Powerful Relaxation of Phosphodiesterase Type 4 Inhibitor Rolipram in the Pig and Human Bladder Neck

• DOI: 10.1111/jsm.12456
• Publication Date: 2014-02-12T12:36:26Z
• Authors: Ana S.F. Ribeiro; Vítor S. Fernandes; Ana Martínez-Sáenz; Pilar Martínez; María Victoria Ba...; Luis M. Orensanz; Igor Blaha; Daniel Serrano-Ma...; Salvador Bustamante; Joaquín Carballido; Albino García-Sac...; Dolores Prieto; Medardo Hernández
• Keywords: Adult; Male; 0301 basic medicine; 61; Ca2+ Signaling; Muscle Relaxation; 610; Fisiología; Nitric Oxide; 612.019; Piperazines; NO; Phenylephrine; 03 medical and health sciences; PDE 4 and 5 Inhibitors; 32 Ciencias Médicas; Animals; Humans; PKA; Phosphodiesterase Inhibitors and Urogenital Function; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; H2S; Imidazoles; Muscle, Smooth; Middle Aged; Phosphodiesterase 5 Inhibitors; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 4; 3. Good health; Pig and Human Bladder Neck; Ciencias Biomédicas; PDE4 Expression; Female; Phosphodiesterase 4 Inhibitors; Nitric Oxide Synthase; Rolipram; K+ Channels; Muscle Contraction

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 (H2S) 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+]idesensitization-dependent mechanisms, this relaxation also being due to neuronal NO and H2S release.