Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels.
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 ≈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 ≈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.
Kappers
Mariëtte H W
MH
Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands. m.h.w.kappers@erasmusmc.nl
van Esch
Joep H M
JH
Sluiter
Wim
W
Sleijfer
Stefan
S
Danser
A H Jan
AH
van den Meiracker
Anton H
AH
D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood* / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012083:Renin / Q000097:blood; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D019332:Endothelin-1; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D020794:Receptor Protein-Tyrosine Kinases; D012083:Renin; D001920:Bradykinin; D000077210:Sunitinib