title: Antagonism of the insulinotropic action of first generation imidazolines by openers of K(ATP) channels.
abstract: The antagonism between K(ATP) channel-blocking insulinotropic imidazolines - phentolamine, alinidine, idazoxan and efaroxan - and K(ATP) channel openers, diazoxide and nucleoside diphosphates, was studied in mouse pancreatic islets and B-cells. In inside-out patches from B-cells, 500muM MgGDP abolished the inhibitory effect of the imidazolines. 300muM diazoxide further increased channel activity. The depolarizing effect of all imidazolines (100muM) on the B-cell membrane potential was practically completely antagonized by 300muM diazoxide. In contrast, diazoxide was unable to decrease the cytosolic Ca(2+) concentration ([Ca(2+)](i)) which was elevated by phentolamine, whereas the [Ca(2+)](i) increases induced by the other imidazolines were promptly antagonized. The effects on [Ca(2+)](i) were reflected by the secretory activity in that the stimulatory effects of alinidine, idazoxan and efaroxan, but not that of phentolamine were antagonized by diazoxide. Metabolic inhibition of intact B-cells by 250muM NaCN, most likely by a decrease of the ATP/ADP ratio, significantly diminished the K(ATP) channel-blocking effect of a low concentration of alinidine (10muM), whereas efaroxan proved to be susceptible even at a highly effective concentration (100muM). This may explain the oscillatory pattern of the [Ca(2+)](i) increase typically produced by efaroxan in pancreatic B-cells. In conclusion, the inhibitory effect of imidazolines on K(ATP) channels, which is exerted at the pore-forming subunit, Kir6.2, is susceptible to the action of endogenous and exogenous K(ATP) channel openers acting at the regulatory subunit SUR, which confers tissue specificity. With intact cells this antagonism can be obscured, possibly by intracellular accumulation of some imidazolines.
authors.affiliation: Institute of Pharmacology and Toxicology, Technical University of Braunschweig, D-38106 Braunschweig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wienbergen
authors.forename: Claudia
authors.initials: C
authors.lastname: Bleck
authors.forename: Timm Grosse
authors.initials: TG
authors.lastname: Lackmann
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D048288:Imidazolines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D048288:Imidazolines; D007328:Insulin; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D014044:Tolbutamide; D003981:Diazoxide; D002118:Calcium