Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

The soluble guanylyl cyclase activator BAY 60-2770 ameliorates detrusor dysfunction in obese mice

  • Gilberto de Nucci1, 2Email author,
  • Luiz Osorio Leiria1,
  • Fábio Henrique da Silva1,
  • Eduardo C Alexandre1,
  • Marina Calixto1,
  • Fabíola Zakia Mónica1 and
  • Edson Antunes1
BMC Pharmacology and Toxicology201314(Suppl 1):P18

DOI: 10.1186/2050-6511-14-S1-P18

Published: 29 August 2013

Background

The obesity-associated insulin resistance has been shown to play an important role in the pathophysiology of overactive bladder in mice [1, 2]. Therefore, we evaluated the beneficial effects of long-term administration of the sGC activator BAY 60-2270 in bladders from lean and obese mice.

Methods

Mice were fed for 12 weeks with either a standard chow diet (carbohydrate: 70%; protein: 20%; fat: 10%) or a high fat diet that induces obesity (carbohydrate: 29%; protein: 16%; fat: 55%). Lean and obese mice were orally treated with BAY 60-2770 (1 mg/kg/day, given as daily gavage from the 10th to the 12th week) or its vehicle (Transcutol®:Cremophor®:water, 1:2:7, v/v/v). Concentration-response curves to full agonist carbachol (CCh, 0.001-100 µM) were obtained. The values of potency (pEC50) and maximal responses (Emax) were calculated. The cGMP levels and Western blotting for α1 and β1-subunit of sGC in the bladder tissues were also determined.

Results

Contractile response to the muscarinic agonist carbachol was greater (p<0.05, n=5) in bladder from the obese in comparison with lean group. Long-term treatment with BAY 60-2770 normalized the enhanced contractile responses of the obese group, driving it to control levels (p<0.05; figure 1). The cGMP levels in the bladder tissues from obese group were significantly lower in comparison with lean mice (0.27 ± 0.04 and 0.95 ± 0.14 pmol/mg tissue, respectively, p<0.05, n=5). Treatment with BAY 60-2770 generated a 10-fold increase (p<0.01) in the bladder cGMP levels of obese mice, without affecting the levels in the lean group (Figure 2A). Protein expression of α1 and β1 subunits of sGC was decreased by 41% and 43% (p<0.05) in bladder tissues of obese animals, respectively. However, oral treatment with BAY 60-2770 restored the protein levels of α1 and β1 subunits to that of lean group (Figure 2B and 2C).
Figure 1

Concentration response curve to cabachol (0.001-100 µM) in isolated bladder from lean and obese mice that received or not BAY 60-2770 (1 mg/Kg, 2 weeks). Data represent mean ± S.E.M.

Figure 2

Effect of chronic treatment with BAY 60-2770 (1 mg/kg, 2 weeks) on cGMP levels (A) and protein expression of α1 (B) and β1 (C) subunits of sGC in bladders from lean + vehicle, lean + BAY 60-2770, obese + vehicle and obese + BAY 60-2770 groups. Data are presented as mean ± SEM. p <0.05 in comparison with lean + vehicle group; †p <0.05 in comparison to obese + vehicle group.

Conclusion

Chronic treatment with BAY 60-2770 results in amelioration of bladder dysfunction in high-fat obese mice.

Authors’ Affiliations

(1)
Department of Pharmacology, State University of Campinas (UNICAMP)
(2)
Institute of Biomedical Sciences, University of Sao Paulo (USP)

References

  1. Leiria LO, Sollon C, Calixto MC, Lintomen L, Mónica FZ, Anhê GF, De Nucci G, Zanesco A, Grant AD, Antunes E: Role of PKC and CaV1.2 in detrusor overactivity in a model of obesity associated with insulin resistance in mice. PLoS One. 2012, 7: e48507-10.1371/journal.pone.0048507.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Leiria LO, Sollon C, Báu FR, Mónica FZ, D Ancona CL, De Nucci G, Grant AD, Anhê GF, Antunes E: Insulin relaxes human and mice bladder via PI3K/AKT/eNOS pathway activation in mucosal cells: UPR-dependent insulin resistance as a cause of obesity-associated overactive bladder. J Physiol. 2013, 591: 2259-2273.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© de Nucci et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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