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Hypertension. 2014 Dec;64(6):1282-9. doi: 10.1161/HYPERTENSIONAHA.114.04187. Epub 2014 Sep 2.

Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study.

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1
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., M.H.W.K., J.H.M.v.E., A.H.J.D., A.H.v.d.M.) and Department of Medical Oncology, Erasmus MC Cancer Institute (S.S., R.H.J.M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pathology, Reinier de Graaf Groep, Delft, The Netherlands (F.M.M.S.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); and Department of Pathology, Leiden University Medical Center, Leiden (H.J.B.).
2
From the Division of Pharmacology and Vascular Medicine, Department of Internal Medicine (S.L., M.H.W.K., J.H.M.v.E., A.H.J.D., A.H.v.d.M.) and Department of Medical Oncology, Erasmus MC Cancer Institute (S.S., R.H.J.M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pathology, Reinier de Graaf Groep, Delft, The Netherlands (F.M.M.S.); Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands (M.H.W.K.); and Department of Pathology, Leiden University Medical Center, Leiden (H.J.B.). a.vandenmeiracker@erasmusmc.nl.

Abstract

Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafil. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ≈30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafil did not. Macitentan, captopril, and sildenafil diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated.

KEYWORDS:

acute renal injury; endothelin-1; hypertension; sunitinib; therapeutics; vascular endothelial growth factor A

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