Renal Nitric Oxide‐Dependent Mechanisms in Early Sunitinib‐Induced Hypertension

Abstract

Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used in cancer treatment. A major adverse effect of sunitinib is a rapidly developing hypertension associated with reduced renal nitric oxide (NO) availability and increased renal fractional sodium reabsorption (FRNa). We tested if NO‐dependent regulation of renal hemodynamics and FRNa are compromised and if nitrate supplementation has antihypertensive effects in early sunitinib‐induced hypertension.Male Wistar rats were treated with sunitinib at 15 mg/(kg*d). Four days after initiation of sunitinib treatment, renal hemodynamics and renal sodium excretion were investigated. Radiotelemetric experiments were performed to study the effects of nitrate supplementation and soluble guanylate cyclase (sGC) activation on arterial pressure. Nitric oxide synthase (NOS) as well as sGC mRNA and protein abundances were studied in renal tissue.Within four days, sunitinib elicited a 20–25 mmHg arterial pressure rise. NOS inhibition elicited similar reductions in total and renal medullary blood flow in sunitinib‐ and vehicle‐treated rats. NO‐dependent and independent components of endothelium‐dependent renal vasodilation were not compromised in early sunitinib‐induced hypertension. Low dose intrarenal NOS inhibition did not differentially affect FRNa in sunitinib‐ and vehicle‐treated rats. In sunitinib‐treated rats, renal nitrite/nitrate excretion was 60 per cent less than in controls (p < 0.05). However, nitrate supplementation did not reduce arterial pressure and renal sodium balance in sunitinib‐treated rats. While sunitinib treatment had no effects on renal NOS mRNA abundances, it significantly reduced renal cortical sGC α‐ and β‐subunit mRNA abundances as well as renal cortical guanylate cyclase protein expression. Pharmacological sGC activation caused a rapid 15–20 mmHg arterial pressure fall in sunitinib‐treated rats (p < 0.05).We conclude that the NO‐dependent regulation of renal hemodynamics is largely unaltered in early sunitinib‐induced hypertension despite evidence for reduced NO formation. Reduced renal sGC expression and activity may contribute to the early arterial pressure rise in sunitinib‐induced hypertension and cause its nitrate resistance.Support or Funding InformationSupported by the German Research Foundation, Grant‐No. KO 4936/2‐1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.