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.