Format

Send to

Choose Destination
FASEB J. 2017 Mar;31(3):1193-1203. doi: 10.1096/fj.201600749R. Epub 2016 Dec 16.

Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats.

Author information

1
Cell Signalling Research Group, School of Life Sciences, Medical School, The University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom; and.
2
Faculty of Health and Life Sciences, De Montfort University, Leicester, United Kingdom.
3
Cell Signalling Research Group, School of Life Sciences, Medical School, The University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom; and jeanette.woolard@nottingham.ac.uk.

Abstract

VEGF inhibitors, including receptor tyrosine kinase inhibitors, are used as adjunct therapies in a number of cancer treatments. An emerging issue with these drugs is that most cause hypertension. To gain insight into the physiological mechanisms involved, we evaluated their regional hemodynamic effects in conscious rats. Male Sprague Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes (renal and mesenteric arteries, and the descending abdominal aorta) and catheters (jugular vein, peritoneal cavity, and distal abdominal aorta). Regional hemodynamics were measured over 4 d, before and after daily administration of cediranib (3 and 6 mg/kg, 3 and 6 mg/kg/h for 1 h, i.v.), sorafenib (10 and 20 mg/kg, 10 and 20 mg kg/h for 1 h, i.v.), pazopanib (30 and100 mg/kg, i.p.), or vandetanib (12.5 and 25 mg/kg, i.p.). All drugs evoked significant increases (P < 0.05; n = 7-8) in mean arterial pressure, which were generally accompanied by significant mesenteric and hindquarters, but not renal, vasoconstrictions. The hypertensive effects of cediranib were unaffected by losartan (10 mg/kg/h), bosentan (20 mg/kg/h), or a combination of phentolamine and propranolol (each 1 mg/kg/h), suggesting a need for new strategies to overcome them.-Carter, J. J., Fretwell, L. V., Woolard, J. Effects of 4 multitargeted receptor tyrosine kinase inhibitors on regional hemodynamics in conscious, freely moving rats.

KEYWORDS:

RTKI; VEGF; cancer therapy; hypertension; regional hemodynamics

PMID:
27986807
PMCID:
PMC5295730
DOI:
10.1096/fj.201600749R
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center