ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1616181
This article is part of the Research TopicExploring Molecular Mechanisms and Novel Diagnostics in Cardiovascular Disease TreatmentView all 15 articles
Agonizing GABABR Suppresses GLP1RA's Chronotropic Effect and Reduces Post Myocardial Infarction Arrhythmogenesis
Provisionally accepted
- 1Xiangyang Central Hospital, Xiangyang, China
- 2Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been reported to improve cardiovascular outcomes, potentially through glucose metabolism -independent mechanisms. However, their mechanism of heart rhythm remain controversial. Methods: We investigated the role of GABAB receptor (GABABR) in mediating GLP-1RA's chronotropic and anti-arrhythmic effects in a murine myocardial infarction (MI) model. MI was induced by left anterior descending artery ligation. Cardiomyocyte-specific Gabbr1 knockout (Gabbr1cKO) mice were generated via AAV9-cTnT-Cre delivery to Gabbr1f/f mice. Cardiac sympathetic denervation was achieved by 6-hydroxydopamine (6-OHDA) treatment and sympathectomy. Mechanistic insights were obtained through western blotting, immunofluorescence, in vivo electrophysiology, and patch-clamp recordings. Results: GLP-1RA increased heart rate independent of sympathetic input, suggesting a cardiac-autonomous mechanism. GABABR activation attenuated GLP-1RA-induced tachycardia, whereas Gabrb1 deficiency exacerbated it. GABABR agonism enhanced resistance to ventricular arrhythmias post-MI in a GLP-1RA-dependent manner. Patch -clamp analysis revealed that GABABR-induced repolarization can be suppressed by semaglutide in a dose dependent manner, indicating the possible mechanism. Conclusion: GABABR activation counteracts GLP-1RA's chronotropic effects while synergistically enhancing anti-arrhythmic efficacy post-MI, highlighting a novel GABABR/GLP-1R interaction in cardiac electrophysiology.
Keywords: Glucagon-like peptide 1 receptor, GABAB receptor, Heart Rate, Myocardial Infarction, Ventricular arrhythmias
Received: 22 Apr 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Run, Zhang, Gu, Li, Hu, Li, Zhao and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yuqin Zhao, Xiangyang Central Hospital, Xiangyang, China
Xiaolin Wu, Xiangyang Central Hospital, Xiangyang, China
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