title: Combination of BAY 60-4552 and vardenafil exerts proerectile facilitator effects in rats with cavernous nerve injury: a proof of concept study for the treatment of phosphodiesterase type 5 inhibitor failure.
abstract: BACKGROUND
  Radical prostatectomy (RP) is frequently responsible for erectile dysfunction (ED). Post-RP patients often show a failure to respond to phosphodiesterase type 5 (PDE5) inhibitors.
  
  
  OBJECTIVE
  The acute effect of BAY 60-4552, the soluble guanylate cyclase (sGC) stimulator, and vardenafil were evaluated alone or in combination on erectile responses to electrical stimulation of the cavernous nerve (ES CN) in rats with cavernous nerve (CN) crush injury-induced ED.
  
  
  METHODS
  Male adult Sprague-Dawley rats underwent laparotomy (sham, n=10) or bilateral CN crush injury (n=56). After 3 wk of recovery, erectile function was evaluated under urethane anaesthesia following ES CN at different frequencies.
  
  
  METHODS
  The acute effects of intravenous (IV) injection of vehicle, vardenafil 0.03 mg/kg, BAY 60-4552 0.03 mg/kg or 0.3 mg/kg, or a BAY 60-4552 0.03 mg/kg plus vardenafil 0.03 mg/kg combination were evaluated in CN-crushed rats.
  
  
  CONCLUSIONS
  Bilateral CN crush injury followed by a 3-wk recovery period decreased erectile responses to ES CN by about 50%. In CN-crushed rats, IV vardenafil 0.03 mg/kg and BAY 60-4552 (0.03 or 0.3 mg/kg) increased erectile responses to ES CN to the same extent: Δ intracavernosal pressure/mean arterial pressure (ICP/MAP) at 10 Hz ES CN was 21±1% after vehicle, 25±3% (p<0.001) after vardenafil, and 26±5% and 27±5% after BAY 60-4552 0.03 mg/kg (p<0.01) and 0.3 mg/kg (p<0.001), respectively. The combination of vardenafil with BAY 60-4552 in CN-crushed rats totally restored erectile responses to ES CN equivalent to sham rats (ΔICP/MAP at 10 Hz ES CN: 34±4% after BAY 60-4552/vardenafil combination vs 39±4% in sham rats; not significant).
  
  
  CONCLUSIONS
  The present study supports the concept that the combined administration of a sGC stimulator, BAY 60-4552, and vardenafil provides synergistic beneficial effects and might therefore salvage patients who experience treatment failures with PDE5 inhibitors after RP.
authors.affiliation: Pelvipharm, Orsay, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oudot
authors.forename: Delphine
authors.initials: D
authors.lastname: Behr-Roussel
authors.forename: Sarah
authors.initials: S
authors.lastname: Poirier
authors.forename: Peter
authors.initials: P
authors.lastname: Sandner
authors.forename: Jacques
authors.initials: J
authors.lastname: Bernabé
authors.forename: Laurent
authors.initials: L
authors.lastname: Alexandre
authors.forename: François
authors.initials: F
authors.lastname: Giuliano
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009409:Nerve Crush; D010413:Penis / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D017211:Treatment Failure; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: C569640:BAY 60-4552; D020536:Enzyme Activators; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase