Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats Through Enhancement of Nitric Oxide Signaling

J Sex Med. 2010 Aug;7(8):2681-97. doi: 10.1111/j.1743-6109.2010.01710.x. Epub 2010 Feb 26.

Abstract

Introduction: Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β(1)-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism.

Aim: We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues.

Methods: Erectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined.

Main outcome measures: The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses.

Results: Treatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals.

Conclusions: Nebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Atenolol / pharmacology
  • Benzopyrans / pharmacology*
  • Blood Glucose / metabolism
  • Blood Pressure / drug effects
  • Cyclic GMP / physiology
  • Diabetes Mellitus, Experimental / physiopathology*
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Erectile Dysfunction / physiopathology*
  • Ethanolamines / pharmacology*
  • Heart Rate / drug effects
  • Humans
  • In Vitro Techniques
  • Injections, Intravenous
  • Male
  • Nebivolol
  • Nitric Oxide / physiology*
  • Penis / blood supply*
  • Piperazines / pharmacology
  • Purines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Sildenafil Citrate
  • Sulfones / pharmacology
  • Sympatholytics / pharmacology
  • Vascular Resistance / drug effects
  • Vasodilator Agents / pharmacology*

Substances

  • Benzopyrans
  • Blood Glucose
  • Ethanolamines
  • Piperazines
  • Purines
  • Sulfones
  • Sympatholytics
  • Vasodilator Agents
  • Nebivolol
  • Nitric Oxide
  • Atenolol
  • Sildenafil Citrate
  • Cyclic GMP