Efaroxan对胰岛素分泌的调控机制研究

目的观察Efaroxan的促胰岛素分泌作用特点,并探讨其相关作用机制。方法应用放免法测定不同条件下Efaroxan对大鼠胰岛素分泌的影响。c AMP放射免疫试剂盒测定胰岛细胞内c AMP含量。结果 Efaroxan促进胰岛素分泌作用具有葡萄糖浓度依赖性,其特点是在高浓度葡萄糖条件下(8.3、11.1 mmol·L-1)增强胰岛素分泌,而在低浓度葡萄糖条件下(0、2.8 mmol·L-1)则没有作用。Efaroxan的拮抗剂KU14R可明显抑制Efaroxan对胰岛素分泌的促进作用,并明显的抑制了forskolin和IBMX对胰岛素分泌的促进作用。胰岛c AMP含量检测发现,forskolin和IBMX明显增加了胰岛细胞c AMP含量,但是Efaroxan和KU14R对胰岛c AMP含量没有影响。结论 Efaroxan促进胰岛素分泌作用与激动c AMP下游信号通路有关,KU14R通过阻断c AMP下游信号转导通路发挥抑制Efaroxan、forskolin和IBMX的促胰岛素分泌作用。

Comparative effects of idazoxan, efaroxan, and BU 224 on insulin secretion in the rabbit: Not only interaction with pancreatic imidazoline I2 binding sites

The nature of the binding site(s) involved in the insulin secretory activity of imidazoline compo- unds remains unclear. An imidazoline I2 binding site (I2BS) has been neglected since the classic I2 ligand, idazoxan, does not release insulin. Using the rabbit as an appropriate model for the study of this type of binding sites, we have tried to re-evaluate the effects of idazoxan, the selective I2 compound BU 224, and efaroxan on insulin secretion. Mimicking efaroxan, idazoxan and BU 224 potentiated insulin release from perifused islets in the presence of 8 mM glucose. In static incubation, insulin secretion induced by idazoxan and BU 224 exhibited both dose and glucose dependencies. ATP-sensitive K+ (KATP) channel blockade, though at a different site from the SUR1 receptor, with subsequent Ca2+ entry, mediates the insulin releasing effect of the three ligands. However, additional MAO independent intracellular steps in stimulus- secretion coupling linked to PKA and PKC activation are only involved in the effect of BU 224. Therefore, both an I2 related binding site at the channel level shared by the three ligands and a putative I3-intracellularly located binding site stimulated by BU 224 would be mediating insulin release by these compounds. In vivo experiments reassess the abilities of idazoxan and BU 224 to enhance glucose-induced insulin secretion and to elicit a modest blood glucose lowering response.

Alpha2-adrenergic receptor activation reinstates motor deficits in rats recovering from cortical injury

Norepinephrine plays an important role in motor functional recovery after a brain injury caused by ferrous chloride.Inhibition of norepinephrine release by clonidine is correlated with motor deficits after motor cortex injury.The aim of this study was to analyze the role ofα-adrenergic receptors in the restoration of motor deficits in recovering rats after brain damage.The rats were randomly assigned to the sham and injury groups and then treated with the following pharmacological agents at 3 hours before and 8 hours,3 days,and 20 days after ferrous chloride-induced cortical injury:saline,clonidine,efaroxan(a selective antagonist ofα-adrenergic receptors)and clonidine+efaroxan.The sensorimotor score,the immunohistochemical staining forα-adrenergic receptors,and norepinephrine levels were evaluated.Eight hours post-injury,the sensorimotor score and norepinephrine levels in the locus coeruleus of the injured rats decreased,and these effects were maintained 3 days post-injury.However,20 days later,clonidine administration diminished norepinephrine levels in the pons compared with the sham group.This effect was accompanied by sensorimotor deficits.These effects were blocked by efaroxan.In conclusion,an increase inα-adrenergic receptor levels was observed after injury.Clonidine restores motor deficits in rats recovering from cortical injury,an effect that was prevented by efaroxan.The underlying mechanisms involve the stimulation of hypersensitiveα-adrenergic receptors and inhibition of norepinephrine activity in the locus coeruleus.The results of this study suggest thatαreceptor agonists might restore deficits or impede rehabilitation in patients with brain injury,and therefore pharmacological therapies need to be prescribed cautiously to these patients.

Imidazolines促胰岛素分泌作用机制的研究

目的观察ｉｍｉｄａｚｏｌｉｎｅｓ：ｐｈｅｎｔｏｌａｍｉｎｅ，ｅｆａｒｏｘａｎ和ｉｄａｚｏｘａｎ对ＡＴＰ调节的钾离子通道的影响，从而探讨其促胰岛素分泌的作用机制。方法用“内面向外”的膜片钳制技术，在培养的无性系的ＲＩＮｍ５Ｆ胰岛素分泌细胞进行实验。结果ｐｈｅｎｔｏｌａｍｉｎｅ５０μｍｏｌ·Ｌ－１明显抑制ＡＴＰ调节的钾离子通道，显著降低通道开放的概率。Ｅｆａｒｏｘａｎ５０μｍｏｌ·Ｌ－１明显降低通道开放的概率，抑制钾离子通道的开放，但作用维持时间短。ｉｄａｚｏｘａｎ５０μｍｏｌ·Ｌ－１对通道开放概率的影响不明显。结论ｐｈｅｎｔｏｌａｍｉｎｅ，ｅｆａｒｏｘａｎ和ｉｄａｚｏｘａｎ促胰岛素分泌的作用与阻断ＡＴＰ调节的钾离子通道有关。

依法克生对胰岛β细胞表达Ras同源物的调节作用

目的 观察 Ras同源物 (Rhes)在胰岛 β细胞中的表达以及依法克生 (efaroxan)对 Rhes表达的影响。 方法 用逆转录 -聚合酶链反应 (RT- PCR)观察 Rhes在克隆大鼠胰岛素分泌细胞(RINm5 F和 BRIN BD11细胞 )以及离体大鼠完整胰岛中的表达。BRIN BD11细胞经依法克生 2 4h预处理后 ,观察依法克生和 (或 )依法克生的结构类似物 (KU14R)对胰岛素释放的影响。 结果 (1)RINm5 F、BRIN BD11细胞和离体完整大鼠胰岛均表达 Rhes。 (2 )依法克生对 Rhes的表达有降调节作用。KU14R对 Rhes的表达无影响 ,但能完全阻断依法克生对 Rhes表达的降调节作用。(3)依法克生可诱导 BRIN BD11细胞对其刺激胰岛分泌作用产生脱敏效应。 (4) KU14R可刺激 BRIB BD11细胞分泌胰岛素。 结论 胰岛 β细胞可表达 Rhes。Rhes是受咪唑啉类调控的分子 ,可能参与调节依法克生诱导的 β细胞胰岛素释放。

咪唑啉受体及其激动剂和拮抗剂的研究进展

咪唑啉受体不仅与血压调节、胰岛素分泌、神经元保护、肾脏排钠利尿、促进细胞增殖等重要生理功能相关,还参与了抑郁症、帕金森病、海洛因成瘾、亨廷顿舞蹈病、阿尔茨海默病等多种精神神经疾病的发生过程。本文就咪唑啉受体的生物学特征及其激动剂和拮抗剂的研究进展做一综述。

莫索尼定对麻醉大鼠颈动脉窦压力感受器反射的影响<英文>

目的:观察莫索尼定对颈动脉窦压力感受器反射的影响。方法:利用灌流左颈动脉窦方法,观察莫索尼定对麻醉大鼠压力反射机能参数的影响。恒流灌流股动脉,记录灌流压变化,确定莫索尼定对血管阻力的影响。结果:莫索尼定32,100μmol·L^(-1)使颈动脉窦压力反射机能曲线向右上移位,曲线最大斜率和反射性平均动脉压下降幅度均减小,提示莫索尼定对压力感受器反射有抑制作用。伊法克生100μmol·L^(-1)完全阻断莫索尼定100μmol·L^(-1)的效应。莫索尼定显著增加血管阻力。结论:莫索尼定对颈动脉窦压力反射有直接抑制作用,此作用可能在于其引起窦壁收缩所致。