title: Reduction of obstruction related bladder overactivity by the guanylyl cyclase modulators BAY 41-2272 and BAY 60-2770 alone or in combination with a phosphodiesterase type 5 inhibitor.
abstract: OBJECTIVE
  To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO).
  
  
  METHODS
  Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization.
  
  
  RESULTS
  Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue.
  
  
  CONCLUSIONS
  Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.
authors.affiliation: Department of Urology, University of Rostock, Rostock, Germany.|Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Füllhase
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hennenberg
authors.affiliation: Bayer Health Care, Global Drug Discovery, Common Mechanism Research, Wuppertal, Germany.|Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Sandner
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Strittmatter
authors.affiliation: Department of Urology, University of Essen, Essen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Niedworok
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Bauer
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Gratzke
authors.affiliation: Division of Urology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Soler
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Stief
authors.affiliation: Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina.
authors.forename: K E
authors.initials: KE
authors.lastname: Andersson
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006162:Guanylate Cyclase / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014524:Urethral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
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; D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: lower urinary tract symptoms; phosphodiesterase type 5 inhibitors; soluble guanylyl cyclase; urinary bladder diseases; urodynamics