Document Detail


Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib.
MedLine Citation:
PMID:  22443474     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vascular endothelial growth factor inhibitors (VEGFi) are known to cause hypertension and renal injury that severely limits their use as an anticancer therapy. We hypothesized that the angiotensin-converting enzyme inhibitor captopril not only prevents hypertension, but also decreases renal injury caused by the VEGFi sorafenib. Rats were administered sorafenib (20 mg/kg per day) alone or in combination with captopril (40 mg/kg per day) for 4 weeks. Sorafenib administration increased blood pressure, which plateaued by day 10. Concurrent treatment with captopril for 4 weeks resulted in a 30 mmHg decrease in blood pressure compared with sorafenib alone (155 ± 5 vs 182 ± 6 mmHg, respectively; P < 0.05). Furthermore, concurrent captopril treatment reduced albuminuria by 50% compared with sorafenib alone (20 ± 8 vs 42 ± 9 mg/day, respectively; P < 0.05) and reduced nephrinuria by eightfold (280 ± 96 vs 2305 ± 665 μg/day, respectively; P < 0.05). Glomerular injury, thrombotic microangiopathy and tubular cast formation were also decreased in captopril-treated rats administered sorafenib. Renal autoregulatory efficiency was determined by evaluating the afferent arteriolar constrictor response to ATP. Sorafenib administration attenuated the vasoconstriction to ATP, whereas concurrent captopril treatment improved ATP reactivity. In conclusion, captopril attenuated hypertension and renal injury and improved renal autoregulatory capacity in rats administered sorafenib. These findings indicate that captopril treatment, in addition to alleviating the detrimental side-effect of hypertension, decreases the renal injury associated with anticancer VEGFi therapies such as sorafenib.
Authors:
Tasuku Nagasawa; Md Abdul Hye Khan; John D Imig
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical and experimental pharmacology & physiology     Volume:  39     ISSN:  1440-1681     ISO Abbreviation:  Clin. Exp. Pharmacol. Physiol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-24     Completed Date:  2013-01-31     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0425076     Medline TA:  Clin Exp Pharmacol Physiol     Country:  Australia    
Other Details:
Languages:  eng     Pagination:  454-61     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.
Affiliation:
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Kidney Injury / chemically induced,  drug therapy*,  pathology
Animals
Benzenesulfonates / antagonists & inhibitors,  toxicity*
Captopril / therapeutic use*
Growth Inhibitors / antagonists & inhibitors,  toxicity*
Hypertension / chemically induced,  drug therapy*,  pathology
Male
Pyridines / antagonists & inhibitors,  toxicity*
Rats
Rats, Sprague-Dawley
Vascular Endothelial Growth Factor A / administration & dosage,  antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
P01 DK038226/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Benzenesulfonates; 0/Growth Inhibitors; 0/Pyridines; 0/Vascular Endothelial Growth Factor A; 0/sorafenib; 0/vascular endothelial growth factor A, rat; 62571-86-2/Captopril
Comments/Corrections

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