The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice.
OBJECTIVE
Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder.


METHODS
C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined.


RESULTS
Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and β1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770.


CONCLUSIONS
Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and β1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Luiz O
LO
Leiria
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Fabio H
FH
Silva
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Ana Paula C
AP
Davel
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Eduardo C
EC
Alexandre
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Marina C
MC
Calixto
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Gilberto
G
De Nucci
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil.
Fabíola Z
FZ
Mónica
Department of Pharmacology, Faculty of Medical Sciences and Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology (APCD), University of Campinas, Campinas, Brazil. Electronic address: antunes@fcm.unicamp.br.
Edson
E
Antunes
D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D020536:Enzyme Activators / Q000627:therapeutic use*; D006162:Guanylate Cyclase / Q000187:drug effects*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology / Q000627:therapeutic use*; D059411:Lower Urinary Tract Symptoms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000453:epidemiology*; D017382:Reactive Oxygen Species; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000453:epidemiology / Q000517:prevention & control
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; D006162:Guanylate Cyclase
LDL; NO; NVC; OAB; ROS; cGMP; cyclic guanosine monophosphate; low density lipoprotein; lower urinary tract symptoms; nitric oxide; nonvoiding contraction; obesity; overactive; overactive bladder; reactive oxygen species; sGC; soluble guanylate cyclase; soluble guanylyl cyclase; urinary bladder