Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1161/HYPERTENSIONAHA.118.10844

Type

Journal article

Journal

Hypertension

Publication Date

06/2018

Volume

71

Pages

1226 - 1238

Keywords

cardiovascular diseases, epinephrine, hypertension, sequence analysis, RNA, stellate ganglion, Adrenergic alpha-Agonists, Animals, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Male, Neurotransmitter Agents, Prehypertension, Rats, Inbred SHR, Receptors, Adrenergic, beta, Signal Transduction, Stellate Ganglion, Sympathetic Nervous System, Synaptic Transmission