Evidence map›Paper›PMID 41052902›Full record

ArticleCardiovascular research2025

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 and 3 more

Abstract read
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In one paragraph

Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Neil R JaniCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Valerie Y H van WeperenCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Thamali AyagamaBurdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Jonathan D HoangCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Maryam EmamimeybodiCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Benjamin Mothibe BussmannBurdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Sartaj BalCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Ashna KumarCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
Artin KhakyCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.
David HamonDivision of Cardiology, Department of Medicine, University of Iowa, Iowa City, IA, USA.
Neil HerringBurdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.ORCID 0000-0001-8453-6133
Corey SmithDepartment of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA.
Marmar VaseghiCardiac Electrophysiology Programs, Division of Cardiology, Department of Medicine, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA 90095, USA.ORCID 0000-0002-9701-9706

Funding

Ventricular arrhythmias and mechanisms of parasympathetic dysfunction following myocardial infarctionR01HL148190 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI VASEGHI, MARMAR · 2020 to 2024
$3.2M
Sex differences in cardiac autonomic remodeling after myocardial infarctionR01HL170626 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Crystal May Ripplinger, Marmar Vaseghi · 2024 to 2026
$2.1M
British Heart Foundation Clinical Research Fellowship FS/CRTF/22/24437British Heart Foundation Senior Clinical Research Fellowship FS/SCRF/20/32005National Institute of Health R01HL148190National Institute of Health R01HL170626NHLBI NIH HHS R01 HL148190NHLBI NIH HHS R01 HL170626
6 · The paper itself

Abstract

aimsVentricular 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 pre-synaptic Y2R can further enhance the effects of VNS and decrease the effects of sympathoexcitation by increasing vagal tone. METHODS AND

resultsSingle-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 haemodynamic 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 MR 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, haemodynamic, and electrophysiological parameters were enhanced by Y2R blockade, heart rate remained unaffected.

conclusionVagal activation reduces interstitial NPY levels via a pre-synaptic 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.

Indexed as

Arrhythmias, CardiacHeartMuscarinic AntagonistsNeuropeptide YReceptor, Muscarinic M2Receptors, Neuropeptide YStellate GanglionVagus NerveVagus Nerve StimulationAction PotentialsAnimalsDisease Models, AnimalHeart RateMaleMuscarinic AgonistsRatsMuscarinic AgonistsMuscarinic AntagonistsNeuropeptide Yneuropeptide Y2 receptorReceptor, Muscarinic M2Receptors, Neuropeptide YCardiac autonomic nervous systemMuscarinic receptorsNeuropeptide YSympatheticVagus nerve stimulationY2 receptor

Identifiers

PMID41052902
PMCPMC12638732

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.