Nitric Oxide Resistance Reduces Arteriovenous Fistula Maturation in Chronic Kidney Disease in Rats

PLoS One. 2016 Jan 4;11(1):e0146212. doi: 10.1371/journal.pone.0146212. eCollection 2016.


Background: Autologous arteriovenous (AV) fistulas are the first choice for vascular access but have a high risk of non-maturation due to insufficient vessel adaptation, a process dependent on nitric oxide (NO)-signaling. Chronic kidney disease (CKD) is associated with oxidative stress that can disturb NO-signaling. Here, we evaluated the influence of CKD on AV fistula maturation and NO-signaling.

Methods: CKD was established in rats by a 5/6th nephrectomy and after 6 weeks, an AV fistula was created between the carotid artery and jugular vein, which was followed up at 3 weeks with ultrasound and flow assessments. Vessel wall histology was assessed afterwards and vasoreactivity of carotid arteries was studied in a wire myograph. The soluble guanylate cyclase (sGC) activator BAY 60-2770 was administered daily to CKD animals for 3 weeks to enhance fistula maturation.

Results: CKD animals showed lower flow rates, smaller fistula diameters and increased oxidative stress levels in the vessel wall. Endothelium-dependent relaxation was comparable but vasorelaxation after sodium nitroprusside was diminished in CKD vessels, indicating NO resistance of the NO-receptor sGC. This was confirmed by stimulation with BAY 60-2770 resulting in increased vasorelaxation in CKD vessels. Oral administration of BAY 60-2770 to CKD animals induced larger fistula diameters, however; flow was not significantly different from vehicle-treated CKD animals.

Conclusions: CKD induces oxidative stress resulting in NO resistance that can hamper AV fistula maturation. sGC activators like BAY 60-2770 could offer therapeutic potential to increase AV fistula maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Arteriovenous Shunt, Surgical*
  • Benzoates / therapeutic use
  • Biphenyl Compounds / therapeutic use
  • Carotid Arteries / drug effects
  • Carotid Arteries / surgery
  • Drug Resistance
  • Guanylate Cyclase / drug effects
  • Guanylate Cyclase / physiology
  • Hydrocarbons, Fluorinated / therapeutic use
  • Jugular Veins / drug effects
  • Jugular Veins / surgery
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nephrectomy / adverse effects
  • Nitric Oxide / physiology*
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Donors / therapeutic use
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitroprusside / pharmacology*
  • Nitroprusside / therapeutic use
  • Oxidative Stress
  • Phenylephrine / pharmacology
  • Rats
  • Rats, Wistar
  • Renal Insufficiency, Chronic / physiopathology
  • Renal Insufficiency, Chronic / therapy*
  • Signal Transduction
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology*
  • Vasodilator Agents / therapeutic use


  • 4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
  • Benzoates
  • Biphenyl Compounds
  • Hydrocarbons, Fluorinated
  • Nitric Oxide Donors
  • Vasodilator Agents
  • Nitroprusside
  • Phenylephrine
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Guanylate Cyclase
  • Acetylcholine
  • NG-Nitroarginine Methyl Ester

Grant support

ILG and FFK are supported by the Translational en Regenerative Medicine (TeRM) Smart Mix Program and the Biomedical Materials Program of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education, Culture and Science, DGMM is supported by the Interreg Euregio Meuse-Rhine IVa grant BioMIMedics and Interreg Flanders-the Netherlands IV grant VaRiA, MGC and JGRDM were supported by TI Pharma project T2-301, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.