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首页> 美国卫生研究院文献>Lippincott Williams Wilkins Open Access >Neurotransmitter Switching Coupled to β-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States
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Neurotransmitter Switching Coupled to β-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States

机译：降压状态下交感神经元中神经递质的转换与β-肾上腺素信号的耦合。

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Single or combinatorial administration of β-blockers is a mainstay treatment strategy for conditions caused by sympathetic overactivity. Conventional wisdom suggests that the main beneficial effect of β-blockers includes resensitization and restoration of β1-adrenergic signaling pathways in the myocardium, improvements in cardiomyocyte contractility, and reversal of ventricular sensitization. However, emerging evidence indicates that another beneficial effect of β-blockers in disease may reside in sympathetic neurons. We investigated whether β-adrenoceptors are present on postganglionic sympathetic neurons and facilitate neurotransmission in a feed-forward manner. Using a combination of immunocytochemistry, RNA sequencing, Förster resonance energy transfer, and intracellular Ca2+ imaging, we demonstrate the presence of β-adrenoceptors on presynaptic sympathetic neurons in both human and rat stellate ganglia. In diseased neurons from the prehypertensive rat, there was enhanced β-adrenoceptor–mediated signaling predominantly via β2-adrenoceptor activation. Moreover, in human and rat neurons, we identified the presence of the epinephrine-synthesizing enzyme PNMT (phenylethanolamine-N-methyltransferase). Using high-pressure liquid chromatography with electrochemical detection, we measured greater epinephrine content and evoked release from the prehypertensive rat cardiac-stellate ganglia. We conclude that neurotransmitter switching resulting in enhanced epinephrine release, may provide presynaptic positive feedback on β-adrenoceptors to promote further release, that leads to greater postsynaptic excitability in disease, before increases in arterial blood pressure. Targeting neuronal β-adrenoceptor downstream signaling could provide therapeutic opportunity to minimize end-organ damage caused by sympathetic overactivity.
机译：β受体阻滞剂的单次或联合给药是治疗交感神经过度活跃引起的疾病的主要治疗策略。传统观点认为，β-受体阻滞剂的主要有益作用包括心肌中β1-肾上腺素能信号通路的重新敏化和恢复，心肌细胞收缩力的改善以及心室敏化的逆转。但是，新出现的证据表明，β-受体阻滞剂在疾病中的另一种有益作用可能存在于交感神经元中。我们调查了β-肾上腺素受体是否存在于神经节后交感神经元上，并以前馈方式促进神经传递。结合免疫细胞化学，RNA测序，Förster共振能量转移和细胞内Ca 2 + 成像，我们证明了在人和大鼠星状神经节突触前交感神经元中都存在β-肾上腺素受体。在高血压前期患病的神经元中，β-肾上腺素受体介导的信号转导主要通过β2-肾上腺素受体激活而增强。此外，在人和大鼠神经元中，我们确定了肾上腺素合成酶PNMT（苯乙醇胺-N-甲基转移酶）的存在。使用带有电化学检测的高压液相色谱，我们测量了更大的肾上腺素含量并诱发了高血压前大鼠心脏星状神经节的释放。我们得出的结论是，导致肾上腺素释放增强的神经递质转换可能会在β-肾上腺素受体上提供突触前正反馈，以促进进一步释放，从而导致疾病中更大的突触后兴奋性，然后才使动脉血压升高。靶向神经元β-肾上腺素受体下游信号传导可提供治疗机会，以最大程度减少由交感神经过度活动引起的终末器官损害。

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