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Nebivolol Potentiates the Efficacy of PDE5 Inhibitors to Relax Corpus Cavernosum and Penile Arteries from Diabetic Patients by Enhancing the NO/cGMP Pathway

Authors

  • Juan I. Martínez-Salamanca MD, PhD,

    1. Servicio de Urología, Hospital Universitario Puerta de Hierro, Madrid, Spain
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  • José M. La Fuente MD, PhD,

    1. Serviço de Urologia, Hospital Santo Antonio, Porto, Portugal
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  • José Cardoso MD,

    1. Serviço de Urologia, Hospital Amadora-Sintra, Lisboa, Portugal
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  • Argentina Fernández LT,

    1. Servicio de Histología-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain
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  • Pedro Cuevas MD, PhD,

    1. Servicio de Histología-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain
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  • Harold M. Wright PhD,

    1. Department of Pharmacology, Forest Research Institute, Jersey City, NJ, USA
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  • Javier Angulo PhD

    Corresponding author
    1. Servicio de Histología-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain
    • Corresponding Author: Javier Angulo, PhD, Servicio Histología-Investigación, Hospital Universitario Ramón y Cajal. Ctra de Colmenar Viejo, km 9.100, Madrid 28034, Spain. Tel: 34 91 336 8481; Fax: 34 91 336 8290; E-mail: jangulo@ibercom.com

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Abstract

Introduction

The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase [PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treating hypertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats.

Aim

To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated.

Methods

HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil, tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA.

Main Outcome Measures

Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation of HPRA and cGMP accumulation in HCC.

Results

Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levels in HCC from DMED.

Conclusions

Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes. Martínez-Salamanca JI, La Fuente JM, Cardoso J, Fernández A, Cuevas P, Wright HM, and Angulo J. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway. J Sex Med 2014;11:1182–1192.

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