Hydrogen Sulfide Facilitates Vaginal Lubrication by Activation of Epithelial ATP-Sensitive K(+) Channels and Cystic Fibrosis Transmembrane Conductance Regulator

Abstract

Introduction: Hydrogen sulfide (H2S) plays a large role in female and male sexual responses characterized by a smooth muscle relaxant effect. Moreover, H2S is a novel pro-secretory neuromodulator that modulates epithelial ion transport. However, whether H2S has a role in regulating vaginal epithelial ion transport and fluid secretion has not been extensively studied.

Aim: To identify the effects of H2S on vaginal epithelial ion transport and lubrication in an exploratory investigation.

Methods: The mRNA, protein expression, and localization of cystathionine γ-lyase (CSE) and H2S production in vaginal epithelium were examined by reverse transcriptase polymerase chain reaction, Western blot, H2S synthesizing activity assay, and immunohistochemistry, respectively. The effect of H2S on vaginal epithelial ion transport, vaginal fluid secretion, and ionic concentration was investigated using a short-circuit current (ISC), a measurement of vaginal lubrication, and ion chromatography, respectively.

Main outcome measures: The mRNA, protein expression, and localization of CSE, H2S formation, changes of ISC responses, vaginal lubrication, and K(+) and Cl(-) concentrations were studied.

Results: CSE mRNA and protein were predominantly expressed in vaginal epithelium. Sodium hydrosulfide hydrate (NaHS) caused concentration-dependent changes in ISC across isolated rat vaginal epithelium, which consisted of an initial decrease phase and then an increase phase. The increase phase in ISC was mainly Cl(-) dependent and abolished by cystic fibrosis transmembrane conductance regulator inhibitor, whereas the decrease phase was sensitive to the adenosine triphosphate-sensitive K(+) (KATP) channel blocker. Furthermore, intravaginal treatment of NaHS significantly enhanced vaginal lubrication in vivo, and this effect was prevented by cystic fibrosis transmembrane conductance regulator and KATP channel inhibitors. In addition, the ionic concentrations of K(+) and Cl(-) in rat vaginal fluid were significantly increased by NaHS treatment.

Conclusion: The CSE-H2S pathway participates in the regulation of vaginal epithelial K(+) and Cl(-) ion transport to modulate lumen fluid secretion.

Keywords: Cystic Fibrosis Transmembrane Conductance Regulator; Hydrogen Sulfide; Ion Transport; K(ATP) Channels; Vaginal Lubrication.