Activation of phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide are needed for the antiarrhythmic effect of centrally administered rilmenidine.
Activation of phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide are needed for the antiarrhythmic effect of centrally administered rilmenidine.
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DOI：
10.1016/j.ejphar.2010.08.035
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发表时间：
2010-11
影响因子：
5
通讯作者：
H. Yamanaka;Y. Hayashi;M. Iwasaki;T. Kamibayashi;A. Yamatodani;T. Mashimo
中科院分区：
文献类型：
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作者：
H. Yamanaka;Y. Hayashi;M. Iwasaki;T. Kamibayashi;A. Yamatodani;T. Mashimo
中枢神经系统中咪唑啉受体的激活对几种类型的心律失常具有保护作用。我们证明，中央管理的利美尼定，选择性咪唑啉受体激动剂，防止肾上腺素诱导的心律失常氟烷麻醉期间。然而，详细的心肌信号的抗心律失常作用仍有待探讨。本研究旨在探讨百日咳毒素敏感G蛋白、磷脂酰肌醇3-激酶/Akt信号通路和内源性一氧化氮在利美尼定抗百日咳作用中的作用。用氟烷麻醉雄性Sprague-Dawley大鼠，并连续监测动脉血压和室性早搏。肾上腺素的致心律失常剂量定义为在15秒内产生3次或3次以上室性早搏的最小剂量。首先，我们证实了在氟烷麻醉期间，中心给药的利美尼定可预防肾上腺素诱导的心律失常，并检查了百日咳毒素、渥曼青霉素（一种磷脂酰肌醇3-激酶抑制剂）和硝基-L-精氨酸甲酯（l-NAME）（一种特异性一氧化氮合成抑制剂）对利美尼定抗心律失常作用的影响。我们还进行了Western印迹分析，以确定在利美尼定的中枢给药后Akt和糖原合成酶激酶3β（Akt下游的直接靶点）的磷酸化。百日咳毒素、渥曼青霉素和L-NAME均能显著抑制利美尼定的抗肿瘤作用。乌美尼定增加Akt和糖原合成酶激酶3β磷酸化（分别为28±13%和32± 13%），这种作用被渥曼青霉素消除。本研究结果提示，百日咳毒素敏感性G蛋白、磷脂酰肌醇3激酶-Akt-GSK 3 β信号通路和内源性一氧化氮可能在利美尼定中枢给药的抗百日咳作用中起关键作用。
Activation of imidazoline receptors in the central nervous system has protective effect on several types of arrhythmias. We demonstrated that centrally administered rilmenidine, a selective imidazoline receptor agonist, prevented adrenaline-induced arrhythmias during halothane anaesthesia. However, detailed myocardial signaling of the antiarrhythmic effect remains to be unexplored. The present study was designed to examine a role of pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide in the antiarrhythmic effect of rilmenidine. Male Sprague–Dawley rats were anaesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of adrenaline was defined as the smallest dose producing 3 or more premature ventricular contractions within 15-s period. Firstly, we confirmed that centrally administered rilmenidine prevented adrenaline-induced arrhythmias during halothane anaesthesia and examined the effect of pertussis toxin, wortmannin (a phosphatidylinositol 3-kinase inhibitor), and nitro-l-arginine methyl ester (l-NAME) (a specific nitric oxide synthesis inhibitors), on the antiarrhythmic effect of rilmenidine. We also performed Western blot analysis to determine phosphorylation of Akt and glycogen synthase kinase 3β, a direct Akt downstream target, following the central administration of rilmenidine. The antiarrhythmic effect of rilmenidine was significantly inhibited by pertussis toxin, wortmannin and l-NAME. Rilmenidine increased Akt and glycogen synthase kinase 3β phosphorylation (28±13% and 32±13%, respectively), and this action was abolished by wortmannin. The present results demonstrated that pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase-Akt-GSK3β signaling pathway and endogenous nitric oxide may play a key role in antiarrhythmic effect of centrally administered rilmenidine.