Hydrogen sulfide regulates Ca(2+) homeostasis mediated by concomitantly produced nitric oxide via a novel synergistic pathway in exocrine pancreas.

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Aim: The present study was designed to explore the effects of hydrogen sulfide (H2S) on Ca(2+) homeostasis in rat pancreatic acini.Results: Sodium hydrosulfide (NaHS; an H2S donor) induced a biphasic increase in the intracellular Ca(2+) concentration ([Ca(2+)]i) in a dose-dependent manner. The NaHS-induced [Ca(2+)]i elevation persisted with an EC50 of 73.3 μM in the absence of extracellular Ca(2+) but was abolished by thapsigargin, indicating that both Ca(2+) entry and Ca(2+) release contributed to the increase. The [Ca(2+)]i increase was markedly inhibited in the presence of NG-monomethyl L-arginine or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), and diaminofluorescein-2/diaminofluorescein-2 triazole (DAF-2/DAF-2T) fluorometry demonstrated that nitric oxide (NO) was also produced by H2S in a dose-dependent manner with an EC50 of 64.8 μM, indicating that NO was involved in the H2S effect. The H2S-induced [Ca(2+)]i increase was inhibited by pretreatment with U73122, xestospongin C, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, KT5823, and GP2A, indicating that phospholipase C (PLC), the inositol 1,4,5-trisphosphate (IP3) receptor, soluble guanylate cyclase (sGC), protein kinase G (PKG), and Gq-protein play roles as intermediate components in the H2S-triggered intracellular signaling.Innovation: To our knowledge, our study is the first one highlighting the effect of H2S on intracellular Ca(2+) dynamics in pancreatic acinar cells. Moreover, a novel cascade was presumed to function via the synergistic interaction between H2S and NO.Conclusion: We conclude that H2S affects [Ca(2+)]i homeostasis that is mediated by H2S-evoked NO production via an endothelial nitric oxide synthase (eNOS)-NO-sGC-cyclic guanosine monophosphate-PKG-Gq-protein-PLC-IP3 pathway to induce Ca(2+) release, and this pathway is identical to the one we recently proposed for a sole effect of NO and the two gaseous molecules synergistically function to regulate Ca(2+) homeostasis.