Objective:

The VEGF antagonistic tyrosine kinase inhibitor sunitinib is used to treat renal cell carcinoma but causes severe arterial hypertension limiting its therapeutic utility. The effects of VEGF and sunitinib on renal vascular function were investigated. We tested if Rho kinase (ROCK) inhibition counteracts hypertension and deleterious effects on renal vascular function induced by sunitinib.

Methods:

Isolated human and rat resistance arteries were investigated by small-vessel myography. In vivo effects of sunitinib and of sunitinib combined with a ROCK inhibitor were investigated in rats. Arterial pressure was recorded telemetrically. Renal blood flow and glomerular filtration rate (GFR) were measured by ultrasound-transit time flowmetry and inulin clearance, respectively. Vasoactive compounds were administered intrarenally.

Results:

VEGF dilated isolated rat renal resistance vessels (log EC50 -11.1 ± 0.25 mol/l). In vitro, sunitinib did not affect basal vascular tone and endothelium-dependent vasodilation but significantly reduced agonist-induced vasoconstriction in renal and non-renal resistance arteries. Within four days, sunitinib (15 mg*kg^-1*d^-1) increased arterial pressure by 25 mmHg, renal vascular resistance (RVR) by 4 mmHg*ml^-1*min*g^-1 (p < 0.01), and decreased GFR by 40% (p < 0.001). This was associated with blunted endothelium-dependent renal vasodilation and reduced angiotensin II-induced renal vasoconstriction while α₁-adrenoceptor-dependent vasoconstriction was unaffected. ROCK inhibition prevented the sunitinib-induced rise in arterial pressure and RVR but not the decline in renal endothelial function and GFR.

Conclusion:

ROCK-inhibition mitigates tyrosine kinase inhibitor-induced hypertension which may be useful to improve treatment of renal cell carcinoma but it does not counteract tyrosine kinase inhibitor-induced renal endothelial and glomerular dysfunction.