Fernandes Ribeiro, Ana SofíaFernandes, Vítor S.Martínez Sáenz, AnaMartínez Sainz, María Del PilarBarahona Gomáriz, María VictoriaOrensanz Muñoz, Luis MiguelBlaha, IgorSerrano Margüello, DanielBustamante, SalvadorCarballido, JoaquínGarcía Sacristán, AlbinoPrieto Ocejo, DoloresHernández Rodríguez, Medardo Vicente2024-02-082024-02-082014-04-01Ribeiro ASF, Fernandes VS, Martínez-Sáenz A, Martínez P, Barahona MV, Orensanz LM, Blaha I, Serrano-Margüello D, Bustamante S, Carballido J, García-Sacristán A, Prieto D, Hernández M. Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck. J Sex Med. 2014 Apr;11(4):930-941. doi: 10.1111/jsm.12456. Epub 2014 Feb 12. PMID: 24754330.1743-609510.1111/jsm.12456https://hdl.handle.net/20.500.14352/100452Introduction: Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility. Aim: To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck. Methods: Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i ) and tension for rolipram in bladder neck samples were used. Main outcome measures: PDE4 expression and relaxations to PDE4 and PDE5 inhibitors and simultaneous measurements of [Ca2+]i and tension. Results: PDE4 expression was observed widely distributed in the smooth muscle layer of the pig and human bladder neck. On urothelium-denuded phenylephrine (PhE)-precontracted strips of pig and human, rolipram, sildenafil and vardenafil produced concentration-dependent relaxations with the following order of potency: rolipram> > sildenafil>vardenafil. In pig, the adenylyl cyclase activator forskolin potentiated rolipram-elicited relaxation, whereas protein kinase A (PKA) blockade reduced such effect. On potassium-enriched physiological saline solution (KPSS)-precontracted strips, rolipram evoked a lower relaxation than that obtained on PhE-stimulated preparations. Inhibition of large (BKCa ) and intermediate (IKCa ) conductance Ca2+ -activated K+ channels, neuronal voltage-gated Ca2+ channels, nitric oxide (NO) and hydrogen sulfide (H2 S) synthases reduced rolipram responses. Rolipram inhibited the contractions induced by PhE without reducing the PhE-evoked [Ca2+]i increase. Conclusions: PDE4 is present in the pig and human bladder neck smooth muscle, where rolipram exerts a much more potent relaxation than that elicited by PDE5 inhibitors. In pig, rolipram-induced response is produced through the PKA pathway involving BKCa and IKCa channel activation and [Ca2+]i desensitization-dependent mechanisms, this relaxation also being due to neuronal NO and H2S release.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://academic.oup.com/jsm/article-abstract/11/4/930/6958258?redirectedFrom=fulltext&login=falseopen access61612.019Phosphodiesterase Inhibitors and Urogenital FunctionPDE4 ExpressionRolipramPDE 4 and 5 InhibitorsPKAK+ ChannelsCa2+ SignalingNOH2SPig and Human Bladder NeckCiencias BiomédicasFisiología32 Ciencias Médicas