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Rho kinase (ROCK) inhibition counteracts tyrosine kinase inhibitor‐induced rise in arterial pressure and renal vascular resistance
Author(s) -
Grisk Olaf,
Meissner Thomas,
Donner Alexander,
Braun Diana,
Zimmermann Uwe,
Rettig Rainer
Publication year - 2013
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.27.1_supplement.1110.1
Subject(s) - sunitinib , vasoconstriction , vascular resistance , medicine , tyrosine kinase inhibitor , vasodilation , endocrinology , kidney , blood pressure , pharmacology , renal cell carcinoma , cancer
The VEGF antagonistic tyrosine kinase inhibitor sunitinib is used to treat renal cell carcinoma but causes severe arterial hypertension limiting its therapeutic utility. We investigated the in vitro and in vivo effects of sunitinib on renal vascular function and tested if ROCK inhibition prevents sunitinib‐induced hypertension in rats. VEGF dilated isolated rat renal resistance vessels (log EC50 −11.1 ± 0.25 mol/l). In in vitro experiments, sunitinib did not affect basal vascular tone and endothelium‐dependent vasodilation but significantly reduced agonist‐induced vasoconstriction in isolated renal resistance arteries. Chronic sunitinib treatment (15 mg*kg −1 *d −1 ) increased arterial pressure by 25 mmHg and renal vascular resistance (RVR) by 4 mmHg*ml −1 *min*g −1 within 4 days (p < 0.05). Sunitinib‐treated rats showed blunted endothelium‐dependent renal vasodilation and reduced angiotensin II‐induced renal vasoconstriction while α 1 ‐adrenoceptor‐dependent vasoconstriction was unaffected. ROCK inhibitor treatment prevented the sunitinib‐induced rises in arterial pressure and RVR but not renal endothelial dysfunction. ROCK‐inhibition may be useful to mitigate tyrosine kinase inhibitor‐induced hypertension thereby improving the treatment of renal cell carcinoma.