title: Prolonged therapy with the soluble guanylyl cyclase activator BAY 60-2770 restores the erectile function in obese mice.
abstract: BACKGROUND
  Cardiovascular and endocrine-metabolic diseases associated with increased oxidative stress such as obesity lead to erectile dysfunction (ED). Activators of soluble guanylyl cyclase (sGC) such as BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases.
  
  
  OBJECTIVE
  This study aimed to evaluate the effects of 2-week oral intake with BAY 60-2270 on a murine model of obesity-associated ED.
  
  
  METHODS
  C57BL/6 male mice were fed for 12 weeks with standard chow or high-fat diet. Lean and obese mice were treated with BAY 60-2770 (1 mg/kg/day, 2 weeks).
  
  
  METHODS
  Measurements of intracavernosal pressure (ICP), along with acetylcholine (10(-9) to 10(-5)  M) and electrical field stimulation (EFS; 4-10 Hz)-induced corpus cavernosum relaxations in vitro, were obtained. Levels of cyclic guanosine monophosphate (cGMP), reactive oxygen species (ROS), and sGC protein expressions in cavernosal tissues were measured.
  
  
  RESULTS
  Cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P < 0.05). Two-week therapy with BAY 60-2770 fully reversed the decreased ICP in obese group. Acetylcholine-induced cavernosal relaxations were 45% lower (P < 0.001) in obese mice, which were fully restored by BAY 60-2770 treatment. Likewise, the EFS-induced relaxations in obese mice were restored by BAY 60-2770. Basal cGMP content in erectile tissue was 68% lower (P < 0.05) in obese mice, an effect normalized by BAY 60-2770. Levels of ROS were 52% higher (P < 0.05) whereas protein expression of α1 sGC subunit was reduced in cavernosal tissue of obese mice, both of which were normalized by BAY 60-2770. In lean group, BAY 60-2770 did not significantly affect any functional, biochemical, or molecular parameter analyzed.
  
  
  CONCLUSIONS
  Two-week therapy with BAY 60-2770 restores the erectile function in obese mice that is associated with reduced ROS levels, up-regulation of α1 sGC subunit, and increased cGMP levels in the erectile tissue.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.
authors.forename: Fábio H
authors.initials: FH
authors.lastname: Silva
authors.forename: Luiz O
authors.initials: LO
authors.lastname: Leiria
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Alexandre
authors.forename: Ana Paula C
authors.initials: AP
authors.lastname: Davel
authors.forename: Fabíola Z
authors.initials: FZ
authors.lastname: Mónica
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D006152:Cyclic GMP / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D020536:Enzyme Activators / Q000008:administration & dosage*; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000098:blood supply; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D015854:Up-Regulation
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D020536:Enzyme Activators; D006845:Hydrocarbons, Fluorinated; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: Corpus Cavernosum; Cyclic GMP; Erectile Dysfunction; Intracavernous Pressure; Obesity; Oxidative Stress; Reactive Oxygen Species