The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: implications for neural control of cardiac excitability.
The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: implications for neural control of cardiac excitability.
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DOI：
10.1016/j.yjmcc.2011.11.016
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发表时间：
2012-03
影响因子：
5
通讯作者：
Paterson DJ
中科院分区：
文献类型：
--
作者：
Herring N;Cranley J;Lokale MN;Li D;Shanks J;Alston EN;Girard BM;Carter E;Parsons RL;Habecker BA;Paterson DJ
充血性心力衰竭的自主表型的特征是交感神经驱动和迷走神经张力受损，这是死亡率的独立预测因素。我们推测，高水平交感神经驱动后，外周迷走神经刺激引起的心动过缓受损是由于肾上腺素能共递质甘丙肽和神经肽Y（NPY）引起的交感神经-迷走神经串扰。此外，我们推测甘丙肽通过受体介导的蛋白激酶依赖性途径减少迷走神经乙酰胆碱释放，其作用类似于NPY。在具有双重自主神经支配的离体豚鼠心房制备物中，延长右星状神经节刺激（10 Hz，2 min，存在10 μM美托洛尔）导致迷走性心动过缓（5 Hz）的幅度显著降低（p < 0.05），并在随后的20 min内维持（n = 6）。免疫组化显示甘丙肽存在于少量的酪氨酸羟化酶阳性神经元从新鲜解剖的星状神经节组织切片。然而，在组织培养3天后，大多数星状神经元表达甘丙肽。星状刺激引起释放低水平的甘丙肽和显着较高水平的NPY到周围灌注液（n = 6，使用ELISA）。交感神经刺激后迷走性心动过缓的减少在10分钟后被甘丙肽受体拮抗剂M40（1 μM，n = 5）部分逆转，并且在所有时间点被NPY Y2受体拮抗剂BIIE 0246（1 μM，n = 6）完全逆转。外源性甘丙肽（n = 6，50-500 nM）也降低了对迷走神经刺激的心率反应，但对产生类似程度心动过缓的氨甲酰胆碱的反应没有影响（n = 6）。甘丙肽（500 nM）也显着衰减释放的3 H-乙酰胆碱从离体心房在现场刺激（5 Hz，n = 5）。甘丙肽对迷走性心动过缓的抑制作用可被甘丙肽受体拮抗剂M40（n = 5）阻断。重要的是GalR 1受体免疫荧光共定位与胆碱乙酰转移酶含有神经元在窦房结。蛋白激酶C抑制剂calphostin（100 nM，n = 6）消除了甘丙肽对迷走性心动过缓的影响，而蛋白激酶A抑制剂H89（500 nM，n = 6）没有影响。这些结果表明，延长的交感神经激活释放缓慢扩散的肾上腺素能共递质甘丙肽，除了NPY，这有助于通过减少乙酰胆碱释放迷走性心动过缓的衰减。这种作用是由迷走神经元上的GalR 1受体介导的，该受体与蛋白激酶C依赖性信号通路偶联。甘丙肽表达增加的急性损伤反应后，甘丙肽的作用可能变得更加重要。在豚鼠星状神经元和心脏迷走神经元上发现GalR 1。细胞培养3天后，星形甘丙肽表达增加。高水平的交感神经刺激释放甘丙肽，减少迷走性心动过缓。甘丙肽通过GalR 1依赖性途径减少乙酰胆碱释放和心动过缓。甘丙肽通过蛋白激酶C而不是蛋白激酶A依赖性途径发出信号。
The autonomic phenotype of congestive cardiac failure is characterised by high sympathetic drive and impaired vagal tone, which are independent predictors of mortality. We hypothesize that impaired bradycardia to peripheral vagal stimulation following high-level sympathetic drive is due to sympatho-vagal crosstalk by the adrenergic co-transmitters galanin and neuropeptide-Y (NPY). Moreover we hypothesize that galanin acts similarly to NPY by reducing vagal acetylcholine release via a receptor mediated, protein kinase-dependent pathway. Prolonged right stellate ganglion stimulation (10 Hz, 2 min, in the presence of 10 μM metoprolol) in an isolated guinea pig atrial preparation with dual autonomic innervation leads to a significant (p < 0.05) reduction in the magnitude of vagal bradycardia (5 Hz) maintained over the subsequent 20 min (n = 6). Immunohistochemistry demonstrated the presence of galanin in a small number of tyrosine hydroxylase positive neurons from freshly dissected stellate ganglion tissue sections. Following 3 days of tissue culture however, most stellate neurons expressed galanin. Stellate stimulation caused the release of low levels of galanin and significantly higher levels of NPY into the surrounding perfusate (n = 6, using ELISA). The reduction in vagal bradycardia post sympathetic stimulation was partially reversed by the galanin receptor antagonist M40 after 10 min (1 μM, n = 5), and completely reversed with the NPY Y2 receptor antagonist BIIE 0246 at all time points (1 μM, n = 6). Exogenous galanin (n = 6, 50–500 nM) also reduced the heart rate response to vagal stimulation but had no effect on the response to carbamylcholine that produced similar degrees of bradycardia (n = 6). Galanin (500 nM) also significantly attenuated the release of 3H-acetylcholine from isolated atria during field stimulation (5 Hz, n = 5). The effect of galanin on vagal bradycardia could be abolished by the galanin receptor antagonist M40 (n = 5). Importantly the GalR1 receptor was immunofluorescently co-localised with choline acetyl-transferase containing neurons at the sinoatrial node. The protein kinase C inhibitor calphostin (100 nM, n = 6) abolished the effect of galanin on vagal bradycardia whilst the protein kinase A inhibitor H89 (500 nM, n = 6) had no effect. These results demonstrate that prolonged sympathetic activation releases the slowly diffusing adrenergic co-transmitter galanin in addition to NPY, and that this contributes to the attenuation in vagal bradycardia via a reduction in acetylcholine release. This effect is mediated by GalR1 receptors on vagal neurons coupled to protein kinase C dependent signalling pathways. The role of galanin may become more important following an acute injury response where galanin expression is increased. ► Galanin is found in guinea pig stellate neurons and GalR1 on cardiac vagal neurons. ► Stellate galanin expression increases following 3 days of cell culture. ► High level sympathetic stimulation releases galanin which reduces vagal bradycardia. ► Galanin reduces acetylcholine release and bradycardia via a GalR1 dependent pathway. ► Galanin signals via protein kinase C rather than protein kinase A dependent pathways.
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DOI：
10.1152/ajpheart.2001.281.6.h2318
发表时间：
2001-12-01
影响因子：
4.8
作者：
Herring, N;Zaman, JAB;Paterson, DJ
通讯作者：
Paterson, DJ
影响因子：
5.5
作者：
Danson, EJF;Paterson, DJ
通讯作者：
Paterson, DJ
影响因子：
3
作者：
Ilebekk, A;Björkman, JA;Nordlander, M
通讯作者：
Nordlander, M
影响因子：
2.5
作者：
Ewert, T. Jarred;Gritman, Kurt R.;Habecker, Beth A.
通讯作者：
Habecker, Beth A.
影响因子：
2.5
作者：
KUMMER, W
通讯作者：
KUMMER, W