Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide Signaling
Corresponding Author
Javier Angulo PhD
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Investigación y Clínica Andrológicas and Instituto de Medicina Sexual, Madrid, Spain;
Javier Angulo, PhD, Departamento de Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar Viejo, km 9.100, 28034-Madrid, Spain. Tel: 34 913368481; Fax: 34 913368290; E-mail: [email protected]Search for more papers by this authorHarold M. Wright PhD
Forest Research Institute, Department of Pharmacology, Jersey City, New Jersey, USA;
Search for more papers by this authorPedro Cuevas MD, PhD
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorRocío González-Corrochano BSc
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorArgentina Fernández LT
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorBegoña Cuevas BSc
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorJosé M. La Fuente MD, PhD
Serviço de Urologia, Hospital Santo Antonio, Porto, Portugal
Search for more papers by this authorSandeep Gupta PhD
Forest Research Institute, Department of Pharmacology, Jersey City, New Jersey, USA;
Search for more papers by this authorIñigo Sáenz de Tejada MD
Investigación y Clínica Andrológicas and Instituto de Medicina Sexual, Madrid, Spain;
Search for more papers by this authorCorresponding Author
Javier Angulo PhD
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Investigación y Clínica Andrológicas and Instituto de Medicina Sexual, Madrid, Spain;
Javier Angulo, PhD, Departamento de Investigación, Hospital Ramón y Cajal, Ctra. de Colmenar Viejo, km 9.100, 28034-Madrid, Spain. Tel: 34 913368481; Fax: 34 913368290; E-mail: [email protected]Search for more papers by this authorHarold M. Wright PhD
Forest Research Institute, Department of Pharmacology, Jersey City, New Jersey, USA;
Search for more papers by this authorPedro Cuevas MD, PhD
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorRocío González-Corrochano BSc
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorArgentina Fernández LT
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorBegoña Cuevas BSc
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain;
Search for more papers by this authorJosé M. La Fuente MD, PhD
Serviço de Urologia, Hospital Santo Antonio, Porto, Portugal
Search for more papers by this authorSandeep Gupta PhD
Forest Research Institute, Department of Pharmacology, Jersey City, New Jersey, USA;
Search for more papers by this authorIñigo Sáenz de Tejada MD
Investigación y Clínica Andrológicas and Instituto de Medicina Sexual, Madrid, Spain;
Search for more papers by this authorABSTRACT
Introduction. 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.
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. 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 oxide signaling. J Sex Med 2010;7:2681–2697.
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