In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters

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Fernandes, Vítor Samuel Leite and López-Oliva Muñoz, María Elvira and Martinez Sainz, María del Pilar and Agis Torres, Ángel and Recio Visedo, María Paz and Navarro Dorado, Jorge and Barahona Gomariz, María Victoria and Benedito Castellote, Sara and Prieto Ocejo, Dolores and Climent Flórez, Belén and Hernández Rodríguez, Medardo Vicente (2022) In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters. Life Sciences, 296 . p. 120432. ISSN 00243205

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Official URL: https://doi.org/10.1016/j.lfs.2022.120432



Abstract

Aims: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation.
Main methods: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and β-adrenoceptor agonist isoproterenol and endogenous H2S production measurement.
Key findings: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endoge-nous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isopro-terenol- and EFS-induced relaxations were increased by roflumilast.
Significance: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by β-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.


Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2022)

Uncontrolled Keywords:Phosphodiesterase type 4, cAMP signaling pathway, Roflumilast, Nerve-mediated relaxation, Rat corpus cavernosum
Subjects:Medical sciences > Pharmacy > Animal physiology
ID Code:72519
Deposited On:26 May 2022 08:51
Last Modified:26 May 2022 10:51

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