Daily treatment with sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance

Eur Urol. 2008 Jun;53(6):1272-80. doi: 10.1016/j.eururo.2007.11.018. Epub 2007 Nov 20.


Objectives: Patients with insulin resistance exhibit endothelial dysfunction with decreased nitric oxide (NO) production and increased oxidative stress. We postulated that daily sildenafil improved endothelial function in fructose-fed rats.

Methods and results: Wistar rats were fed a standard or fructose-enriched diet (FFR) for 9 wk. From weeks 6-8, sildenafil was administered twice daily (sc, 20 m g/kg), followed by a 1-wk washout. Concentration-response curves (CRCs) to endothelium-dependent (acetylcholine [Ach] and A23187) and -independent (sodium nitroprusside [SNP]) relaxing agents were performed on isolated precontracted aortas and superior mesenteric arteries (SMAs). Vascular cyclic guanosine monophosphate (cGMP) content, urinary excretion of nitrates/nitrites (NOx) and 8-isoprostanes (IPT), and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were evaluated. Relaxations to ACh were significantly reduced in aortas and SMAs of FFR. Sildenafil restored ACh-induced relaxations in aortas and provoked a significant leftward shift of the CRC to ACh in SMAs, whereas it did not modify the enhanced relaxations to SNP in FFR. IL-6, TNF-alpha, vascular cGMP, and urinary NOx levels were not modified by the fructose or sildenafil treatment. Urinary IPT levels were significantly elevated in FFR and normalized by sildenafil.

Conclusions: Endothelial dysfunction and oxidative stress associated with insulin resistance can be reversed by daily sildenafil, even 1 wk after treatment cessation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drug Administration Schedule
  • Endothelium / drug effects*
  • Endothelium / physiopathology*
  • Insulin Resistance*
  • Male
  • Oxidative Stress / drug effects*
  • Phosphodiesterase Inhibitors / administration & dosage*
  • Piperazines / administration & dosage*
  • Purines / administration & dosage
  • Rats
  • Rats, Wistar
  • Sildenafil Citrate
  • Sulfones / administration & dosage*


  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate