Dual effect of nitric oxide on cytosolic Ca2+ concentration and insulin secretion in rat pancreatic beta-cells.
In isolated rat pancreatic beta-cells, the nitric oxide (NO) donor NOC-7 at 1 microM reduced the amplitude of the oscillations of cytosolic Ca(2+) concentration ([Ca(2+)](c)) induced by 11.1 mM glucose, and at 10 microM terminated them. In the presence of N(G)-nitro-l-arginine (l-NNA), however, NOC-7 at 0.5 and 1 microM increased the amplitude of the [Ca(2+)](c) oscillations, although the NO donor at 10 microM still suppressed them. Aqueous NO solution also had a dual effect on the [Ca(2+)](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 [Ca(2+)](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 beta-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 [Ca(2+)](c) oscillations. In the presence of l-NNA, the glucose-induced insulin secretion from isolated islets was facilitated by 0.5 microM NOC-7, whereas it was suppressed by 10 microM NOC-7. These results suggest that NO facilitates glucose-induced [Ca(2+)](c) oscillations of beta-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.
Kaneko
Yukiko
Y
Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka City, Shizuoka 422-8526, Japan.
Ishikawa
Tomohisa
T
Amano
Satoshi
S
Nakayama
Koichi
K
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar
C115239:3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine; D004791:Enzyme Inhibitors; D006834:Hydrazines; D007328:Insulin; D020030:Nitric Oxide Donors; D019335:Nitroarginine; D009569:Nitric Oxide; D002118:Calcium