Oxyntomodulin increases intrinsic heart rate through the glucagon receptor.
Oxyntomodulin increases intrinsic heart rate through the glucagon receptor.
复制标题
DOI：
10.1002/phy2.112
复制
发表时间：
2013-10
影响因子：
2.5
通讯作者：
Swoap, Steven J
中科院分区：
文献类型：
--
作者：
Mukharji, Auyon;Drucker, Daniel J;Charron, Maureen J;Swoap, Steven J
来自胃肠道的两种激素，胰高血糖素和胃泌酸调节素（OXM），可显着提高小鼠的内在心率（IHR）。我们之前已经证明 OXM 影响小鼠心率 (HR)，与胰高血糖素样肽 1 (GLP-1) 受体无关。在这里，我们在缺乏胰高血糖素受体 (Gcgr −/−) 的小鼠中使用无线电遥测技术证明，OXM 和胰高血糖素都需要胰高血糖素受体才能对心脏产生变时作用。此外，我们发现其他与饥饿和饱腹感相关的激素（生长素释放肽、瘦素和 PYY3-36）对 IHR 没有影响，而胆囊收缩素则适度升高 IHR。最后，在中性温度 (30°C) 下，Gcgr −/− 小鼠的静息 HR 高于对照小鼠（Gcgr +/+ 和 Gcgr +/-）。使用阿托品，我们证明 Gcgr −/− 小鼠在此温度下对心脏的副交感神经 (PNS) 影响减弱。与对照组相比，Gcgr −/− 小鼠在给予醋甲胆碱（激活毒蕈碱乙酰胆碱受体）或甲氧胺（通过激动 α1 肾上腺素受体激动剂激活压力感受反射）时表现出正常的心动过缓，表明 Gcgr −/− 小鼠的迷走神经通路是完整的。由于 OXM 是 GLP-1 受体和 Gcgr 的激动剂，具有抗糖尿病活性，因此我们建议 OXM 可以作为胰高血糖素的替代品，用于治疗过量的 β 受体阻滞剂以提高临床条件下的 HR。
Two hormones from the gastrointestinal tract, glucagon and oxyntomodulin (OXM), vigorously elevate the intrinsic heart rate (IHR) of mice. We have previously shown that OXM influences murine heart rate (HR) independent of the glucagon-like peptide 1 (GLP-1) receptor. Here, we demonstrate using radiotelemetry in mice deficient in the glucagon receptor (Gcgr −/−) that both OXM and glucagon require the glucagon receptor for their chronotropic effects on the heart. Furthermore, we found that other hormones associated with hunger and satiety (ghrelin, leptin, and PYY3-36) had no effect on IHR, while cholecystokinin moderately elevated the IHR. Finally, the resting HR of Gcgr −/− mice was higher than in control mice (Gcgr +/+ and Gcgr +/−) at thermal neutral temperature (30°C). Using atropine, we demonstrated that Gcgr −/− mice have diminished parasympathetic (PNS) influence of the heart at this temperature. Gcgr −/− mice displayed a normal bradycardia as compared to controls in response to administration of either methacholine (to activate the muscarinic acetylcholine receptor) or methoxamine (to activate the baroreflex through agonism of the α1 adrenergic receptor agonist) suggesting that vagal pathways are intact in the Gcgr −/− mice. As OXM is an agonist of the GLP-1 receptor and Gcgr with antidiabetic activity, we suggest OXM may be an alternative to glucagon in the treatment of overdose of beta-blockers to elevate HR in clinical conditions.