Frontiers in pharmacology · 2025
Agonizing GABABR suppresses GLP-1RA's chronotropic effect and reduces post-myocardial infarction arrhythmogenesis.
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Qi Run, Jingjing Zhang, Hongchang Gu, Chenyu Li, He Hu, Juan Li, Yuqin Zhao, Xiaolin Wu
Аннотация
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 remains controversial.
METHODS: We investigated the role of the 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 (Gabbr1 cKO) mice were generated via AAV9-cTnT-Cre delivery to Gabbr1 f/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 the heart rate independent of the 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.
METHODS: We investigated the role of the 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 (Gabbr1 cKO) mice were generated via AAV9-cTnT-Cre delivery to Gabbr1 f/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 the heart rate independent of the 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.