title: Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa.
abstract: BACKGROUND
  RhoA-Rho kinase complex contributes to keep the cavernosus smooth muscle contracted and its inhibition is considered a potential strategy for the therapy of erectile dysfunction (ED).
  
  
  METHODS
  We compared the effects of SAR407899, the Rho-kinase inhibitor Y-27632 and the PDE5 inhibitor sildenafil for their ability to relax corpus cavernosum strips contracted with phenylephrine in healthy and diabetic animals. Strips were obtained from WKY, spontaneous hypertensive (SHR), control CD, and diabetic CD rats, humans, control and diabetic rabbits. Diabetes was induced by streptozotocin or alloxan injection. In vivo penile erection (length) induced by drugs was measured in conscious rabbits.
  
  
  RESULTS
  SAR407899 dose-dependently relaxed the pre-contracted corpora cavernosa in all species, with similar potency and efficacy in healthy vs diabetic rats, WKY vs SHR rats, healthy vs diabetic rabbits (IC(50) range from 0.05 to 0.29 μM, Emax range 89 to 97%). In the presence of the NO-synthase (NOS) inhibitor, L-NAME, the SAR407899 response did not decrease in any of the species or experimental conditions. The effect was confirmed in human strips where sildenafil was significantly less potent and effective, with IC50 respectively 0.13 and 0.51 μM; Emax 92 and 43%. Unlike SAR407899, the potency and efficacy of sildenafil and Y27632 were significantly reduced by diabetes and L-NAME. In vivo, SAR407899 dose-dependently induced rabbit penile erection, with greater potency and longer duration of action than sildenafil. Sildenafil, but not SAR407899, was less effective in alloxan-induced diabetes.
  
  
  CONCLUSIONS
  The induction of penile erection by SAR407899, unlike that by sildenafil, is largely independent of e-NO activity. This suggests its use in erectile dysfunction for diabetic and hypertensive patients where e-NO activity is impaired.
authors.affiliation: Research Center Sanofi-Midy, Exploratory Unit, sanofi R&D, Milano, Italy. fabio.guagnini@sanofi.com
authors.forename: Fabio
authors.initials: F
authors.lastname: Guagnini
authors.forename: Mara
authors.initials: M
authors.lastname: Ferazzini
authors.forename: Marco
authors.initials: M
authors.lastname: Grasso
authors.forename: Salvatore
authors.initials: S
authors.lastname: Blanco
authors.forename: Tiziano
authors.initials: T
authors.lastname: Croci
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects* / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D013450:Sulfones; D010656:Phenylephrine; D000068677:Sildenafil Citrate; D054460:rho-Associated Kinases