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

• Published in: Life sciences (1973) 2022-05, Vol.296, p.120432, Article 120432
• Main Authors: Fernandes, Vítor S., López-Oliva, María Elvira, Martínez, María Pilar, Agis-Torres, Ángel, Recio, Paz, Navarro-Dorado, Jorge, Barahona, María Victoria, Benedito, Sara, Prieto, Dolores, Climent, Belén, Hernández, Medardo
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Adenosine monophosphate; Adrenergic receptors; Aminopyridines - administration & dosage; Aminopyridines - pharmacology; Animals; Benzamides - administration & dosage; Benzamides - pharmacology; cAMP signaling pathway; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Cyclopropanes - administration & dosage; Cyclopropanes - pharmacology; Dose-Response Relationship, Drug; Gasotransmitters - metabolism; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Immunohistochemistry; Inhibitors; Isoproterenol; Localization; Male; Muscle contraction; Muscle Relaxation - drug effects; Muscles; Nerve-mediated relaxation; Nerves; Nitric oxide; Nitroarginine - pharmacology; Penis; Penis - drug effects; Penis - physiology; Peripheral Nerves - drug effects; Peripheral Nerves - physiology; Phosphodiesterase; Phosphodiesterase type 4; Positive feedback; Rat corpus cavernosum; Rats; Rats, Wistar; Roflumilast; Signal transduction; Smooth muscle; Tadalafil - pharmacology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120432

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. 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. 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. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. 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. [Display omitted] •A marked PDE4A expression is detected within nerves of the rat corpus cavernosum.•Roflumilast, a PDE4 inhibitor, produces a potent cavernous smooth muscle relaxation.•Endogenous hydrogen sulfide (H2S) production is increased by roflumilast.•A pivotal role for neuronal PDE4 in penile erection is suggested.