A novel role for carbon monoxide as a potent regulator of intracellular Ca2+ and nitric oxide in rat pancreatic acinar cells

Carbon monoxide (CO) is known as an essential gaseous messenger that regulates a wide array of physiological and pathological processes, similar to nitric oxide (NO) and hydrogen sulfide. The aim of the present study was to elucidate the potential role of CO in CA(2+) homeostasis and to explore the underlying mechanisms in pancreatic acinar cells. The exogenous application of a CO-releasing molecule dose-dependently increased intracellular CA(2+) concentration ([CA(2+)]i). A heme oxygenase (HO) inducer increased [CA(2+)]i in a concentration-dependent manner, and the increase was diminished by an HO inhibitor. The CO-induced [CA(2+)]i increase persisted in the absence of extracellular CA(2+), indicating that CA(2+) release is the initial source for the increase. The inhibition of G protein, Phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP3) receptor diminished the CO-induced [CA(2+)]i increase. CO upregulated endothelial nitric oxide synthase (eNOS) expression and stimulated NO production, and NOS inhibitor, Calmodulin inhibitor, or the absence of extracellular CA(2+) eliminated the latter response. Blocking the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway abolished CO-induced NO production. Pretreatment with an NOS inhibitor, NO scavenger, or soluble Guanylate Cyclase inhibitor, did not affect the CO-induced [CA(2+)]i increase, indicating that NO, soluble Guanylate Cyclase, and cyclic guanosine 5'-monophosphate are not involved in the CO-induced [CA(2+)]i increase. CO inhibited the secretory responses to CCK-octapeptide or carbachol. We conclude that CO acts as a regulator not only for [CA(2+)]i homeostasis via a PLC-IP3-IP3 receptor cascade but also for NO production via the Calmodulin and PI3K-Akt/PKB pathway, and both CO and NO interact. Moreover, CO may provide potential therapy to ameliorate acute pancreatitis by inhibiting amylase secretion.

Ca2+; carbon monoxide; nitric oxide; pancreatic acinar cells.