期刊
FASEB JOURNAL
卷 31, 期 3, 页码 1193-1203出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201600749R
关键词
cancer therapy; hypertension; RTKI; VEGF; regional hemodynamics
资金
- Biotechnology and Biological Sciences Research Council [BB/L19418]
- University of Nottingham
- School of Biomedical Sciences
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 and100mg/kg, i.p.), or vandetanib (12.5 and 25mg/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 multitargetedreceptor tyrosinekinase inhibitors on regional hemodynamics in conscious, freelymoving rats.
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