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

Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β1-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism. We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphat...

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Published in:Journal of sexual medicine 2010-08, Vol.7 (8), p.2681-2697
Main Authors: Angulo, Javier, Wright, Harold M., Cuevas, Pedro, González-Corrochano, Rocío, Fernández, Argentina, Cuevas, Begoña, La Fuente, José M., Gupta, Sandeep, Sáenz de Tejada, Iñigo
Format: Article
Language:English
Subjects:
Animals
Atenolol - pharmacology
Benzopyrans - pharmacology
Blood Glucose - metabolism
Blood Pressure - drug effects
Cyclic GMP - physiology
Diabetes
Diabetes Mellitus, Experimental - physiopathology
Dose-Response Relationship, Drug
Endothelium, Vascular - drug effects
Erectile Dysfunction - physiopathology
Erectile Dysfunction and Hypertensive Agents
Ethanolamines - pharmacology
Heart Rate - drug effects
Humans
In Vitro Techniques
Injections, Intravenous
Male
Nebivolol
Nitric Oxide
Nitric Oxide - physiology
Penis - blood supply
Piperazines - pharmacology
Purines - pharmacology
Rats
Rats, Sprague-Dawley
Signal Transduction - drug effects
Sildenafil Citrate
Sulfones - pharmacology
Sympatholytics - pharmacology
Type 5 Phosphodiesterase Inhibitors
Vascular Resistance - drug effects
Vasodilator Agents - pharmacology
β-Blockers
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Summary:Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β1-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism. 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. 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. The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses. 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 3Hz 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. 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. Angulo J, Wright HM, Cuevas P, González-Corrochano R, Fernández A, Cuevas B, La Fuente JM, Gupta S, and de Tejada IS. Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric o
ISSN:1743-6095
1743-6109
DOI:10.1111/j.1743-6109.2010.01710.x