Mechanisms of the hypoglycemic effects of the alpha2-adrenoceptor antagonists SL84.0418 and deriglidole.
The effects of the alpha2-adrenoceptor antagonist SL84.0418 and its two enantiomers, (+) deriglidole and (-)SL86.0714 on glucose and insulin levels were examined in mice and in neonatal streptozotocin-induced diabetic rats. It was recently demonstrated in mouse pancreatic beta-cells that both deriglidole and SL86.0714 inhibit ATP-sensitive K+ channel with similar potency whereas alpha2-adrenoceptors are blocked only by deriglidole. In the present study, we showed, in vivo in mice, that SL84.0418 and deriglidole potently reduced glycemia and antagonized diazoxide-induced hyperglycemia, whereas SL86.0714 and tolbutamide were markedly less potent. In diabetic rats, SL84.0418 and deriglidole (10 mg/kg i.p.) fully normalized glucose tolerance whereas SL86.0714 and tolbutamide only slightly improved it. Five min after deriglidole administration in mice a marked and short lasting rise in insulin levels was observed, followed by a progressive reduction of glycemia. In diabetic rats, insulin and norepinephrine levels rose 15 min after deriglidole administration. Sympathetic outflow blockade by chlorisondamine, beta-adrenoceptor blockade by propranolol or their combination markedly reduced deriglidole-induced rise in insulin levels in a similar manner. Furthermore, in chlorisondamine-treated animals norepinephrine levels were strongly lowered and not modified by deriglidole and propranolol administration. However, in spite of sympathetic outflow and beta-adrenoceptor blockade, a moderate rise in insulinemia was still observed after deriglidole administration. Taken together these data demonstrate that deriglidole is the enantiomer that mediates the antihyperglycemic and insulin secretory effects of SL84.0418. Our study suggests that the major part of deriglidole effects is the consequence of the blockade of prejunctional alpha2-adrenoceptors that have reinforced the release of catecholamines in adrenergic nerve endings and indirectly activated postjunctional beta-adrenoceptors to further potentiate insulin secretion. However, it is also suggested that another undefined mechanism is involved in deriglidole potentiation of insulin secretion.
Guillot
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Department of Internal Medicine, Synthélabo Recherche, Rueil-Malmaison, France.
Coste
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Eon
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Angel
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D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002714:Chlorisondamine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D003981:Diazoxide / Q000494:pharmacology; D005260:Female; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000097:blood; D011433:Propranolol / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D007329:Insulin Antagonists; D011758:Pyrroles; C074936:SL 84.0418; C097987:deriglidole; D011433:Propranolol; D002714:Chlorisondamine; D003981:Diazoxide; D009638:Norepinephrine