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Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide–cyclic GMP pathway in mice

International Journal of Impotence Research volume 25, pages 69–73 (2013)Cite this article

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Abstract

Phosphodiesterase-9 (PDE9) specifically hydrolyzes cyclic GMP, and was detected in human corpus cavernosum. However, no previous studies explored the selective PDE9 inhibition with BAY 73-6691 in corpus cavernosum relaxations. Therefore, this study aimed to characterize the PDE9 mRNA expression in mice corpus cavernosum, and investigate the effects of BAY 73-6691 in endothelium-dependent and -independent relaxations, along with the nitrergic corpus cavernosum relaxations. Male mice received daily gavage of BAY 73-6691 (or dimethylsulfoxide) at 3 mg kg−1 per day for 21 days. Relaxant responses to acetylcholine (ACh), nitric oxide (NO) (as acidified sodium nitrite; NaNO2 solution), sildenafil and electrical-field stimulation (EFS) were obtained in corpus cavernosum in control and BAY 73-6691-treated mice. BAY 73-6691 was also added in vitro 30 min before construction of concentration–responses and frequency curves. PDE9A and PDE5 mRNA expression was detected in the mice corpus cavernosum in a similar manner. In vitro addition of BAY 73-6691 neither itself relaxed mice corpus cavernosum nor changed the NaNO2, sildenafil and EFS-induced relaxations. However, in mice treated chronically with BAY 73-6691, the potency (pEC50) values for ACh, NaNO2 and sildenafil were significantly greater compared with control group. The maximal responses (Emax) to NaNO2 and sildenafil were also significantly greater in BAY 73-6691-treated mice. BAY 73-6691 treatment also significantly increased the magnitude and duration of the nitrergic corpus cavernosum relaxations (8–32 Hz). In conclusion, murine corpus cavernosum expresses PDE9 mRNA. Prolonged PDE9 inhibition with BAY 73-6691 amplifies the NO-cGMP-mediated cavernosal responses, and may be of therapeutic value for erectile dysfunction.

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Acknowledgements

Fábio Henrique da Silva was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Mário Angelo Claudino thanks Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). We are also grateful to Nicola Conran for providing us with BAY 73-6691.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

    F H da Silva, M N Pereira, G De Nucci & E Antunes

  2. Hematology and Hemotherapy Center, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

    C F Franco-Penteado

  3. Laboratory of Multidisciplinary Research, São Francisco University (USF), Bragança Paulista, São Paulo, Brazil

    M A Claudino

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  1. F H da Silva
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  4. G De Nucci
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  6. M A Claudino
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Correspondence to M A Claudino.

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da Silva, F., Pereira, M., Franco-Penteado, C. et al. Phosphodiesterase-9 (PDE9) inhibition with BAY 73-6691 increases corpus cavernosum relaxations mediated by nitric oxide–cyclic GMP pathway in mice. Int J Impot Res 25, 69–73 (2013). https://doi.org/10.1038/ijir.2012.35

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