Flos carthami is a traditional Chinese herbal medicine. Clinically, the Flos carthami Injection has been used concomitantly with other Western drugs and may be used concomitantly with β-blockers, such as metoprolol, to treat cerebrovascular and coronary heart diseases, in China. Metoprolol is a CYP2D6 substrate and is predominantly metabolized by this isozyme. However, we do not know whether there is an effect of Flos carthami on CYP2D6 and the consequences of such an effect. Concern is raised regarding the possible herb-drug interaction. In this report, the effects of Flos carthami on the activity of CYP2D6 in vivo and in vitro and on the pharmacokinetics of metoprolol, in rats, are investigated. To assess the inhibitory potency of Flos carthami, the concentration associated with 50% inhibition (IC(50)) of dextromethorphan metabolism was determined based on the concentration-inhibition curves. The inhibitory effect of Flos carthami on CYP2D6 was also compared with cimetidine in vitro. Flos carthami could significantly inhibit CYP2D6 in rats both in vitro and in vivo (P < .05) and could slow down the metabolic rate of metoprolol as suggested by prolonged t(1/2) (67.45%), by increased C(max) (74.51%) and AUC(0-∞) (76.89%). These results suggest that CYP2D6 is a risk factor when Flos carthami is administered concomitantly with metoprolol or other CYP2D6 substrates.

Naoxintong capsule (NXT), a prescribed Chinese medicine, has been used clinically for more than 20 years and is widely received by patients. We determined five probe drugs, namely, omeprazole (CYP2C19), midazolam (CYP3A4), phenacetin (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) to study the potential influences of NXT on the activities of CYP enzymes and assessed the pharmacokinetics effect of NXT on metoprolol tartrate in rat plasma. The study showed that AUC(0-24) and AUC(0-∞) of midazolam (CYP3A4) in NXT coadministration group (283.7 ± 65.2 h·ng·mL-1 and 292.0 ± 75.1 h·ng·mL-1 in group B; 295.7 ± 62.7 h·ng·mL-1 and 299.5 ± 60.0 h·ng·mL-1 in group C) were significantly decreased as compared to another group (416.8 ± 82.3 h·ng·mL-1 and 424.9 ± 77.9 h·ng·mL-1 in group A), while that of dextromethorphan (CYP2D6) showed an opposite tendency (540.7 ± 119.7 h·ng·mL-1 and 595.3 ± 122.2 h·ng·mL-1 in group A, 760.6 ± 184.9 h·ng·mL-1 and 788.7 ± 211.0 h·ng·mL-1 in group B, and 734.3 ± 118.5 h·ng·mL-1 and 757.2 ± 105.4 h·ng·mL-1 in group C). Moreover, NXT preadministration can enhance the metabolism of metoprolol tartrate and reduce the metabolism of O-demethylmetoprolol. The results indicated that NXT had potential effects in inducing CYP3A4 and inhibiting CYP2D6 in the metabolism of metoprolol tartrate. It suggests that patients who coadministered NXT and metoprolol tartrate should be advised of potential herb-drug interactions (HDIs) to reduce therapeutic failure or accelerated toxicity of conventional drug treatment.

Both oxidative stress and endoplasmic reticulum stress (ERS) have been implicated in carcinogenesis and neurological diseases, while there are few reports about the mechanisms of them in the progression of acute myocardial infarction (AMI). This study examined oxidative stress and ERS in a rat model of AMI and evaluated their role in therapy by metoprolol and effective components of Panax quinquefolius and Corydalis tuber (EPC). In the present study a rat model of AMI was established by ligation of the left anterior descending coronary artery. After oral administration of metoprolol or low-to-high doses of EPC for 2 weeks, serum malondialdehyde (MDA), superoxide dismutase (SOD), and 8-iso-prostaglandin F2 α (8-iso-PGF2 α ) were detected using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time PCR and Western blotting were used to examine mRNA and protein expressions of the hallmarks of ERS-glucose-regulated protein-78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP). We confirmed that both metoprolol and moderate-to-high dose of EPC decreased 8-iso-PGF2 α serum level and downregulated the mRNA and protein expressions of GRP78 and CHOP in myocardium, while EPC also increased SOD serum level. These results indicated that metoprolol and EPC protect the myocardium by attenuating oxidative stress and ERS induced by myocardial infarction, highlighting the ERS pathways as potential therapeutic targets for AMI.

Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase-like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced (P < 0.01), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased (P < 0.01). The ventricular fibrillation threshold decreased significantly (P < 0.01). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased (P < 0.01, P < 0.05), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased (P < 0.01). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group (P < 0.01, P < 0.05), and p-PERK and ATF6 decreased (P < 0.01, P < 0.05). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups (P < 0.01, P < 0.05), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased (P < 0.01, P < 0.05). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group (P < 0.01, P < 0.05), whereas Bcl-2 and the Bcl-2/Bax ratio increased (P < 0.01, P < 0.05). LVIDd and Bax decreased in the metoprolol group (P < 0.01, P < 0.05), and the Bcl-2/Bax ratio increased (P < 0.05). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced (P < 0.05). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

Aim. To determine the effect of a Chinese herbal compound named Wenxin Granule on ventricular remodeling and myocardial apoptosis in rats with myocardial infarction (MI). Methods. Male Sprague-Dawley (SD) rats were randomly divided into four groups: the control group, the model group, the metoprolol group, and the Wenxin Granule group (WXKL group) with sample size (n) of 7 rats in each group. An MI model was established in all rats by occlusion of the left anterior descending coronary artery (the control group was without occlusion). Wenxin Granule (1.35 g/kg/day), metoprolol (12 mg/kg/day), and distilled water (5 mL/kg/day for the control and model groups) were administered orally for 4 weeks. Ultrasonic echocardiography was used to examine cardiac structural and functional parameters. Myocardial histopathological changes were observed using haematoxylin and eosin (H&E) dyeing. Myocardial apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Serum angiotensin II (Ang II) concentration was measured using the enzyme-linked immunosorbent assay (ELISA). Results. It was found that Wenxin Granule could partially reverse ventricular remodeling, improve heart function, alleviate the histopathological damage, inhibit myocardial apoptosis, and reduce Ang II concentration in rats with MI. Conclusions. The results of the current study suggest that Wenxin Granule may be a potential alternative and complementary medicine for the treatment of MI.

Dingji Fumai decoction (DFD) is used to treat ventricular arrhythmia, and it has provided a very good curative effect. However, its cellular electrophysiological mechanism is unknown.

Objective. To explore the mechanism of cardioprotective effects of Chinese medicine, Yiqi Huoxue recipe, in rats with myocardial infarction- (MI-) induced heart failure. Methods. Male Sprague-Dawley rats underwent left anterior descending artery (LAD) ligation or sham operation. The surviving MI rats were divided randomly into three groups: MI (5 mL/kg/d NS by gavage), MI + Metoprolol Tartrate (MT) (12 mg/kg/d MT by gavage), and MI + Yiqi Huoxue (5 mL/kg recipe by gavage). And the sham operation rats were given 5 mL/kg/d normal saline. Treatments were given on the day following surgery for 4 weeks. Then rats were detected for heart structure and function by transthoracic echocardiography. Apoptosis in heart tissues was detected by TUNEL staining. To determine whether the endoplasmic reticulum (ER) stress response pathway is included in the cardioprotective function of the recipe, ER stress related proteins such as GRP78 and caspase-12 were examined. Results. Yiqi Huoxue recipe attenuated heart function injury, reversed histopathological damage, alleviated myocardial apoptosis and inhibited ER stress in MI rats. Conclusion. All the results suggest that Yiqi Huoxue recipe improves the injured heart function maybe through inhibition of ER stress response pathway, which is a promising target in therapy for heart failure.

Qili Qiangxin capsule (QQC) is a formulation of traditional Chinese medicine commonly used for the treatment of heart failure in China. This meta-analysis aimed to assess the clinical efficacy of QQC combined with western medicine in the treatment of chronic heart failure (CHF). We conducted a systematic review and meta-analysis abided by the PRISMA guidelines. Literature search was conducted in the China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journals Database, PubMed, and Web of Science from inception to August 2020. A total of 52 eligible studies were obtained, and 42 of these studies were included in the meta-analysis. The results showed that, compared with western medicine alone, the combination of Qili Qingxin capsule and Western medicine treatment has better efficacy (metoprolol: RR: 1.24, 95%CI 1.14-1.34; carvedilol: RR: 1.24, 95%CI 1.14-1.34; trimetazidine: RR: 1.20, 95%CI: 1.12-1.27; sacubitril valsartan sodium: RR: 1.23, 95%CI: 1.11-1.36; sodium nitroprusside: RR: 1.33, 95%CI: 1.23-1.45; and bisoprolol: RR: 1.31, 95%CI: 1.15-1.49) and increased the level of LVEF, LVEDD, and 6MWT of patients with CHF and reduced the adverse effects and the level of HR, LVESD, BNP, and Hs-cTnT as well. However, there is high heterogeneity in the meta-analysis of LVEDV, BNP, NT-proBNP, Hs-cTnT, 6MWT, and adverse effects, and the methodological quality of the included studies was poor. Therefore, further studies with good methodological quality and large sample size are required to validate our findings. In our study, evidence suggests that Qili Qiangxin capsule combined with Western medicine may improve therapeutic effect and the quality of life of patients with CHF.

Sympathetic remodeling may cause severe arrhythmia after myocardial infarction (MI). Thus, targeting this process may be an effective strategy for clinical prevention of arrhythmias. LianXia Formula Granule (LXFG) can effectively improve the symptoms of patients with arrhythmia after MI, and modern pharmacological studies have shown that Coptidis Rhizoma and Rhizoma Pinelliae Preparata, the components of LXFG, have antiarrhythmia effects. Here, we investigated whether LXFG can mitigate sympathetic remodeling and suppress arrhythmia and then elucidated its underlying mechanism of action in rats after MI. Sprague-Dawley (SD) rats that had undergone a myocardial infarction model were randomly divided into 6 groups, namely, sham, model, metoprolol, and LXFG groups, with high, medium, and low dosages. We exposed the animals to 30 days of treatment and then evaluated incidence of arrhythmia and arrhythmia scores in vivo using programmed electrical stimulation. Moreover, we determined plasma catecholamines contents via enzyme-linked immunosorbent assay and detected expression of tyrosine hydroxylase (TH) at infarcted border zones via western blot, real-time PCR, and immunohistochemical analyses to assess sympathetic remodeling. Finally, we measured key molecules involved in the NGF/TrKA/PI3K/AKT pathways via western blot and real-time PCR. Compared with the model group, treatment with high dose of LXFG suppressed arrhythmia incidence and arrhythmia scores. In addition, all the LXFG groups significantly decreased protein and mRNA levels of TH, improved the average optical density of TH-positive nerve fibers, and reduced the levels of plasma catecholamines relative to the model group. Meanwhile, expression analysis revealed that key molecules in the NGF/TrKA/PI3K/AKT pathways were downregulated in the LXFG group when compared with model group. Overall, these findings indicate that LXFG suppresses arrhythmia and attenuates sympathetic remodeling in rats after MI. The mechanism is probably regulated by suppression of the NGF/TrKA/PI3K/AKT signaling pathway.

Background. Stable angina pectoris with moderate coronary artery lesions is a syndrome caused by coronary artery stenosis, which endangers the quality of life. Previous acupuncture studies have shown effectiveness as a complementary therapy for ischaemic heart disease. However, more clinical evidence is needed for verification, and the mechanism should be investigated, especially involving the functional interactions between the heart and brain. Therefore, we designed a clinical trial to provide more evidence for acupuncture efficacy and its mechanism in ischaemic heart disease. Methods/Design. A total of 80 participants will be randomized to the electroacupuncture group and sham-electroacupuncture group at a ratio of 1 : 1. This trial will be conducted over 8 weeks, including a 2-week screening, 2-week treatment, and 4-week follow-up. All participants will continue to receive similar basic disease treatment procedures before the trial (including lifestyle changes and treatment for standard supportive medications, hypertension, and hyperlipidaemia, such as aspirin, metoprolol succinate, atorvastatin, and sodium fosinopril). Additionally, 12 sessions of acupuncture will be administered during the treatment period. The main outcome is Seattle Angina Questionnaire scores. The other observation indices are the heart rate variability and self-rating anxiety scale and self-rating depression scale scores. To explore mechanisms based on the hypothesis of a correlation between heart and brain function, fMRI scans will be used to detect functional brain changes in 15 patients from each group at baseline and at the end of treatment. Finally, the efficacy of acupuncture will be evaluated, and the HRV and imaging data will be correlated with clinical data to investigate the possible relationships between the brain and heart activity. Discussion. This trial will provide evidence for acupuncture as adjuvant therapy for the treatment of stable angina pectoris with moderate coronary artery lesions. The results will shed light on potential mechanisms of heart-brain interactions underlying acupuncture as an adjuvant therapy for treating ischaemic heart disease. Trials registration: Clinical Trial, https://clinicaltrials.gov/ct2/show/ChiCTR1900024937. Registered 4 August 2019, http://www.chictr.org.cn/.