l-Cys/CSE/H2S pathway modulates mouse uterus motility and sildenafil effect.
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 (H2S) signaling. H2S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed from l-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 H2S 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 convert l-Cys into H2S in mouse uterus. Thereafter, sildenafil significantly increased H2S production in mouse uterus and this effect was abrogated by CBS or CSE inhibition. In parallel, l-Cys, sodium hydrogen sulfide or sildenafil but not d-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 H2S production mediated by l-Cys or by sildenafil was not found in CSE(-/-) mice. Besides, the effect of H2S or sildenafil on spontaneous contractility was reduced in CSE(-/-) mice. A decisive proof for the involvement of H2S 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/H2S 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.
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
Emma
E
Mitidieri
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
Teresa
T
Tramontano
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
Erminia
E
Donnarumma
Department of Science, University of Basilicata, Via dell⿿Ateneo Lucano, 85100 Potenza, Italy.
Vincenzo
V
Brancaleone
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
Giuseppe
G
Cirino
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy. Electronic address: demmanue@unina.it.
Roberta
R
D Emmanuele di Villa Bianca
Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy. Electronic address: rafsorre@unina.it.
Raffaella
R
Sorrentino
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D066298:In Vitro Techniques; D008190:Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018345:Mice, Knockout; D010641:Phenotype; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013447:Sulfites / Q000378:metabolism*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D013447:Sulfites; D000068677:Sildenafil Citrate; D008190:Lyases; D003542:Cystathionine gamma-Lyase; C019965:cystathionine beta-lyase; D006152:Cyclic GMP; D003545:Cysteine; C042345:hydrogen sulfite
CSE; Hydrogen sulfide; Mouse uteri; Sildenafil; Sodium hydrogen sulfide; cGMP; l-Cysteine; l-cysteine