title: Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study.
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.
authors.affiliation: 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.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lankhorst
authors.affiliation: 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.).
authors.forename: Mariëtte H W
authors.initials: MH
authors.lastname: Kappers
authors.affiliation: 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.).
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.affiliation: 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.).
authors.forename: Frank M M
authors.initials: FM
authors.lastname: Smedts
authors.affiliation: 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.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: 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.).
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: 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.).
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: 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.).
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: 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.
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017311:Amlodipine / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000633:toxicity*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D011921:Rats, Inbred WKY; D013449:Sulfonamides / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D065130:Endothelin A Receptor Antagonists; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D017311:Amlodipine; D000077210:Sunitinib; C533860:macitentan
keywords: acute renal injury; endothelin-1; hypertension; sunitinib; therapeutics; vascular endothelial growth factor A