W1728 Lubiprostone Stimulates CFTR-Dependent Duodenal Bicarbonate Secretion in Rats

Background/Aim: Hydrogen sulfide (H2S), generated endogenously from L-cysteine by cystationine-β-synthase (CBS) and cystathionine-g-lyase (CSE) in mammalian cells, has recently been recognized as an important mediator that affects various functions under pathophysiological conditions.However, the functional role H2S plays in the gastrointestinal tract remains largely unknown.In the present study, we examined the effects of NaHS, a H2S donor, on HCO3-secretion in the rat stomach and duodenum and investigated the mechanism involved in these responses.Methods: Male SD rats were used after 18 h fasting.Under urethane anesthesia, an ex-vivo chambered stomach or a duodenal loop was perfused with saline, and HCO3-secretion was measured at pH 7.0 using a pH stat-method.NaHS (0.1~10 µmol/ ml) or HCl (mucosal acidification; 200 mM) was applied topically to the mucosa for 5 min or 10 min, respectively, while PGE2 (0.3 mg/kg) was given IV as a single injection.Indomethacin (5 mg/kg, SC), glibenclamide (KATP channel blocker; 10 mg/kg, IP) was given 30 min before NaHS, while L-NAME (nitric oxide (NO) synthase inhibitor; 20 mg/kg, SC) was given 3 h before.Propargylglycine (CSE antagonist; 10 mg/kg/h) was infused IV starting 1 h before mucosal acidification.Results: Intraluminal application of NaHS significantly and dosedependently increased the secretion of HCO3-in both the stomach and duodenum.The HCO3-stimulatory action of NaHS in these tissues were significantly attenuated by indomethacin and L-NAME as well as sensory deafferentation.Gastric but not duodenal HCO3 response was also attenuated by gibenclamide.PGE2 stimulated gastric and duodenal HCO3secretions, and these effects were both partially mitigated by glibenclamide but not indometahcin, L-NAME or sensory deafferentation.The acid-induced HCO3-secretion was significantly mitigated by propargylglycine, the inhibitor of H2S production, in the duodenum but not the stomach.In addition, the duodenal lesions induced by acid perfusion (150 mM HCl for 4 h) was significantly aggravated by pretreatment with propargylglycine.Conclusions: These results suggest that H2S increases HCO3-secretion in the rat gastroduodenal mucosa, and this action is partly mediated by PG, NO and sensory neurons in these tissue and partly associated with the activation of ATP-sensitive K+ channels in the stomach.In addition, it is assumed that endogenous H2S is involved in the regulatory mechanism of HCO3-secretion and mucosal protection in the duodenum but not the stomach, because the acid-induced HCO3-secretion was attenuated only in the duodenum by the inhibitor of H2S production.