Agonizing GABAR suppresses GLP-1RA's chronotropic effect and reduces post-myocardial infarction arrhythmogenesis.

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 GABAreceptor (GABAR) 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-knockout () mice were generated via AAV9-cTnT-Cre delivery tomice. Cardiac sympathetic denervation was achieved by 6-hydroxydopamine (6-OHDA) treatment and sympathectomy. Mechanistic insights were obtained through Western blotting, immunofluorescence,electrophysiology, and patch-clamp recordings. RESULTS: GLP-1RA increased the heart rate independent of the sympathetic input, suggesting a cardiac-autonomous mechanism. GABAR activation attenuated GLP-1RA-induced tachycardia, whereas Gabrb1 deficiency exacerbated it. GABAR agonism enhanced resistance to ventricular arrhythmias post-MI in a GLP-1RA-dependent manner. Patch-clamp analysis revealed that GABAR-induced repolarization can be suppressed by semaglutide in a dose-dependent manner, indicating the possible mechanism. CONCLUSION: GABAR activation counteracts GLP-1RA's chronotropic effects while synergistically enhancing anti-arrhythmic efficacy post-MI, highlighting a novel GABAR/GLP-1R interaction in cardiac electrophysiology.