Neurotransmitter Switching Coupled to beta-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States

Single or combinatorial admt. s Mockers is a mainstay treatment strategy for conditions caused by sympathetic overactivity. Conventional wisdom suggests that the main beneficial effect of beta-Mockers includes resensitization and restoration of beta 1-adrenergic signaling pathways in the myocardium, improvements in cardiomyocyte contractility, and reversal of ventricular sensitization. However, emerging evidence indicates that another beneficial effect of beta-blockers in disease may reside in sympathetic neurons. We investigated whether beta-adrenoceptors are present on postganglionic sympathetic neurons and facilitate neurotransmission in a feed-forward manner, Using a combination of iinmunocytochemistry, RNA sequencing, Forster resonance energy transfer, and intracellular Ca2+ imaging, we demonstrate the presence of beta-adrenoceptors on presynaptic sympathetic neurons in both human and rat stellate ganglia. In diseased neurons from the prehypertensive rat, there was enhanced beta-adrenoceptor-mediated signaling predominantly via beta,-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 beta-adrenoceptors to promote further release, that leads to greater postsynaptic excitability in disease, before increases in arterial blood pressure. Targeting neuronal beta-adrenoceptor downstream signaling could provide therapeutic opportunity to minimize end-organ damage caused by sympathetic overactivity.