In vitro stimulation of insulin release by SL 84.0418, a new alpha 2-adrenoceptor antagonist.
SL 84.0418 (2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2-propyl-pyrrolo[3, 2,1- hi]-indole hydrocholoride) is a novel alpha 2-adrenoceptor antagonist which possesses anti-hyperglycaemic properties in vitro study, we tested its effects on insulin release from isolated mouse islets. In the presence of 15 mM glucose, SL 84.0418 produced a concentration-dependent (0.1-100 microM) increase of insulin release with a slightly higher potency than tolbutamide. SL 84.0418 antagonized the inhibition of glucose-induced insulin release caused either by the alpha 2-adrenoceptor agonist clonidine or by diazoxide, a selective opener of ATP-sensitive K+ channels in the beta-cell membrane. Its potency was greater on the inhibition by clonidine than on that by diazoxide, complete antagonism of the inhibition being achieved by 0.9 microM and 6 microM SL 84.0418 respectively. When alpha 2-adrenoceptors were blocked by the antagonist idazoxan, the low concentrations of SL 84.0418 (0.1-0.3 microM) no longer increased insulin release, whereas the effect of higher concentrations (> or = 1 microM) was not affected. SL 84.0418 (> or = 1 microM) inhibited 86Rb efflux from islets perifused with a medium containing 3 mM glucose, i.e. under conditions where many ATP-sensitive K+ channels are open. It also reduced the acceleration of 86Rb efflux that diazoxide caused in the presence of 6 mM glucose. Moreover, SL 84.0418 directly inhibited ATP-sensitive K+ currents measured in single beta-cells by the whole-cell mode of the patch-clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)
Jonas
J C
JC
Unit of Endocrinology and Metabolism, University of Louvain, Brussels, Belgium.
Plant
T D
TD
Angel
I
I
Langer
S Z
SZ
Henquin
J C
JC
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004594:Electrophysiology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D019329:Idazoxan; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012414:Rubidium Radioisotopes; D014044:Tolbutamide / Q000494:pharmacology
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007211:Indoles; D007328:Insulin; D015221:Potassium Channels; D011758:Pyrroles; D012414:Rubidium Radioisotopes; C074936:SL 84.0418; D014044:Tolbutamide; D005947:Glucose; D003000:Clonidine; D003981:Diazoxide; D019329:Idazoxan