Hanbang Body-fluid Research Center & College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea; and.
Am J Physiol Heart Circ Physiol. 2013 Oct 1;305(7):H1050-6. doi: 10.1152/ajpheart.00469.2013. Epub 2013 Aug 2.
Exogenous acetylcholine (ACh) is known to stimulate atrial natriuretic peptide (ANP) secretion concomitantly with a decrease in atrial pulse pressure. However, the role of intrinsic ACh in the regulation of ANP secretion remains unknown. Recently, it was shown that nonneuronal and neuronal ACh is present in the cardiac atria. From this finding we hypothesize that endogenously released ACh is involved in the regulation of ANP secretion in an autocrine or paracrine manner in the atria. Experiments were performed in isolated beating rat atria. ANP was measured using radioimmunoassay. To increase the availability of the ACh in the extracellular space of the atrium, its degradation was inhibited with an inhibitor of acetylcholinesterase. Acetylcholinesterase inhibition with physostigmine increased ANP secretion concomitantly with a decrease in atrial dynamics in a concentration-dependent manner. Inhibitors of M2 muscarinic ACh receptor (mAChR), methoctramine, and ACh-activated K(+) (KACh(+)) channels, tertiapin-Q, abolished the physostigmine-induced changes. The effects were not observed in the atria from rats treated with pertussis toxin. Furthermore, the physostigmine-induced effects were attenuated by an inhibitor of high-affinity choline transporter, hemicholinium-3, which is a rate-limiting step of ACh synthesis. Inhibitors of the mAChR signaling pathway and ACh synthesis also attenuated the basal levels of ANP secretion and accentuated atrial dynamics. These findings suggest that endogenously released ACh tonically stimulates ANP secretion from atrial cardiomyocytes via activation of M2 mAChR-Gi/o-KACh(+) channel signaling. It is also suggested that the ACh-ANP signaling is implicated in cardiac physiology and pathophysiology.
外源性乙酰胆碱（ACh）已知可刺激心房利钠肽（ANP）分泌，同时降低心房脉冲压力。然而，内源性 ACh 在调节 ANP 分泌中的作用尚不清楚。最近，研究表明非神经元和神经元 ACh 存在于心脏心房中。基于这一发现，我们假设内源性释放的 ACh 通过自分泌或旁分泌方式参与心房中 ANP 分泌的调节。实验在分离的跳动大鼠心房中进行。使用放射免疫测定法测量 ANP。为了增加 ACh 在心房细胞外空间中的可利用性，用乙酰胆碱酯酶抑制剂抑制其降解。毒扁豆碱抑制乙酰胆碱酯酶增加了 ANP 分泌，同时伴有心房动力学的浓度依赖性降低。M2 毒蕈碱型乙酰胆碱受体（mAChR）抑制剂甲硫氯胺和 ACh 激活的 K(+)（KACh(+)）通道抑制剂 tertiapin-Q 消除了毒扁豆碱诱导的变化。在用百日咳毒素处理的大鼠的心房中未观察到这些效应。此外，高亲和力胆碱转运体抑制剂 hemicholinium-3 减弱了毒扁豆碱诱导的作用，而 hemicholinium-3 是 ACh 合成的限速步骤。mAChR 信号通路和 ACh 合成抑制剂也减弱了 ANP 分泌的基础水平，并加重了心房动力学。这些发现表明，内源性释放的 ACh 通过激活 M2 mAChR-Gi/o-KACh(+) 通道信号，持续刺激心房肌细胞的 ANP 分泌。还表明 ACh-ANP 信号参与了心脏生理学和病理生理学。
