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Long‐term cardiovascular effects of vandetanib and pazopanib in normotensive rats

Cooper, Samantha L.; Carter, Joanne J.; March, Julie; Woolard, Jeanette

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Authors

Joanne J. Carter

Julie March

JEANETTE WOOLARD Jeanette.Woolard@nottingham.ac.uk
Professor of Cardiovascular Physiology and Pharmacology



Abstract

Vandetanib and pazopanib are clinically available, multi‐targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF) receptor tyrosine kinases. Short‐term VEGF receptor inhibition is associated with hypertension in 15%‐60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer‐term cardiovascular implications of treatment, we investigated the “on”‐treatment (21 days) and “off”‐treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague‐Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.

Citation

Cooper, S. L., Carter, J. J., March, J., & Woolard, J. (2019). Long‐term cardiovascular effects of vandetanib and pazopanib in normotensive rats. Pharmacology Research and Perspectives, 7(3), Article e00477. https://doi.org/10.1002/prp2.477

Journal Article Type Article
Acceptance Date Apr 8, 2019
Online Publication Date May 31, 2019
Publication Date 2019-06
Deposit Date Jan 8, 2020
Publicly Available Date Mar 29, 2024
Journal Pharmacology Research & Perspectives
Print ISSN 2052-1707
Electronic ISSN 2052-1707
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 7
Issue 3
Article Number e00477
DOI https://doi.org/10.1002/prp2.477
Public URL https://nottingham-repository.worktribe.com/output/2469954
Publisher URL https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.477

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