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

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

doi:10.1016/j.bcp.2023.116007

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

Biochem Pharmacol. 2023 Dec 23:116007. doi: 10.1016/j.bcp.2023.116007. Online ahead of print.

Authors

Patrizia Pannucci¹, Marieke Van Daele¹, Samantha L Cooper¹, Edward S Wragg¹, Julie March², Marleen Groenen², Stephen J Hill³, Jeanette Woolard⁴

Affiliations

¹ Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK.
² Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
³ Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK. Electronic address: steve.hill@Nottingham.ac.uk.
⁴ Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and Nottingham, The Midlands, UK. Electronic address: jeanette.woolard@Nottingham.ac.uk.

PMID: 38145828
DOI: 10.1016/j.bcp.2023.116007

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 ET_A receptor selective antagonist sitaxentan (5 mg.kg^-1) or the mixed ET_A/ET_B 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 ET_A receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.

Keywords: ET(A) receptors; ET-1; Haemodynamics; Hypertension; RTKI; VEGF.