The imidazoline NNC77-0020 affects glucose-dependent insulin, glucagon and somatostatin secretion in mouse pancreatic islets.
The effect of the novel imidazoline compound 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-(5-methyl-2,3-dihydrobenzofuran-7-yl)-ethyl]-pyridine (NNC77-0020) on stimulus-secretion coupling and hormone secretion was investigated in mouse pancreatic islets and isolated alpha- and beta-cells. In the presence of elevated glucose concentrations NNC77-0020 stimulated insulin secretion concentration dependently (EC(50) 64 nM) by 200% without affecting the whole-cell K(+) current or cytoplasmic Ca(2+) levels. Capacitance measurements in single mouse beta-cells showed that intracellular application of NNC77-0020 via the recording pipette enhanced Ca(2+)-dependent exocytosis. This action was dependent on protein kinase C (PKC) and cytoplasmic phospholipase A(2) (cPLA(2)) activity and required functional granular ClC-3 Cl(-) channels. In intact islets NNC77-0020 stimulated glucose-dependent somatostatin secretion, an effect that was also dependent on PKC and cPLA(2) activity. NNC77-0020 also inhibited glucagon secretion. In single mouse alpha-cells this action was not associated with a change in spontaneous electrical activity and resulted from a reduction in the rate of Ca(2+)-dependent exocytosis. Inhibition of exocytosis by NNC77-0020 was pertussis toxin sensitive and mediated by activation of the protein phosphatase calcineurin. In conclusion, our data suggest that the imidazoline compound NNC77-0020 modulates pancreatic hormone secretion in a complex fashion, comprising glucose-dependent stimulation of insulin and somatostatin secretion and inhibition of glucagon release. These mechanisms of action constitute an ideal basis for the development of novel imidazoline-containing anti-diabetic compounds.
D000818:Animals; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000378:metabolism; D003062:Codon; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016376:Oligonucleotides, Antisense; D018408:Patch-Clamp Techniques; D010741:Phospholipases A / Q000378:metabolism; D015221:Potassium Channels; D011493:Protein Kinase C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013004:Somatostatin / Q000378:metabolism*
C481159:2-(2-(4,5-dihydro-1H-imidazol-2-yl)-1-(5-methyl-2,3-dihydrobenzofuran-7-yl)-ethyl)-pyridine; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D003062:Codon; D007093:Imidazoles; D007328:Insulin; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D015221:Potassium Channels; D011725:Pyridines; C117780:mitochondrial K(ATP) channel; D013004:Somatostatin; D005934:Glucagon; D011493:Protein Kinase C; D010741:Phospholipases A; D005947:Glucose