title: Soluble Guanylate Cyclase Modulators, BAY 41-2272 and BAY 60-2770, Inhibit Human and Rabbit Prostate Contractility.
abstract: OBJECTIVE
  To evaluate the inhibitory effect of soluble guanylate cyclase (sGC) stimulator, BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine) or activator, BAY 60-2770 (4-({(4- carboxybutyl) [2- (5-fluoro-2-{[40-(trifluoromethyl) biphenyl- 4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid), in human and rabbit prostate smooth muscle contractility.
  
  
  METHODS
  In rabbit or human prostate, contractions induced by electrical field stimulation or phenylephrine (PE) were carried out in the presence of sGC stimulator, BAY 41-2272, or sGC activator, BAY 60-2770. The potency (pEC50) and maximal response (Emax) values were determined. Immunohistochemistry analysis for sGC α1-subunit and quantification of intracellular levels of cyclic guanosine monophosphate (cGMP) were also performed.
  
  
  RESULTS
  In rabbit prostate, BAY 60-2770 (30 and 300 nM) inhibited the contractions induced by PE and electrical field stimulation. The coincubation with sGC inhibitor, ODQ, produced greater inhibitions on PE-induced contractions in comparison with BAY 60-2770 alone, mainly due to greater cGMP accumulation (70- and 5.7-fold, respectively). BAY 41-2272 (300 nM) increased and decreased, respectively, cGMP levels and PE-induced contractions, but in the presence of ODQ these effects were reversed. In human prostate, immunohistochemistry analysis revealed the presence of sGC α1-subunit on the transition zone. BAY 60-2770 (300 nM) reduced significantly Emax induced by PE in human prostate.
  
  
  CONCLUSIONS
  sGC activator seems to be a promising alternative to treat benign prostatic hyperplasia because it increases cGMP levels even when sGC is oxidized.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Fabiano B
authors.initials: FB
authors.lastname: Calmasini
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Alexandre
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Fabio Henrique
authors.initials: FH
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, 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, SP, Brazil.
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
authors.affiliation: Division of Urology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: D'Ancona
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil; Department of Biochemistry and Molecular Medicines, George Washington University, Washington, DC. Electronic address: fabiolataufic@gmail.com.
authors.forename: Fabíola Z
authors.initials: FZ
authors.lastname: Mónica
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D011467:Prostate / Q000187:drug effects* / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; 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; D011720:Pyrazoles; D011725:Pyridines