Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric oxide signaling.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.
Angulo
Javier
J
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain. jangulo@ibercom.com
Wright
Harold M
HM
Cuevas
Pedro
P
González-Corrochano
Rocío
R
Fernández
Argentina
A
Cuevas
Begoña
B
La Fuente
José M
JM
Gupta
Sandeep
S
Sáenz de Tejada
Iñigo
I
D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D007172:Erectile Dysfunction / Q000503:physiopathology*; D004983:Ethanolamines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D000068577:Nebivolol; D009569:Nitric Oxide / Q000502:physiology*; D010413:Penis / Q000098:blood supply*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D001786:Blood Glucose; D004983:Ethanolamines; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013565:Sympatholytics; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide; D001262:Atenolol; D000068677:Sildenafil Citrate; D006152:Cyclic GMP