H2S is a key antisecretory molecule against cholera toxin-induced diarrhoea in mice: Evidence for non-involvement of the AC/cAMP/PKA pathway and AMPK

Abstract Hydrogen sulphide (H 2 S) is a gasotransmitter that participates in various physiological and pathophysiological processes within the gastrointestinal tract. We studied the effects and possible mechanism of action of H 2 S in secretory diarrhoea caused by cholera toxin (CT). The possible mechanisms of action of H 2 S were investigated using an intestinal fluid secretion model in isolated intestinal loops on anaesthetized mice treated with CT. NaHS and Lawesson's reagent and l -cysteine showed antisecretory activity through reduction of intestinal fluid secretion and loss of Cl − induced by CT. Pretreatment with an inhibitor of cystathionine-γ-lyase (CSE), dl -propargylglycine (PAG), reversed the effect of l -cysteine and caused severe intestinal secretion. Co-treatment with PAG and a submaximal dose of CT increased intestinal fluid secretion, thus supporting the role of H 2 S in the pathophysiology of cholera. CT increased the expression of CSE and the production of H 2 S. Pretreatment with PAG did not reverse the effect of SQ 22536 (an AC inhibitor), bupivacaine (inhibitor of cAMP production), KT-5720 (a PKA inhibitor), and AICAR (an AMPK activator). The treatment with Forskolin does not reverse the effects of the H 2 S donors. Co-treatment with either NaHS or Lawesson's reagent and dorsomorphin (an AMPK inhibitor) did not reverse the effect of the H 2 S donors. H 2 S has antisecretory activity and is an essential molecule for protection against the intestinal secretion induced by CT. Thus, H 2 S donor drugs are promising candidates for cholera therapy. However, more studies are needed to elucidate the possible mechanism of action.