L-Cys/CSE/H2S pathway modulates mouse uterus motility and sildenafil effect. (September 2016)

• Record Type: Journal Article
• Authors: Mitidieri, Emma; Tramontano, Teresa; Donnarumma, Erminia; Brancaleone, Vincenzo; Cirino, Giuseppe; d'Emmanuele di Villa Bianca, Roberta; Sorrentino, Raffaella
• Is Part Of: Pharmacological research. Volume 111(2016:Sep.)
• Page Start: 283
• Page End: 289
• Publication Date: 2016-09
• Subjects: Sildenafil -- l-Cysteine -- Sodium hydrogen sulfide; PDE5 phosphodiesterase type 5 -- H2S hydrogen sulfide -- l-Cys l-Cysteine -- CBS cystathionine-β-synthase -- CSE cystathionine-γ-lyase -- PAG DL-propargilglycine -- AOAA aminooxiacetic acid -- Emax maximum effect; Sildenafil -- l-cysteine -- Hydrogen sulfide -- Mouse uteri -- CSE -- cGMP; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.06.017
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, commonly used in the oral treatment for erectile dysfunction, relaxes smooth muscle of human bladder through the activation of hydrogen sulfide (H2 S) signaling. H2 S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed froml -cysteine (l -Cys) by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Sildenafil also relaxes rat and human myometrium during preterm labor but the underlying mechanism is still unclear. In the present study we investigated the possible involvement of H2 S as a mediator of sildenafil-induced effect in uterine mouse contractility. We firstly demonstrated that both enzymes, CBS and CSE were expressed, and able to convertl -Cys into H2 S in mouse uterus. Thereafter, sildenafil significantly increased H2 S production in mouse uterus and this effect was abrogated by CBS or CSE inhibition. In parallel, l -Cys, sodium hydrogen sulfide or sildenafil but notd -Cys reduced spontaneous uterus contractility in a functional study. The blockage of CBS and CSE reduced this latter effect even if a major role for CSE than CBS was observed. This data was strongly confirmed by using CSE −/− mice. Indeed, the increase in H2 S production mediated byl -Cys or by sildenafil was not found in CSE −/− mice. Besides, the effect of H2 S or sildenafil on spontaneous contractility was reduced in CSE −/− mice. A decisive proof for the involvement of H2 S signaling in sildenafil effect in mice uterus was given by the measurement of cGMP. Sildenafil increased cGMP level that was significantly reduced by CSE inhibition. In conclusion, l -Cys/CSE/H2 S signaling modulates the mouse uterus motility and the sildenafil effect. Therefore the study may open different therapeutical approaches for the management of the uterus abnormal contractility disorders.