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首页> 外文期刊>Life sciences >Mechanisms of the hypoglycemic effects of the alpha2-adrenoceptor antagonists SL84.0418 and deriglidole.
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Mechanisms of the hypoglycemic effects of the alpha2-adrenoceptor antagonists SL84.0418 and deriglidole.

机译：α2-肾上腺素受体拮抗剂SL84.0418和去甲利多尔的降血糖作用机理。

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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.
机译：在小鼠和新生的链脲佐菌素诱导的糖尿病大鼠中检查了α2-肾上腺素受体拮抗剂SL84.0418及其两个对映体（+）脱利多和（-）SL86.0714对葡萄糖和胰岛素水平的影响。最近在小鼠胰腺β细胞中证实，去甲戊二烯和SL86.0714均以相似的效力抑制ATP敏感的K +通道，而α2-肾上腺素受体仅被去甲乙二烯阻断。在本研究中，我们在小鼠体内显示，SL84.0418和去甲利托利可有效降低血糖并拮抗二氮嗪诱导的高血糖，而SL86.0714和甲苯磺丁酰胺的效价则明显较低。在糖尿病大鼠中，SL84.0418和去甲利多利（10 mg / kg腹腔内注射）使葡萄糖耐量完全正常化，而SL86.0714和甲苯磺丁酰胺仅略微改善了糖耐量。在小鼠中给予去甲吡咯五分钟后，观察到胰岛素水平显着且短暂的升高，随后血糖逐渐降低。在糖尿病大鼠中，给予三环利托15分钟后，胰岛素和去甲肾上腺素水平上升。毒死d的交感神经外流阻滞，普萘洛尔或它们的组合对β-肾上腺素受体的阻滞以类似的方式显着降低了去甲利多尔诱导的胰岛素水平的升高。此外，在用毒死胺治疗的动物中，去甲肾上腺素的水平大大降低，而未被去甲环戊二烯和普萘洛尔给药改变。然而，尽管发生了交感神经外流和β-肾上腺素受体阻滞，但在服用三氟哌啶醇后仍观察到胰岛素血症的中度升高。这些数据加在一起表明，去甲戊二烯是介导SL84.0418的降血糖和胰岛素分泌作用的对映体。我们的研究表明，去甲环戊二烯作用的主要部分是结前α2-肾上腺素受体被阻滞的结果，该受体增强了肾上腺能神经末梢中儿茶酚胺的释放，并间接激活结后β-肾上腺素受体以进一步增强胰岛素的分泌。但是，还提示胰岛素分泌的三环戊二烯增效作用涉及另一种不确定的机制。

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