title: Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain.
authors.forename: Ana S F
authors.initials: ASF
authors.lastname: Ribeiro
authors.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain.
authors.forename: Vítor S
authors.initials: VS
authors.lastname: Fernandes
authors.affiliation: Unidad ExperimentalFundación de Investigación BiomédicaHospital Puerta de Hierro-MajadahondaMadridSpain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-Sáenz
authors.affiliation: Departamento de Anatomía y Anatomía Patológica ComparadasFacultad de VeterinariaUniversidad Complutense de MadridMadridSpain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez
authors.affiliation: Departamento de Toxicología y FarmacologíaFacultad de VeterinariaUniversidad Complutense de MadridMadridSpain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Barahona
authors.affiliation: Departamento de InvestigaciónHospital Universitario Ramón y CajalMadridSpain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Orensanz
authors.affiliation: Departamento de UrologíaHospital General Universitario Gregorio MarañónMadridSpain.
authors.forename: Igor
authors.initials: I
authors.lastname: Blaha
authors.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serrano-Margüello
authors.affiliation: Departamento de UrologíaHospital Universitario Puerta de Hierro-MajadahondaMadridSpain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Bustamante
authors.affiliation: Departamento de UrologíaHospital Universitario Puerta de Hierro-MajadahondaMadridSpain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Carballido
authors.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain.
authors.forename: Albino
authors.initials: A
authors.lastname: García-Sacristán
authors.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Prieto
authors.affiliation: Departamento de FisiologíaFacultad de FarmaciaUniversidad Complutense de MadridMadridSpain. Electronic address: medardo@farm.ucm.es.
authors.forename: Medardo
authors.initials: M
authors.lastname: Hernández
mesh_terms: D000328:Adult; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D034421:Sus scrofa; D014227:Triazines / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D019459:Urothelium / Q000378:metabolism; D000069058:Vardenafil Dihydrochloride
chemical_list: D007093:Imidazoles; D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D010656:Phenylephrine; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D020889:Rolipram
keywords: Ca2+ Signaling; H2S; K+ Channels; NO; PDE 4 and 5 Inhibitors; PDE4 Expression; PKA; Phosphodiesterase Inhibitors and Urogenital Function; Pig and Human Bladder Neck; Rolipram