Resveratrol and sildenafil synergistically improve diabetes-associated erectile dysfunction in streptozotocin-induced diabetic rats

Life Sci. 2015 Aug 15;135:43-8. doi: 10.1016/j.lfs.2015.04.020. Epub 2015 May 23.


Aims: Despite effective control of blood glucose levels in diabetic patients, complaints of diabetes-associated erectile dysfunction (ED) persist. Resveratrol has been indicated to possess anti-diabetic effects and therapeutic potential for ED. This study was conducted to observe the effect of resveratrol alone or in combination with sildenafil on ED in streptozotocin (STZ)-induced diabetic rats.

Main method: Among 58 adult male STZ-induced (60 mg/kg) diabetic Sprague-Dawley rats, 48 STZ-induced diabetic rats were randomized equally to four groups: untreated diabetic rats, resveratrol (25mg/kg), sildenafil (5mg/kg) or resveratrol (25mg/kg) plus sildenafil (5mg/kg) through oral gavage for 8 weeks. Additionally, 12 age-matched rats were chosen as controls. Intracavernous pressure (ICP) and mean arterial blood pressure (MAP) were used to measure erectile function. The cavernous level of cyclic guanosine monophosphate (cGMP), protein and mRNA of endothelial NO synthase (eNOS), neuronal NOS (nNOS), and phosphodiesterase-5 (PDE5) was measured.

Key findings: Treatment with either resveratrol or sildenafil improved ICP/MAP compared to the untreated diabetic rats (P<0.05). Treatment with resveratrol increased nNOS and eNOS expression, inhibited PDE5 expression, and increased the cavernous cGMP level compared to the untreated diabetic rats. Resveratrol significantly decreased superoxide anion and ROS production. Two-way ANOVA indicated that resveratrol in combination with sildenafil therapy had a significant synergistic effect in improving ICP/MAP and cavernous cGMP levels.

Significance: Resveratrol improves diabetes-associated ED in rats. Combination therapies with resveratrol and sildenafil have a synergistic effect in improving ED. The mechanisms might be attributed to its anti-oxidative properties and NO-cGMP signaling pathway upregulation.

Keywords: Diabetes mellitus; Erectile dysfunction; NO–cGMP; Reactive oxygen species; Resveratrol; Superoxide anion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Blood Pressure / drug effects
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
  • Diabetes Complications* / drug therapy
  • Diabetes Complications* / metabolism
  • Diabetes Complications* / pathology
  • Diabetes Complications* / physiopathology
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetes Mellitus, Experimental* / physiopathology
  • Erectile Dysfunction* / drug therapy
  • Erectile Dysfunction* / metabolism
  • Erectile Dysfunction* / physiopathology
  • Male
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Piperazines / pharmacology*
  • Purines / pharmacology
  • Rats
  • Resveratrol
  • Second Messenger Systems / drug effects
  • Sildenafil Citrate
  • Stilbenes / pharmacology*
  • Sulfonamides / pharmacology*


  • Antioxidants
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Purines
  • Stilbenes
  • Sulfonamides
  • Sildenafil Citrate
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type III
  • Nos1 protein, rat
  • Nos3 protein, rat
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP
  • Resveratrol