Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1).
Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1).
复制标题
DOI：
10.1161/circep.118.006740
复制
发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Gourine AV
中科院分区：
文献类型：
--
作者：
Ang R;Mastitskaya S;Hosford PS;Basalay M;Specterman M;Aziz Q;Li Y;Orini M;Taggart P;Lambiase PD;Gourine A;Tinker A;Gourine AV
胰升糖素样肽-1受体(GLP-1R)激动剂可改善2型糖尿病患者的心血管预后。然而，这些药物的全身作用会引起交感神经激活，这通常被认为在心血管疾病中是有害的。尽管GLP-1在心血管生物学方面有很大的研究兴趣，但GLP-1R在心室肌细胞中的存在仍然是一个有争议的问题，而且GLP-1R对完整心肌电特性的影响尚不清楚。本实验旨在研究GLP-1R激动剂exendin-4(Exendin-4)对大鼠在体及离体室性心律失常易感性和室性动作电位时程的影响。在麻醉(乌拉坦)大鼠和离体灌流的大鼠心脏上记录到窦性心律和心室起搏时的心室单相动作电位。在体内，静脉注射EX4(5μg/kg)可增加心率，这种作用可被β-肾上腺素能受体阻断所阻断。尽管EX4引起交感神经兴奋，但在心室起搏时，90%复极时的动作电位时程增加7%(P=0.044；n=6)，并翻转β受体激动剂多巴酚丁胺对90%复极时时程的影响。在离体灌流心脏上，EX4(3nmol/L)使复极90%时的动作电位时程增加14%(P=0.015；n=6)，但对心率无影响。EX4还可降低异丙肾上腺素刺激β-肾上腺素能受体时诱发的室性心律失常。阻断M受体或抑制一氧化氮合酶可阻止EX4对动作电位时程和室性心律失常易感性的影响。这些数据表明，GLP-1R的激活有效地对抗了刺激β-肾上腺素能受体对心脏心室兴奋性的影响，并减少了室性心律失常的电位。GLP-1R的激活对心室肌的作用是间接的，由乙酰胆碱和一氧化氮介导，因此可以通过刺激心脏副交感(迷走神经)神经元来解释。
Glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular outcomes in patients with type 2 diabetes mellitus. However, systemic actions of these agents cause sympathetic activation, which is generally considered to be detrimental in cardiovascular disease. Despite significant research interest in cardiovascular biology of GLP-1, the presence of GLP-1R in ventricular cardiomyocytes remains a controversial issue, and the effects of this peptide on the electrical properties of intact ventricular myocardium are unknown. We sought to determine the effects of GLP-1R agonist exendin-4 (Ex4) on ventricular action potential duration (APD) and susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo. Ventricular monophasic action potentials were recorded in anaesthetized (urethane) rats in vivo and isolated perfused rat hearts during sinus rhythm and ventricular pacing. In vivo, systemic administration of Ex4 (5 μg/kg intravenously) increased heart rate, and this effect was abolished by β-adrenoceptor blockade. Despite causing sympathetic activation, Ex4 increased APD at 90% repolarization during ventricular pacing by 7% (P=0.044; n=6) and reversed the effect of β-adrenoceptor agonist dobutamine on APD at 90% repolarization. In isolated perfused hearts, Ex4 (3 nmol/L) increased APD at 90% repolarization by 14% (P=0.015; n=6) with no effect on heart rate. Ex4 also reduced ventricular arrhythmia inducibility in conditions of β-adrenoceptor stimulation with isoproterenol. Ex4 effects on APD and ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase. These data demonstrate that GLP-1R activation effectively opposes the effects of β-adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential. The effect of GLP-1R activation on the ventricular myocardium is indirect, mediated by acetylcholine and nitric oxide and, therefore, can be explained by stimulation of cardiac parasympathetic (vagal) neurons.