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Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib
Author(s) -
Nagasawa Tasuku,
Hye Khan Md Abdul,
Imig John D
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05699.x
Subject(s) - captopril , sorafenib , medicine , blood pressure , endocrinology , angiotensin converting enzyme , vascular endothelial growth factor , pharmacology , angiotensin ii , vegf receptors , hepatocellular carcinoma
Summary Vascular endothelial growth factor inhibitors ( VEGF i) 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 VEGF i 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 VEGF i therapies such as sorafenib.