| Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress. | |
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MedLine Citation:
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PMID: 22124432 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Angiogenesis inhibition with agents targeting tyrosine kinases of vascular endothelial growth factor receptors is an established anticancer treatment, but is, unfortunately, frequently accompanied by systemic hypertension and cardiac toxicity. Whether vascular endothelial growth factor receptor antagonism also has adverse effects on the pulmonary and coronary circulations is presently unknown. In chronically instrumented awake swine, the effects of the vascular endothelial growth factor receptor antagonist sunitinib on the systemic, pulmonary, and coronary circulation were studied. One week after sunitinib (50 mg PO daily), mean aortic blood pressure (MABP) had increased from 83±5 mm Hg at baseline to 97±6 mm Hg (P<0.05) because of a 57±20% increase in systemic vascular resistance as cardiac output decreased. In contrast, sunitinib had no discernible effects on pulmonary and coronary hemodynamics or cardiac function. We subsequently investigated the mechanisms underlying the sunitinib-induced systemic hypertension. Intravenous administration of NO synthase inhibitor N(G)-nitro-l-arginine increased MABP by 24±1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32±3 mm Hg; P<0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13±2 mm Hg before but only by 5±2 mm Hg (P<0.05) after sunitinib administration. However, intravenous administration of the dual endothelin A/endothelin B receptor blocker tezosentan, which did not lower MABP at baseline, completely reversed MABP to presunitinib values. These findings indicate that sunitinib produces vasoconstriction selectively in the systemic vascular bed, without affecting pulmonary or coronary circulations. The sunitinib-mediated systemic hypertension is principally attributed to an increased vasoconstrictor influence of endothelin, with no apparent contributions of a loss of NO bioavailability or increased oxidative stress. |
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Authors:
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Mariëtte H W Kappers; Vincent J de Beer; Zhichao Zhou; A H Jan Danser; Stefan Sleijfer; Dirk J Duncker; Anton H van den Meiracker; Daphne Merkus |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-28 |
Journal Detail:
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Title: Hypertension Volume: - ISSN: 1524-4563 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, and Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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