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VEGF Inhibition with Sunitinib Results in Endothelin Mediated Hypertension
Author(s) -
Beer Vincent J,
Kappers Mariëtte HW,
Verzijl Annemarie,
Danser AH Jan,
Meiracker Anton H,
Duncker Dirk J,
Merkus Daphne
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.822.8
Inhibition of VEGF signaling is an established therapy for various forms of cancer. Unfortunately, this therapy is associated with hypertension and increased endothelin (ET) plasma levels. We investigated whether hypertension was exacerbated during exercise and was the result of an increased vasoconstrictor effect of endogenous ET. Chronically instrumented swine underwent a control exercise protocol followed by an exercise protocol during which we infused the ET A /ET B receptor blocker Tezosentan. Subsequently, 50mg/day Sunitinib (a VEGF inhibitor) was administered orally for one week, after which the exercise experiment in the absence and presence of Tezosentan was repeated. Sunitinib increased mean arterial pressure (MAP) from 79±3 to 96±9 mmHg and systemic vascular resistance (SVR) from 19±2 to 31±5 mmHg l −1 min −1 at rest, exercise did not exacerbate the increases in MAP or SVR. Subsequent infusion of Tezosentan resulted in greater decreases in MAP and SVR than under control conditions, both at rest and during exercise, thereby neutralizing the hemodynamic effects of Sunitinib. VEGF inhibition results in sustained hypertension. This hypertension appears to be, for the most part, the result of increased ET effects in the systemic circulation. In patients receiving Sunitinib, combined ET A /ET B receptor antagonism could be useful in limiting the hypertensive side effects of VEGF inhibition.