To investigate the improving effect of ginseng (GS) on metoprolol（meto） induced bradycardia in mice with chronic heart failure（CHF）and its molecular mechanism.

The CHF model in C57BL/6J mouse was established through left anterior descending coronary artery ligation. Mice were randomly divided into 6 groups, including sham group（underwent the same surgical procedure without coronary artery ligation）, model group, control group（26 mg·kg^-1·d^-1 metoprolol）, experimental-low group（26 mg·kg^-1·d^-1 metoprolol + 1.3 g·kg^-1·d^-1 GS）, experimental-midium group（26 mg·kg^-1·d^-1 metoprolol + 2.6 g·kg^-1·d^-1 GS）and experimental-high group（26 mg·kg^-1·d^-1 metoprolol + 5.2 g·kg^-1·d^-1 GS）. Each group contained 9 mice. After continuous administration for 8 weeks, heart rate changes were monitored using non-invasive blood pressure monitors in small animals; transcriptome sequencing was employed to analyze differentially expressed genes in cardiac tissues with functional enrichment analysis; calcium ion concentration in myocardial tissue was measured using a calorimetric assay; Western blot analysis was used to detect relative expression levels of sarcoplasmic reticulum calcium ATPase 2a（SERCA2a）, phosphorylated phospholamban（p-PLB）and sodium-calcium exchanger 1（NCX1）in myocardial tissue.

The heart rates of sham group, model group, control group and experimental-L, -M, -H groups were（528.61±60.86），（448.67±84.58）,（260.07±74.97）,（352.84±40.47）,（436.27±90.84）and（501.91±43.11）beats·min^-1, respectively. Control group was compared with model group, experimental-L, -M, -H groups were compared with control group, the differences showed statistical significance in heart rates（P<0.05，P<0.01）. Transcriptome gene ontology（GO）analysis revealed that differentially expressed genes were significantly enriched in pathways related to myocardial contraction and calcium ion transmembrane transport（all P<0.05）. The myocardial tissue calcium ion concentrations in sham group, model group, control group and experimental-L, -M, -H groups were（30.09±2.36）,（35.97±1.15）,（16.15±2.37）,（19.59±1.04）, （23.64±0.54）and（28.54±2.82）mmol·L^-1，respectively. Compared with control group, experimental-L, -M, -H groups all showed significantly increase（P<0.01, P<0.05）. The relative expression levels of SERCA2a in sham group, model group, control group and experimental-L, -M, -H groups were 1.00±0.14, 0.83±0.05, 1.23±0.12, 1.00±0.03, 0.98±0.05 and 0.90±0.11, respectively; the relative expression levels of p-PLB were 1.38±0.24, 1.05±0.19, 2.12±0.35, 1.08±0.24, 0.54±0.57,and 0.52±0.13; while the relative expression levels of NCX1 were 1.00±0.13, 1.08±0.20, 1.69±0.34, 1.06±0.35, 1.15±0.22 and 0.81±0.21. Compared with model group, the relative expression levels of all 3 proteins in control group showed significant increases. Except for SERCA2a in experimental -L group and NCX1 in experimental -M group, the relative expression levels of the above three proteins in the experimental group were significantly lower than that in the control group (P<0.01, P<0.05).

Meto may induce bradycardia adverse drug reaction by increasing the p-PLB/PLB ratio and elevating the expression levels of SERCA2a and NCX1 proteins, which reduces intracellular free calcium ion concentration in cardiomyocytes. Ginseng could significantly down regulate the p-PLB/PLB ratio, increase the protein expression levels of SERCA2a and NCX1, and up regulate the concentration of intracellular free calcium ion, so as to improve Meto induced bradycardia, suggesting that it may antagonize the negative frequency effect of Meto by remodeling the calcium cycle homeostasis.