Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Cardiothoracic Surgery, RadboudUMC, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
Nat Commun. 2018 Oct 19;9(1):4357. doi: 10.1038/s41467-018-06530-5.
The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardiac ANS produces various neuropeptides, among which the neurokinins, whose actions on atrial electrophysiology are largely unknown. We here demonstrate that the neurokinin substance-P (Sub-P) activates a neurokinin-3 receptor (NK-3R) in rabbit, prolonging action potential (AP) duration through inhibition of a background potassium current. In contrast, ventricular AP duration was unaffected by NK-3R activation. NK-3R stimulation lengthened atrial repolarization in intact rabbit hearts and consequently suppressed arrhythmia duration and occurrence in a rabbit isolated heart model of atrial fibrillation (AF). In human atrial appendages, the phenomenon of NK-3R mediated lengthening of atrial repolarization was also observed. Our findings thus uncover a pathway to selectively modulate atrial AP duration by activation of a hitherto unidentified neurokinin-3 receptor in the membrane of atrial myocytes. NK-3R stimulation may therefore represent an anti-arrhythmic concept to suppress re-entry-based atrial tachyarrhythmias, including AF.
心脏自主神经系统（ANS）控制正常的心房电功能。心脏 ANS 产生各种神经肽，其中神经激肽，其对心房电生理学的作用在很大程度上是未知的。我们在这里证明，神经激肽 P 物质（Sub-P）在兔中激活神经激肽-3 受体（NK-3R），通过抑制背景钾电流延长动作电位（AP）持续时间。相比之下，心室 AP 持续时间不受 NK-3R 激活的影响。NK-3R 刺激在完整的兔心中延长心房复极，并因此抑制心律失常的持续时间和发生在兔孤立的心房颤动（AF）心脏模型中。在人类的心房附件中，也观察到 NK-3R 介导的心房复极延长的现象。因此，我们的发现揭示了通过激活心房肌细胞膜中 hitherto 尚未鉴定的神经激肽-3 受体来选择性调节心房 AP 持续时间的途径。NK-3R 刺激可能因此代表一种抗心律失常的概念，以抑制包括 AF 在内的基于折返的房性心动过速。
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