Neuropharmacology · 2026
Dexmedetomidine induces bradycardia through vagal-nucleus tractus solitarius glutamatergic circuit.
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Sun Jiahui, Fang Yuanyuan, Tao Wanjiang, Kang Yuan, Chen Ting, Zhong Qi, Zhu Jinpiao, Ma Daqing, Zhang Zongze, Chen Chang
Аннотация
BACKGROUND: Dexmedetomidine (DEX) often causes bradycardia. While sympathetic suppression is involved, its effects on vagal component remains elusive.
METHODS: C57BL/6J male mice were treated with different doses of DEX (50, 100, or 200 μg/kg), heart rate was recorded with an electrophysiology recording system. Neuronal activity in the vagal nodose ganglion (NG) was assessed by in-vitro two-photon calcium imaging, patch-clamp recordings, phosphorylated ERK (p-Erk) staining, in-vivo electrophysiological recordings. Chemo-inactivation was targeted on vagal glutamatergic neurons and the vagal-nucleus tractus solitary (NTS) glutamatergic circuit to investigate the role of this neuronal population in mediating DEX-induced bradycardia. Additionally, glutamate release in the NTS was monitored using fiber photometry.
RESULTS: DEX induced a dose-dependent bradycardia from 408.4 [4.2] beats/min to 255.5 [3.8] beats/min at the dose texted (P < 0.001). Concomitantly, DEX increased the number of p-Erk-positive glutamatergic neurons in the NG (137.9 [4.3] vs 23.3 [2.4], P < 0.001), and increased vagal neuronal firing rate (3.8 [0.2] Hz vs 0.8 [0.1] Hz, P < 0.001), and these neuronal changes were inversely correlated with heart rate decreasing. Furthermore, DEX directly increased calcium activity and action potential firing, and induced significant membrane depolarization of NG neurons in ex vivo. Chemogenetic inactivation of NG glutamatergic neurons and NG-NTS glutamatergic circuit attenuated neuronal hyperactivity and reversed DEX-induced bradycardia. Consistently, DEX increased glutamate release in the NTS.
CONCLUSIONS: These findings identified that DEX directly activates vagal nodose ganglion neurons and induces bradycardia through vagal-NTS glutamatergic circuit, suggesting that targeting this pathway may be a potential therapeutic strategy to mitigate bradycardia in clinical practice.
METHODS: C57BL/6J male mice were treated with different doses of DEX (50, 100, or 200 μg/kg), heart rate was recorded with an electrophysiology recording system. Neuronal activity in the vagal nodose ganglion (NG) was assessed by in-vitro two-photon calcium imaging, patch-clamp recordings, phosphorylated ERK (p-Erk) staining, in-vivo electrophysiological recordings. Chemo-inactivation was targeted on vagal glutamatergic neurons and the vagal-nucleus tractus solitary (NTS) glutamatergic circuit to investigate the role of this neuronal population in mediating DEX-induced bradycardia. Additionally, glutamate release in the NTS was monitored using fiber photometry.
RESULTS: DEX induced a dose-dependent bradycardia from 408.4 [4.2] beats/min to 255.5 [3.8] beats/min at the dose texted (P < 0.001). Concomitantly, DEX increased the number of p-Erk-positive glutamatergic neurons in the NG (137.9 [4.3] vs 23.3 [2.4], P < 0.001), and increased vagal neuronal firing rate (3.8 [0.2] Hz vs 0.8 [0.1] Hz, P < 0.001), and these neuronal changes were inversely correlated with heart rate decreasing. Furthermore, DEX directly increased calcium activity and action potential firing, and induced significant membrane depolarization of NG neurons in ex vivo. Chemogenetic inactivation of NG glutamatergic neurons and NG-NTS glutamatergic circuit attenuated neuronal hyperactivity and reversed DEX-induced bradycardia. Consistently, DEX increased glutamate release in the NTS.
CONCLUSIONS: These findings identified that DEX directly activates vagal nodose ganglion neurons and induces bradycardia through vagal-NTS glutamatergic circuit, suggesting that targeting this pathway may be a potential therapeutic strategy to mitigate bradycardia in clinical practice.