title: Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60-2770 in rabbit corpus cavernosum.
abstract: OBJECTIVE
  To characterise the relaxation induced by the soluble guanylate cyclase (sGC) activator, BAY 60-2770 (4-({(4-carboxybutyl) [2- (5-fluoro-2-{[4'-(trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid) in rabbit corpus cavernosum (CC).
  
  
  METHODS
  The penis from male New Zealand rabbits was removed and fours strips of CC were obtained. Concentration-response curves to BAY 60-2770 were constructed in the absence and presence of inhibitors of nitric oxide synthase, N (G)-nitro-L- arginine methyl ester (L-NAME, 100 μm), sGC, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 μm) and phosphodiesterase type 5 (PDE-5), tadalafil (0.1 μm). The potency (pEC50 ) and maximal response (Emax ) values were determined. Then, electrical-field stimulation (EFS)-induced contraction or relaxation was tested in the absence and presence of BAY 60-2770 (0.1 or 1 μm) alone or combined with ODQ (10 μm). For EFS-induced relaxation two protocols were used: (i) ODQ (10 μm) was first incubated for 20 min and then BAY 60-2770 (1 μm) was added for another 20 min (ODQ + BAY 60-2770); (ii) in different CC strips, BAY 60-2770 was incubated for 20 min followed by another 20 min with ODQ (BAY 60-2770 + ODQ). The intracellular levels of cyclic guanosine monophosphate (cGMP) were also determined.
  
  
  RESULTS
  BAY 60-2770 potently relaxed rabbit CC with mean (sem) pEC50 and Emax values of 7.58 (0.19) and 81 (4)%, respectively. The inhibitors ODQ (n = 7) or tadalafil (n = 7) produced 4.2- and 6.3-leftward shifts, respectively in BAY 60-2770-induced relaxation without interfering with the Emax values. The intracellular levels of cGMP were augmented after stimulation with BAY 60-2770 (1 μm) alone, whereas its co-incubation with ODQ produced even higher levels of cGMP. The EFS-induced contraction was reduced in the presence of BAY 60-2770 (1 μm) and this inhibition was even greater when BAY 60-2770 was co-incubated with ODQ. The nitrergic stimulation induced CC relaxation, which was abolished in the presence of ODQ. BAY 60-2770 alone increased the amplitude of relaxation. Co-incubation of ODQ and BAY 60-2770 did not alter the relaxation in comparison with ODQ alone. Interestingly, when BAY 60-2770 was incubated before ODQ, EFS-induced relaxation was partly restored in comparison with ODQ alone or ODQ + BAY 60-2770.
  
  
  CONCLUSIONS
  The relaxation induced by the sGC activator, BAY 60-2770 was increased after sGC oxidation and unaltered in the absence of nitric oxide. Thus, this class of substances may have advantages over sGC stimulators or PDE-5 inhibitors for treating patients with erectile dysfunction and extensive endothelial damage.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Camila S
authors.initials: CS
authors.lastname: Estancial
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Renata L
authors.initials: RL
authors.lastname: Rodrigues
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: De Nucci
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Fabiola Z
authors.initials: FZ
authors.lastname: Mónica
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006152:Cyclic GMP / Q000032:analysis; D007172:Erectile Dysfunction; D006162:Guanylate Cyclase; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D010413:Penis / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000071756:Soluble Guanylyl Cyclase
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; D006845:Hydrocarbons, Fluorinated; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: corpus cavernosum; erectile dysfunction; soluble guanylate cyclase