Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release?
Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release?
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发表时间：
1999-08
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通讯作者：
N. Seyedi;R. Maruyama;R. Levi
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作者：
N. Seyedi;R. Maruyama;R. Levi
我们已经表明，由心脏交感神经末梢产生的缓激肽（BK）（即，突触体）以自分泌模式促进胞吐去甲肾上腺素（NE）释放。由于突触体的准备可能包括感觉C-纤维末梢，其中BK是已知的刺激，感觉神经可能有助于BK在心脏中的肾上腺素能作用。我们报道BK是来自豚鼠心脏突触体的NE的有效释放剂（EC（50）约20 nM），该作用由B（2）受体介导，并且几乎完全被先前的C纤维破坏或降钙素基因相关肽和神经激肽-1受体的阻断所消除。C-纤维破坏也大大降低BK诱导的NE释放从完整的心脏，而酪胺诱导的NE释放不受影响。此外，C-纤维刺激辣椒素和降钙素基因相关肽和神经激肽-1受体的激活启动NE从心脏突触体的释放，表明刺激感觉神经元反过来激活交感神经末梢。因此，BK可能通过首先从感觉神经末梢释放降钙素基因相关肽和P物质而在心脏中释放NE;这些神经肽然后刺激交感神经末梢上的特异性受体。BK的这种作用受到环氧合酶产物的正向调节，通过组胺H（3）受体的激活而减弱，并在较低pH下增强。BK的NE释放作用可能在心肌缺血时增强，此时质子积聚，C纤维被激活，并且野牡丹素和BK的产生增加。由于NE是一种主要的促肾上腺素生成剂，因此感觉神经元和肾上腺素能神经元之间的这种神经元间信号系统的激活可能导致缺血性心律失常和心源性猝死。
We had shown that bradykinin (BK) generated by cardiac sympathetic nerve endings (i.e., synaptosomes) promotes exocytotic norepinephrine (NE) release in an autocrine mode. Because the synaptosomal preparation may include sensory C-fiber endings, which BK is known to stimulate, sensory nerves could contribute to the proadrenergic effects of BK in the heart. We report that BK is a potent releaser of NE from guinea pig heart synaptosomes (EC(50) approximately 20 nM), an effect mediated by B(2) receptors, and almost completely abolished by prior C-fiber destruction or blockade of calcitonin gene-related peptide and neurokinin-1 receptors. C-fiber destruction also greatly decreased BK-induced NE release from the intact heart, whereas tyramine-induced NE release was unaffected. Furthermore, C-fiber stimulation with capsaicin and activation of calcitonin gene-related peptide and neurokinin-1 receptors initiated NE release from cardiac synaptosomes, indicating that stimulation of sensory neurons in turn activates sympathetic nerve terminals. Thus, BK is likely to release NE in the heart in part by first liberating calcitonin gene-related peptide and Substance P from sensory nerve endings; these neuropeptides then stimulate specific receptors on sympathetic terminals. This action of BK is positively modulated by cyclooxygenase products, attenuated by activation of histamine H(3) receptors, and potentiated at a lower pH. The NE-releasing action of BK is likely to be enhanced in myocardial ischemia, when protons accumulate, C fibers become activated, and the production of prostaglandins and BK increases. Because NE is a major arrhythmogenic agent, the activation of this interneuronal signaling system between sensory and adrenergic neurons may contribute to ischemic dysrhythmias and sudden cardiac death.