Nitric oxide-cyclic GMP system potentiates glucose-induced rise in cytosolic Ca2+ concentration in rat pancreatic β-cells

Involvement of nitric oxide (NO) in the regulation of insulin secretion from pancreatic beta-cells was investigated by measuring cytosolic Ca2+ concentration ([Ca2+](i)) in isolated rat pancreatic beta-cells. At 7.0 mM glucose, L-arginine (0.1 mM) elevated [Ca2+](i) in about 50% of the beta-cells examined. The response was partially inhibited by an NO synthase inhibitor, N-G-monomethyl-L-arginine (L-NMA; 0.1 mM), suggesting that part of the response was mediated by the production of NO from L-arginine. D-Arginine at higher concentrations (3 or 10 mM) also increased [Ca2+](i) at 7.0 mM glucose; however, the response was not affected by L-NMA (0.1 mM). Similar [Ca2+](i) elevation was produced by NO (10 nM) and sodium nitroprusside (SNP; 10 mu M) at 7.0 mM glucose. The SNP-induced increase in [Ca2+](i) was abolished by nicardipine (1 mu M), suggesting that the [Ca2+](i) response is mediated by Ca2+ influx through L-type voltage-operated Ca2+ channels. In the presence of oxyhemoglobin (1 mu M), the [Ca2+](i) elevation induced by NO (10 nM) was abolished. Neither degradation products of NO, NO2- nor NO3-, caused any changes in [Ca2+](i). 8-Bromo-cyclic GMP (8-Br-cGMP; 3 mM) and atrial natriuretic peptide (0.1 mu M) elevated [Ca2+](i) at 7.0 mM glucose. We conclude that NO, which is produced from L-arginine in pancreatic islets, facilitates glucose-induced [Ca2+](i) increase via the elevation of cGMP in rat pancreatic beta-cells. NO-cGMP system may physiologically regulate insulin secretion from pancreatic beta-cells.