title: Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment of Pharmacology-Toxicology bDepartment of Medical Oncology cDepartment of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anna M J
authors.initials: AM
authors.lastname: Thijs
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Vivienne
authors.initials: V
authors.lastname: Verweij
authors.forename: Jeanne
authors.initials: J
authors.lastname: Pertijs
authors.forename: Petra H H
authors.initials: PH
authors.lastname: van den Broek
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D000077210:Sunitinib