Role of endothelin ETA receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats

Pannucci, Patrizia; Van Daele, Marieke; Cooper, Samantha L.; Wragg, Edward S.; March, Julie; Groenen, Marleen; Hill, Stephen J.; Woolard, Jeanette

Abstract

Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350-500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg-1) or lenvatinib (1 or 3 mg.kg-1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p<0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p<0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ETA receptor selective antagonist sitaxentan (5 mg.kg-1) or the mixed ETA/ETB receptor antagonist bosentan (15 mg.kg-1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p<0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ETA receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.

Citation

Pannucci, P., Van Daele, M., Cooper, S. L., Wragg, E. S., March, J., Groenen, M., Hill, S. J., & Woolard, J. (2024). Role of endothelin ETA receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats. Biochemical Pharmacology, 228, Article 116007. https://doi.org/10.1016/j.bcp.2023.116007

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2023
• Online Publication Date: Dec 23, 2023
• Publication Date: 2024-10
• Deposit Date: Dec 29, 2023
• Publicly Available Date: Mar 19, 2024
• Journal: Biochemical Pharmacology
• Print ISSN: 0006-2952
• Electronic ISSN: 1873-2968
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 228
• Article Number: 116007
• DOI: https://doi.org/10.1016/j.bcp.2023.116007
• Keywords: Hypertension; RTKI; VEGF; ET-1; Haemodynamics; ETA receptors
• Public URL: https://nottingham-repository.worktribe.com/output/29000718
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0006295223006007?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Role of endothelin ETA receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats; Journal Title: Biochemical Pharmacology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bcp.2023.116007; Content Type: article; Copyright: © 2023 The Author(s). Published by Elsevier Inc.