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

作者：Martinez Salamanca Juan I; La Fuente Jose M; Cardoso Jose; Fernandez Argentina; Cuevas Pedro; Wright Harold M; Angulo Javier^*

来源：The Journal of Sexual Medicine, 2014, 11(5): 1182-1192.

DOI：10.1111/jsm.12477

• Nebivolol
• Erectile Dysfunction and Hypertensive Agents
• Nitric Oxide
• -Blockers
• Type 5 Phosphodiesterase Inhibitors
• Diabetes
• Corpus Cavernosum and Penile Arteries

IntroductionThe efficacy of oral pharmacotherapy for erectile dysED) (i.e., type 5 phosphodiesterase [PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective (1)-blocker used for treating hypertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats.
AimTo 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.
MethodsHCC 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 MeasuresEffects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation of HPRA and cGMP accumulation in HCC.
ResultsTreatment with nebivolol (1M) 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.
ConclusionsNebivolol 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. Martinez-Salamanca JI, La Fuente JM, Cardoso J, Fernandez 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.

• 出版日期2014-5