甲酯（L-NAME）存在的情况下，对照组和舒尼替尼治疗组动物之间内皮依赖性血管舒张的差异消失。在转移性肾细胞癌患者中，在开始舒尼替尼治疗前和治疗1周后，采用静脉闭塞体积描记法评估动脉内注射乙酰胆碱后的内皮依赖性血管舒张反应和动脉内注射硝普钠后的非内皮依赖性血管舒张反应。未观察到前臂血流比值的变化。治疗1周后平均动脉压从101.9 ± 3.8显著升高至106.1 ± 2.6 mmHg，治疗2周后进一步升高至115.8（±4.9）mmHg。