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Updated: Jan 11, 2026

Semi-Minimal Invasive Method to Induce Myocardial Infarction in Rats and the Assessment of Cardiac Function by an Isolated Working Heart System
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Agonizing GABABR suppresses GLP-1RA's chronotropic effect and reduces post-myocardial infarction arrhythmogenesis

Run Qi1,2,3, Zhang Jingjing4,5,6, Gu Hongchang1,2

  • 1Department of Cardiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.

Frontiers in Pharmacology
|November 17, 2025
PubMed

Insights

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) impact heart rhythm via cardiac-autonomous mechanisms involving the GABAB receptor. GABABR activation counteracts GLP-1RA tachycardia but enhances anti-arrhythmic effects post-myocardial infarction.

Area of Science:

  • Cardiology
  • Neuropharmacology
  • Molecular Biology

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show cardiovascular benefits independent of glucose control.
  • The precise mechanisms by which GLP-1RAs influence cardiac rhythm remain incompletely understood and are a subject of ongoing research.
  • Investigating novel pathways is crucial for understanding GLP-1RA cardiovascular effects.

Purpose of the Study:

  • To elucidate the role of the GABAB receptor (GABABR) in mediating the chronotropic and anti-arrhythmic effects of GLP-1RAs.
  • To determine if GLP-1RA actions on heart rhythm are cardiac-autonomous or dependent on sympathetic input.
  • To explore the interaction between GABABR and GLP-1R signaling in the context of myocardial infarction (MI).

Main Methods:

  • Utilized a murine myocardial infarction model induced by left anterior descending artery ligation.
  • Generated cardiomyocyte-specific Gabbr1-knockout mice using adeno-associated virus serotype 9 (AAV9) delivery.
  • Assessed cardiac function and electrophysiology using Western blotting, immunofluorescence, in vivo electrophysiology, and patch-clamp recordings.
  • Investigated sympathetic influence via 6-hydroxydopamine (6-OHDA) treatment and sympathectomy.

Main Results:

  • GLP-1RA administration increased heart rate through a cardiac-autonomous pathway, independent of sympathetic nervous system activity.
  • GABABR activation attenuated GLP-1RA-induced tachycardia, while its deficiency exacerbated it.
  • GABABR agonism conferred enhanced resistance to ventricular arrhythmias following myocardial infarction in a GLP-1RA-dependent manner.
  • Patch-clamp studies indicated that semaglutide could suppress GABABR-induced repolarization in a dose-dependent manner.

Conclusions:

  • GABAB receptor activation counterbalances the chronotropic effects of GLP-1RAs.
  • GABABR activation synergistically enhances the anti-arrhythmic efficacy of GLP-1RAs in the post-myocardial infarction setting.
  • A novel interaction between GABABR and GLP-1R signaling pathways significantly impacts cardiac electrophysiology.
Abstract

Keywords:
GABAB receptorglucagon-like-peptide 1 receptorheart ratemyocardial infarctionventricular arrhythmias

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