Journal of hypertension · 2015
Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.
Предметные рубрики MeSH
AcetylcholineAdultAgedAngiogenesis InhibitorsAnimalsCarcinoma, Renal CellEndothelium, VascularForearmHumansHypertensionIndolesKidney NeoplasmsMaleMesenteric ArteriesMiddle AgedNG-Nitroarginine Methyl EsterNitric OxideNitroprussidePyrrolesRatsRegional Blood FlowSunitinibVascular Endothelial Growth Factor AVasodilationVasodilator Agents