Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn Reduce NPY levels via muscarinic receptor activation

Neil R Jani; Valerie Y H van Weperen; Thamali Ayagama; Jonathan D Hoang; Maryam Emamimeybodi; Benjamin Mothibe Bussmann; Sartaj Bal; Ashna Kumar; Artin Khaky; David Hamon; Neil Herring; Corey Smith; Marmar Vaseghi

doi:10.1093/cvr/cvaf180

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Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn Reduce NPY levels via muscarinic receptor activation

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Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn Reduce NPY levels via muscarinic receptor activation

Neil R Jani, Valerie Y H van Weperen, Thamali Ayagama, Jonathan D Hoang, Maryam Emamimeybodi, Benjamin Mothibe Bussmann, Sartaj Bal, Ashna Kumar, Artin Khaky, David Hamon, …

Cardiovascular research, Vol.121(14), pp.2189-2203

10/06/2025

DOI: 10.1093/cvr/cvaf180

PMCID: PMC12638732

PMID: 41052902

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Abstract

Ventricular arrhythmias are associated with sympathoexcitation and increased co-transmitter neuropeptide Y (NPY) levels. Vagal nerve stimulation (VNS) has been reported to decrease release of norepinephrine, while NPY has been reported to decrease acetylcholine release ex-vivo by binding Y2 receptors on parasympathetic nerves. We hypothesized that VNS reduces NPY levels via a muscarinic receptor (MR) mediated mechanism in-vivo and that, in turn, blockade of presynaptic Y2R can further enhance the effects of VnS and decrease the effects of sympathoexcitation by increasing vagal tone. Single-cell RNA sequencing of rat stellate ganglia and immunohistochemistry were performed and identified the M2 receptor as the predominant subtype on NPY-expressing sympathetic neurons. Ex-vivo field stimulation of rat stellate ganglia, before and after application of carbamylcholine (CCH; muscarinic agonist) and atropine (muscarinic blocker) showed that CCH reduced NPY release, while the addition of atropine increased NPY levels. Subsequently, to validate ex-vivo findings, in-vivo effects of VNS during bilateral stellate ganglia stimulation (BSS) on NPY release with and without atropine were evaluated and hemodynamic and electrophysiological parameters, including ventricular activation recovery intervals (ARIs, a surrogate for action potential duration), and real-time in-vivo interstitial NPY levels were measured. Post-atropine, suppression of NPY by VNS was significantly diminished, confirming a muscarinic receptor mediated mechanism in-vivo. Finally, in a porcine model in-vivo, effects of VNS on NPY levels and of the Y2R blocker, BIIE0246, during BSS were tested. These studies demonstrated that Y2R blockade significantly reduced the cardiac effects of BSS on systolic pressure, inotropy, and ARIs. While the ventricular effects of VNS, including suppression of interstitial NPY levels, hemodynamic, and electrophysiological parameters were enhanced by Y2R blockade, heart rate remained unaffected. Vagal activation reduces interstitial NPY levels via a presynaptic sympathetic M2R mechanism.Y2R inhibition reduces effects of sympathoexcitation and enhances the effects of VNS in-vivo. These findings highlight the role of NPY in sympathovagal crosstalk and suggest Y2R as a potential target to modulate autonomic balance.

Neuropeptide Y

Y2 Receptor

Muscarinic Receptors

Cardiac Autonomic Nervous System

Sympathetic

Vagus Nerve Stimulation

Details

Title: Subtitle: Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn Reduce NPY levels via muscarinic receptor activation
Creators: Neil R Jani - University of California, Los Angeles
Valerie Y H van Weperen - University of California, Los Angeles
Thamali Ayagama - University of Oxford
Jonathan D Hoang - University of California, Los Angeles
Maryam Emamimeybodi - University of California, Los Angeles
Benjamin Mothibe Bussmann - University of Oxford
Sartaj Bal - University of California, Los Angeles
Ashna Kumar - University of California, Los Angeles
Artin Khaky - University of California, Los Angeles
David Hamon - University of Iowa
Neil Herring - University of Oxford
Corey Smith - Case Western Reserve University
Marmar Vaseghi - University of California, Los Angeles
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.121(14), pp.2189-2203
DOI: 10.1093/cvr/cvaf180
PMID: 41052902
PMCID: PMC12638732
NLM abbreviation: Cardiovasc Res
ISSN: 1755-3245
eISSN: 1755-3245
Publisher: OXFORD UNIV PRESS
Grant note: National Heart, Lung, and Blood Institute at the National Institute of Health: R01HL148190, R01HL170626 British Heart Foundation: FS/CRTF/22/24437, FS/SCRF/20/32005
This work was supported by the National Heart, Lung, and Blood Institute at the National Institute of Health (R01HL148190 and R01HL170626 to M.V.). B.M.B. is supported by the British Heart Foundation (FS/CRTF/22/24437) and N.H. by the British Heart Foundation (FS/SCRF/20/32005).
Language: English
Date published: 10/06/2025
Academic Unit: Internal Medicine
Record Identifier: 9984969107902771

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