Ana S F Ribeiro1, Vítor S Fernandes1, Ana Martínez-Sáenz2, Pilar Martínez3, María Victoria Barahona4, Luis M Orensanz5, Igor Blaha6, Daniel Serrano-Margüello1, Salvador Bustamante7, Joaquín Carballido7, Albino García-Sacristán1, Dolores Prieto1, Medardo Hernández8. 1. Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain. 2. Unidad ExperimentalFundación de Investigación BiomédicaHospital Puerta de Hierro-MajadahondaMadridSpain. 3. Departamento de Anatomía y Anatomía Patológica ComparadasFacultad de VeterinariaUniversidad Complutense de MadridMadridSpain. 4. Departamento de Toxicología y FarmacologíaFacultad de VeterinariaUniversidad Complutense de MadridMadridSpain. 5. Departamento de InvestigaciónHospital Universitario Ramón y CajalMadridSpain. 6. Departamento de UrologíaHospital General Universitario Gregorio MarañónMadridSpain. 7. Departamento de UrologíaHospital Universitario Puerta de Hierro-MajadahondaMadridSpain. 8. Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain. Electronic address: medardo@farm.ucm.es.
Abstract
INTRODUCTION: 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.
INTRODUCTION: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.
Authors: Brian M Balog; Abhilasha Tangada; Pooja Sheth; Qi-Xiang Song; Bruna M Couri; Leah L Porras; Gary G Deng; Margot S Damaser Journal: PLoS One Date: 2019-08-28 Impact factor: 3.240
Authors: Ángel Agis-Torres; Paz Recio; María Elvira López-Oliva; María Pilar Martínez; María Victoria Barahona; Sara Benedito; Salvador Bustamante; Miguel Ángel Jiménez-Cidre; Albino García-Sacristán; Dolores Prieto; Vítor S Fernandes; Medardo Hernández Journal: Sci Rep Date: 2018-03-16 Impact factor: 4.379