title: Glucose dependence of imidazoline-induced insulin secretion: different characteristics of two ATP-Sensitive K+ channel-blocking compounds.
abstract: The glucose dependence of the insulinotropic action of KATP channel-blocking imidazoline compounds was investigated. Administration of 100 micromol/l phentolamine, but not 100 micromol/l efaroxan, markedly increased insulin secretion of freshly isolated mouse islets when the perifusion medium contained 5 mmol/l glucose. When the glucose concentration was raised to 10 mmol/l in the continued presence of either imidazoline, a clear potentiation of secretion occurred as compared with 10 mmol/l glucose alone. In the presence of efaroxan, a brisk first-phase-like increase was followed by a sustained phase, whereas a more gradual increase resulted in the presence of phentolamine. Administration of 100 micromol/l phentolamine was somewhat more effective than 100 micromol/l efaroxan to inhibit KATP channel activity in intact cultured beta-cells (reduction by 96 vs. 83%). Both compounds were similarly effective to depolarize the beta-cells. When measured by the perforated patch-technique, the depolarization by efaroxan was often oscillatory, whereas that by phentolamine was sustained. In perifused cultured islets, both compounds increased the cytosolic calcium concentration ([Ca2+]c) in the presence of 5 and 10 mmol/l glucose. Efaroxan induced large amplitude oscillations of [Ca2+]c, whereas phentolamine induced a sustained increase. It appears that a KATP channel block by imidazolines is not incompatible with a glucose-selective enhancement of insulin secretion. The glucose selectivity of efaroxan may involve an inhibitory effect distal to [Ca2+]c increase and/or the generation of [Ca2+]c oscillations.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bleck
authors.forename: Antje
authors.initials: A
authors.lastname: Wienbergen
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*
chemical_list: D001572:Benzofurans; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; C062597:efaroxan; D005947:Glucose