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.

Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis

“…This hyperpolarises the apical membrane potential and facilitates apical chloride efflux 18,19 . Similar observations were recently reported in a rat vaginal epithelial preparation, where exogenous H 2 S elicits a chloride secretion which involved activation of basolateral ATP-sensitive potassium channels and apical chloride efflux via CFTR 21 . However, the mechanism of how H 2 S might facilitate opening of CFTR remains elusive.…”

“…In this study we investigated the regulation of CFTR by H 2 S. Previous studies using the mouse hippocampal cell line HT22 25 or rat vaginal epithelial preparations 21 suggested that CFTR might be a target for H 2 S. In order to elaborate on this hypothesis, human CFTR was heterologously expressed in Xenopus oocytes and functional CFTR expression was confirmed by application of the cAMP-elevating compounds forskolin and IBMX, which resulted in a transient increase in transmembrane currents which did not occur in native, non-injected oocytes. These observations are consistent with previously published functional electrophysiological analyses of human CFTR in Xenopus oocytes 23,26 .…”

“…The herein reported cAMP-mediated stimulation of CFTR activity would be consistent with a pro-secretory action on chloride-secreting epithelia. A recent study demonstrated a CFTR-mediated chloride secretion across rat vaginal epithelial preparations 21 . The authors speculated that this might be due to an increase in cAMP 21 and our findings would support this hypothesis.…”

“…A recent study demonstrated a CFTR-mediated chloride secretion across rat vaginal epithelial preparations 21 . The authors speculated that this might be due to an increase in cAMP 21 and our findings would support this hypothesis. Since H 2 S is not directly targeting CFTR, the PDE repertoire of epithelial cells will determine whether or not H 2 S triggers CFTR-mediated electrolyte secretion.…”

Sulfur-containing gaseous signaling molecules

“…Ферменти синтезу H 2 S наявні в епітелії піхви. Встановлено, що він сприяє вагінальній лубрикації (змащуванню піхви) через вплив на транспорт К + та Clвагінальним епітелієм [63]. H 2 S викликає релаксацію гладеньких м'язів кавернозних тіл пеніса.…”