title: Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway.
abstract: BACKGROUND
  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 treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA 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 levelsin 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.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Martínez-Salamanca
authors.forename: José M
authors.initials: JM
authors.lastname: La Fuente
authors.forename: José
authors.initials: J
authors.lastname: Cardoso
authors.forename: Argentina
authors.initials: A
authors.lastname: Fernández
authors.forename: Pedro
authors.initials: P
authors.lastname: Cuevas
authors.forename: Harold M
authors.initials: HM
authors.lastname: Wright
authors.forename: Javier
authors.initials: J
authors.lastname: Angulo
mesh_terms: D001158:Arteries / Q000503:physiopathology; D001578:Benzopyrans / Q000627:therapeutic use*; D002243:Carbolines / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004357:Drug Synergism; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000503:physiopathology; D004983:Ethanolamines / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000098:blood supply*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D002243:Carbolines; D004983:Ethanolamines; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; D000068577:Nebivolol; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D006152:Cyclic GMP