title: Dual effect of nitric oxide on ATP-sensitive K+ channels in rat pancreatic beta cells.
abstract: We have previously shown that NO has stimulatory and inhibitory effects on insulin secretion at low and high concentrations, respectively. The present study investigated effects of NO on K ATP channels of rat beta cells by patch clamp analysis to elucidate the mechanism for the dual effect. NOC7 at 0.5 microM suppressed K ATP channels activated by diazoxide in the cell-attached and perforated whole-cell modes but failed to suppress them in the inside-out mode. The inhibitory effect in the cell-attached mode was abolished by the soluble guanylate cyclase inhibitor ODQ and by the protein kinase G inhibitor KT5823. Moreover, 0.5 microM NOC7 failed to suppress the channel activity in the presence of the mitochondrial uncoupler FCCP. In contrast, 10 microM NOC7 activated K ATP channels in the cell-attached and perforated whole-cell modes, although it had no effect on the channels in the inside-out mode. The K ATP currents evoked by 10 microM NOC7 in the cell-attached mode were not inhibited by ODQ. The dual effect of NOC7 at 0.5 and 10 microM was observed in the same patch. Taken together, these results suggest that low-concentration NO exerts an inhibitory effect on K ATP channels of beta cells, which is induced through the cGMP/protein kinase G pathway, whereas high-concentration NO activates K ATP channels through the mechanism independent of cGMP.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sunouchi
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Suzuki
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014226:Triazenes / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: C100973:(1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-3-aminopropyl)-3-methyl-1-triazene; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D002227:Carbazoles; D007328:Insulin; D054086:KATP Channels; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D014226:Triazenes; D014475:Uncoupling Agents; C073601:KT 5823; D009569:Nitric Oxide; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D003981:Diazoxide