RGD Reference Report - Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. - Rat Genome Database

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Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels.

Authors: Kappers, MH  Van Esch, JH  Sluiter, W  Sleijfer, S  Danser, AH  Van den Meiracker, AH 
Citation: Kappers MH, etal., Hypertension. 2010 Oct;56(4):675-81. Epub 2010 Aug 23.
RGD ID: 4144829
Pubmed: PMID:20733093   (View Abstract at PubMed)
DOI: DOI:10.1161/HYPERTENSIONAHA.109.149690   (Journal Full-text)

Angiogenesis inhibition with sunitinib, a multitarget tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, is associated with hypertension and cardiac toxicity, of which the underlying pathophysiological mechanism is unknown. We investigated the effects of sunitinib on blood pressure (BP), its circadian rhythm, and potential mechanisms involved, including the endothelin-1 system, in 15 patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors. In addition, we investigated in rats the effect of sunitinib on BP, serum endothelin-1 levels, coronary microvascular function, cardiac structure, and cardiac mitochondrial function. In patients, BP increased by approximately 15 mm Hg, whereas heart rate decreased after 4 weeks of treatment. Furthermore, the nocturnal dipping of BP diminished. Plasma endothelin-1 concentration increased 2-fold (P<0.05) and plasma renin decreased (P<0.05), whereas plasma catecholamines and renal function remained unchanged. In rats, 8 days of sunitinib administration induced an approximately 30-mm Hg rise in BP, an attenuation of the circadian BP rhythm, and a 3-fold rise in serum endothelin-1 and creatinine, of which all but the rise in creatinine reversed after sunitinib withdrawal. Coronary microvascular function studies after 8 days of sunitinib administration showed decreased responses to bradykinin, angiotensin II, and sodium nitroprusside, all normalizing after sunitinib withdrawal. Cardiac structure and cardiac mitochondrial function did not change. In conclusion, sunitinib induces a reversible rise in BP in patients and in rats associated with activation of the endothelin-1 system, suppression of the renin-angiotensin system, and generalized microvascular dysfunction.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypertension  ISOEdn1 (Rattus norvegicus)4144829; 4144829protein:increased secretion:plasma (rat)RGD 
hypertension  IEP 4144829protein:increased secretion:plasma (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Edn1  (endothelin 1)

Genes (Mus musculus)
Edn1  (endothelin 1)

Genes (Homo sapiens)
EDN1  (endothelin 1)


Additional Information