Dual effect of nitric oxide on cytosolic Ca concentration and insulin secretion in rat pancreatic -cells

Kaneko, Yukiko, Tomohisa Ishikawa, Satoshi Amano, and Koichi Nakayama. Dual effect of nitric oxide on cytosolic Ca2 concentration and insulin secretion in rat pancreatic -cells. Am J Physiol Cell Physiol 284: C1215–C1222, 2003. First published January 15, 2003; 10.1152/ajpcell.00223.2002.—In isolated rat pancreatic -cells, the nitric oxide (NO) donor NOC-7 at 1 M reduced the amplitude of the oscillations of cytosolic Ca2 concentration ([Ca2 ]c) induced by 11.1 mM glucose, and at 10 M terminated them. In the presence of NG-nitro-L-arginine (LNNA), however, NOC-7 at 0.5 and 1 M increased the amplitude of the [Ca2 ]c oscillations, although the NO donor at 10 M still suppressed them. Aqueous NO solution also had a dual effect on the [Ca2 ]c oscillations. The soluble guanylate cyclase inhibitor LY-83583 and the cGMP-dependent protein kinase inhibitor KT5823 inhibited the stimulatory effect of NO, and 8-bromo-cGMP increased the amplitude of the [Ca2 ]c oscillations. Patch-clamp analyses in the perforated configuration showed that 8-bromo-cGMP inhibited whole cell ATP-sensitive K currents in the isolated rat pancreatic -cells, suggesting that the inhibition by cGMP of ATP-sensitive K channels is, at least in part, responsible for the stimulatory effect of NO on the [Ca2 ]c oscillations. In the presence of L-NNA, the glucose-induced insulin secretion from isolated islets was facilitated by 0.5 M NOC-7, whereas it was suppressed by 10 M NOC-7. These results suggest that NO facilitates glucose-induced [Ca2 ]c oscillations of -cells and insulin secretion at low concentrations, which effects are mediated by cGMP, whereas NO inhibits them in a cGMP-independent manner at high concentrations.