The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice.

Abstract

PURPOSE:

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.

MATERIALS AND 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.

• Authors: Luiz O Leiria, Fabio H Silva, Ana Paula C Davel, Eduardo C Alexandre, Marina C Calixto, Gilberto De Nucci, Fabíola Z Mónica, Edson Antunes
• Journal: The Journal of urology (J Urol) Vol. 191 Issue 2 Pg. 539-47 (Feb 2014) ISSN: 1527-3792 [Electronic] United States
• PMID: 24050894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• 4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
• Benzoates
• Biphenyl Compounds
• Enzyme Activators
• Hydrocarbons, Fluorinated
• Reactive Oxygen Species
• Guanylate Cyclase

Topics

• Animals
• Benzoates (pharmacology, therapeutic use)
• Biphenyl Compounds (pharmacology, therapeutic use)
• Blotting, Western
• Enzyme Activators (therapeutic use)
• Guanylate Cyclase (drug effects)
• Hydrocarbons, Fluorinated (pharmacology, therapeutic use)
• Lower Urinary Tract Symptoms (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Obesity (epidemiology)
• Reactive Oxygen Species
• Urinary Bladder, Overactive (drug therapy, epidemiology, prevention & control)