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Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension
Anna M J Thijs1, Carla M L van Herpen, Vivienne Verweij
1aDepartment of Pharmacology-Toxicology bDepartment of Medical Oncology cDepartment of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
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.
Insights
Sunitinib treatment in rats reduced blood vessel dilation by impairing nitric oxide release. However, this endothelial dysfunction did not precede hypertension development in human cancer patients receiving sunitinib.
Area of Science:
- Cardiovascular Pharmacology
- Oncology
- Endothelial Function
Background:
- Tyrosine kinase inhibitors (TKIs) targeting angiogenesis are crucial cancer treatments.
- Hypertension is a common side effect of vascular endothelial growth factor receptor (VEGFR)-targeted therapies.
- Sunitinib, a multitargeted TKI, is associated with hypertension, prompting investigation into its vascular effects.
Purpose of the Study:
- To investigate if sunitinib-induced hypertension is preceded by reduced endothelium-dependent vasodilation.
- To determine if endothelial dysfunction is linked to impaired nitric oxide (NO) release.
- To assess vascular responses in rats and humans treated with sunitinib.
Main Methods:
- A placebo-controlled experiment using isolated rat mesenteric arteries after 7 days of sunitinib treatment.
- Assessment of endothelium-dependent and -independent vasodilation in rat arteries, with and without the nitric oxide antagonist N-nitro-L-arginine methyl ester (L-NAME).
- Evaluation of endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilator responses in human patients with metastatic renal cell carcinoma before and after sunitinib initiation, using venous occlusion plethysmography.
Main Results:
- Sunitinib significantly reduced endothelium-dependent vasodilation in rat arteries, an effect abolished by L-NAME, indicating impaired nitric oxide release.
- No significant changes in forearm blood flow ratios were observed in human patients.
- Mean arterial pressure significantly increased in human patients after 1 and 2 weeks of sunitinib treatment.
Conclusions:
- High concentrations of sunitinib reduce endothelium-dependent vasodilation by decreasing endothelial nitric oxide release in animals.
- In human patients, reduced endothelium-dependent vasodilation does not precede the development of sunitinib-induced hypertension.
- The mechanisms underlying sunitinib-induced hypertension in humans may differ from those observed in animal models.
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