Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.
Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.
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DOI：
10.1371/journal.pone.0133664
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ishikawa Y
中科院分区：
文献类型：
--
作者：
Suita K;Fujita T;Hasegawa N;Cai W;Jin H;Hidaka Y;Prajapati R;Umemura M;Yokoyama U;Sato M;Okumura S;Ishikawa Y
心房颤动（AF）是老年人中最常见的心律失常。它会导致严重的长期健康问题，影响生活质量。有人提出，自主神经系统参与人类房颤的发生和维持。然而，由于缺乏合适的实验动物房颤模型，对其发病机制和潜在治疗方法的研究受到了阻碍。我们的目标是在小鼠中建立持久的 AF 模型。我们还研究了肾上腺素能受体 (AR) 亚型的作用，其可能与 AF 的发作和持续时间有关。如前所述，小鼠经食管心房突发起搏可以诱发房颤，但持续时间很短（29.0±8.1秒）。我们发现腹腔内注射去甲肾上腺素（NE）激活肾上腺素能显着增加房颤持续时间。它将持续时间增加到10分钟以上，即增加了20倍以上（656.2±104.8秒；P<0.001）。在该模型中，预先注射特定的 β1-AR 阻滞剂美托洛尔和 α1-AR 阻滞剂哌唑嗪均显着减弱 NE 诱导的 AF 延长。为了进一步探讨这些受体对 AF 影响的机制，我们评估了 SR Ca2+ 渗漏（AF 的主要触发因素），以及心房肌细胞中随之而来的自发 SR Ca2+ 释放 (SCR)。与我们的体内实验结果一致，美托洛尔和哌唑嗪均显着抑制 NE 诱导的 SR Ca2+ 渗漏和 SCR。这些发现表明β1-AR和α1-AR可能在房颤的发生发展中发挥重要作用。我们在肾上腺素能激活诱导的小鼠中建立了持久的房颤模型，这对于未来使用实验动物（例如转基因小鼠）进行房颤研究具有重要意义。我们还通过体内和体外实验揭示了 β1- 和 α1-AR 介导的信号在 AF 发生中的重要作用。
Atrial fibrillation (AF) is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals. Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR) subtypes, which may be involved in the onset and duration of AF. Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0±8.1 sec). We found that adrenergic activation by intraperitoneal norepinephrine (NE) injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2±104.8 sec; P<0.001). In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors’ effects on AF, we assessed the SR Ca2+ leak, a major trigger of AF, and consequent spontaneous SR Ca2+ release (SCR) in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF. We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.