Seyedi N, Maruyama R, Levi R
Department of Pharmacology, Cornell University Weill Medical College, New York, New York, USA.
J Pharmacol Exp Ther. 1999 Aug;290(2):656-63.
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.
我们已经表明，心脏交感神经末梢（即突触体）产生的缓激肽（BK）以自分泌方式促进去甲肾上腺素（NE）的胞吐释放。由于突触体制备可能包括感觉C纤维末梢（已知BK可刺激该末梢），感觉神经可能有助于BK在心脏中的促肾上腺素能作用。我们报告称，BK是豚鼠心脏突触体释放NE的强效物质（EC50约为20 nM），该效应由B2受体介导，并且在预先破坏C纤维或阻断降钙素基因相关肽和神经激肽-1受体后几乎完全消除。C纤维破坏也大大降低了BK诱导的完整心脏中NE的释放，而酪胺诱导的NE释放不受影响。此外，用辣椒素刺激C纤维以及激活降钙素基因相关肽和神经激肽-1受体可引发心脏突触体释放NE，表明刺激感觉神经元进而激活交感神经末梢。因此，BK可能部分通过首先从感觉神经末梢释放降钙素基因相关肽和P物质来释放心脏中的NE；这些神经肽随后刺激交感神经末梢上的特定受体。BK的这一作用受到环氧化酶产物的正向调节，被组胺H3受体激活减弱，并在较低pH值下增强。当质子积累、C纤维被激活以及前列腺素和BK的产生增加时，BK的NE释放作用在心肌缺血时可能会增强。由于NE是主要的致心律失常因子，感觉神经元和肾上腺素能神经元之间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。
