title: Selective enhancement of nutrient-induced insulin secretion by ATP-sensitive K+ channel-blocking imidazolines.
abstract: The contribution of ATP-sensitive K(+) channel (K(ATP) channel)-dependent and -independent signaling to the insulinotropic characteristics of imidazolines was explored using perifused mouse islets and beta-cells. Up to a concentration of 100 muM efaroxan had no insulinotropic effect in the presence of a basal glucose concentration, but enhanced the effect of a stimulatory concentration of glucose or nonglucidic nutrients (ketoisocaproate plus glutamine). The secretion by a non-nutrient (40 mM KCl) was not enhanced. At 500 microM, efaroxan stimulated insulin secretion when glucose was basal. Likewise, at 0.1 to 10 microM RX871024 [2-(imidazolin-2-yl)-1-phenylindole] showed a purely enhancing effect, but at 100 microM it elicited a strong KCl-like secretory response in the presence of basal glucose. At 0.1 and 1 microM RX871024 did not significantly depolarize the beta-cell membrane. However, at a purely enhancing drug concentration (10 microM RX871024 or 100 microM efaroxan) K(ATP) channel activity was strongly reduced, the membrane was depolarized, and the cytosolic Ca(2+) concentration was elevated in the presence of basal glucose. Insulin secretion by sulfonylurea receptor (SUR)1 knockout (KO) islets, which have no functional K(ATP) channels, was not increased by efaroxan (100 or 500 microM) or by 10 microM RX871024 but was increased by 100 microM RX871024. The imidazolines phentolamine and alinidine (100 microM) were also ineffective on SUR1 KO islets. It is concluded that a significant K(ATP) channel block is compatible with a purely enhancing effect of the imidazolines on nutrient-induced insulin secretion. Only RX871024 has an additional, nondepolarizing effect, which at a high drug concentration is able to elicit a K(ATP) channel-independent secretion.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, Mendelssohnstr. 1, D-38106 Braunschweig, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hatlapatka
authors.forename: Antje
authors.initials: A
authors.lastname: Wienbergen
authors.forename: Claudia
authors.initials: C
authors.lastname: Kühne
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Michael
authors.initials: M
authors.lastname: Willenborg
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D048288:Imidazolines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D048288:Imidazolines; D007328:Insulin; D054086:KATP Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D005947:Glucose; D002118:Calcium