Hyperuricemia attenuates aortic nitric oxide generation, through inhibition of arginine transport, in rats

J Vasc Res. 2011;48(3):252-60. doi: 10.1159/000320356. Epub 2010 Nov 23.


Objectives: Hyperuricemia provokes endothelial dysfunction (ECD). Decreased endothelial nitric oxide synthase (eNOS) activity is an important source of ECD. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. We hypothesize that hyperuricemia inhibits arginine uptake.

Methods: Experiments were performed in freshly harvested aortas from untreated animals and rats fed with oxonic acid (hyperuricemia), and compared to hyperuricemic rats treated with either allopurinol, benzbromarone or arginine.

Results: Arginine transport was significantly decreased in hyperuricemia. Benzbromarone and arginine prevented the decrease in arginine transport in hyperuricemic rats while allopurinol did not. Arginine transport was significantly decreased in control rats treated with allopurinol. Blood pressure response to acetylcholine was significantly attenuated in hyperuricemic rats, an effect which was prevented in all other experimental groups. L-NAME inhibitable cGMP response to carbamyl-choline was significantly decreased in hyperuricemic rats and this was completely prevented by both benzbromarone and arginine, while allopurinol partially prevented the aforementioned phenomenon. Hyperuricemia induced a significant increase in protein nitration that was prevented by benzbromarone, allopurinol, and arginine. Protein abundance of CAT-1, PKCα, and phosphorylated PKCα remained unchanged in all experimental groups.

Conclusions: In hyperuricemia, the decrease in aortic eNOS activity is predominantly the result of attenuated arginine uptake.

MeSH terms

  • Allopurinol / pharmacology
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism*
  • Aorta / physiopathology
  • Arginine / metabolism*
  • Arginine / pharmacology
  • Benzbromarone / pharmacology
  • Biological Transport
  • Blood Pressure / drug effects
  • Cationic Amino Acid Transporter 1 / metabolism*
  • Disease Models, Animal
  • Hyperuricemia / chemically induced
  • Hyperuricemia / drug therapy
  • Hyperuricemia / metabolism*
  • Hyperuricemia / physiopathology
  • Male
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxonic Acid
  • Phosphorylation
  • Protein Kinase C-alpha / metabolism
  • Rats
  • Rats, Wistar
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Uric Acid / blood
  • Uricosuric Agents / pharmacology


  • Cationic Amino Acid Transporter 1
  • Uricosuric Agents
  • Uric Acid
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • Benzbromarone
  • Oxonic Acid
  • Allopurinol
  • Arginine
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Protein Kinase C-alpha