TABLE 1.
Basic characteristics of the included studies.
| In vivo study | |||||||
|---|---|---|---|---|---|---|---|
| Study (year) | Species (gender) | Weight (g) | Anesthetic | Method of administration | Result | Intergroup difference | |
| Liang et al. (1991) | SD, male | 150 ± 10 | NR | 0.5, 2, 4, 12, and 24 h after 1.46 mg/kg, i.g. | (1) ↓NADHD | (1) NR | |
| Zhang et al. (2012) | SD, male | 210–220 | Chloral hydrate | 0.2 ml/h, ivgtt | (1) ↑Heart rate (2) ↑RPP |
(1) p < 0.05 (2) NR |
|
| Wang (2013) | Guinea pig, male | 300–350 | Pentobarbital sodium | 25 μg/kg, IV | (1) Arrhythmia | (1) NR | |
| Sun et al. (2014) | Wistar, male | 220–240 | Pentobarbital sodium | 10 ml/kg for 3, 6, and 10 days, qd, i.g. | (1) Arrhythmia (2) ↑Apoptotic rate (3) Ultrastructural changes (4) Proteins expression: ↑RyR, ↑NCX, ↓Bcl-2, ↑P53, and ↑caspase-9/3 |
(1) NR (2) NR (3) NR (4) p < 0.05 |
|
| Deng (2010) | Guinea pig, both | 250–350 | NR | 3 × 10−8, 1 × 10−7, and 3 × 10−7 M | (1) ↓APD50/90, ↑VDD, and ↓APA | (1) p < 0.05 | |
| In vitro study | |||||||
| Study (year) | Cell lines | Concentration | Result | Intergroup difference | |||
| Zhang et al. (2020) | H9c2 | 10, 30, 50, 70, 90, and 110 μM | (1) ↓Cell viability (2) Protein expression: ↓α-actinin (3) Genes expression: ↓actc1, ↓myl1, ↓myl2, and ↓tnnt2 |
(1) p < 0.05 (2) NR (3) p < 0.01 |
|||
| Fang et al. (2012) | Zebrafish embryos | 5, 10, 30, and 60 mg/L | (1) Pericardium edema and hemorrhage; ↑blood cells (2) ↑Heart rate |
(1) NR (2) p < 0.05 |
|||
| Liu (2009) | Primary cardiomyocytes of SD neonatal rats | 0.25, 0.5, 0.75, 1.0, 2.0, and 3.0 μg/L for 0.5, 1, 2, and 4 h | (1) ↓Pulse rhythm (2) ↑LDH (3) ↓Cell viability |
(1) NR (2) p < 0.05 (3) p < 0.05 |
|||
| 0.1, 0.5, 1, and 2 μM for 0.5 h | (4) DNA damage: ↓HDNA%, ↓TDNA%, ↑TL, ↑TM, and ↑OTM | (4) p < 0.05 | |||||
| 1.0 μM for 1 h | (5) Proteins expression: ↓P-Cx43(Ser–368), ↑NP-Cx43(Ser–368), and ↓P-PKCα(Ser–657) (6) Protein expression: ↓P-PKCα (Ser–657) (7) Genes expression: ↑NCX, ↑RYR2, ↓SERCA2, and ↓PLB |
(5) p < 0.01 (6) p < 0.01 (7) p < 0.01 |
|||||
| Zhang (2007) | Primary cardiomyocytes of SD neonatal rats | 0.25, 0.5, 0.75, 1.0, 1.5, and 2.0 μΜ for 1 h | (1) Proteins expression: ↓(P2+P1) Cx43 and ↑NP Cx43 (2) →Morphology (3) Proteins expression: ↓P-Cx43 (Ser–368) and ↑NP-Cx43 (Ser–368) |
(1) p < 0.05 (2) NR (3) p < 0.01 |
|||
| Wang et al. (2007) | Primary cardiomyocytes of SD neonatal rats | 100.0, 10.0, 1.0, and 0.1 μg/ml for 24 and 48 h | (1) ↓Cell viability (2) ↓MDA (3) ↑Beating rate (4) Cell shrinkage and ↑pseudopodia |
(1) p < 0.01 (2) p < 0.01 (3) NR (4) NR |
|||
| Meng (2006) | Primary cardiomyocytes of SD neonatal rats | 3% for 0.5, 1 and 30 min | (1) Morphological changes (2) ↑LDH (3) ↑MDA (4) ↑Acid phosphatase activity (5) ↑Na+, ↓K+, ↑Ca+, and ↓Mg+ (6) ↓Na+-K+ATP (7) ↓OPTDM (8) ↓SDH (9) Cell cycle: ↑(G0/G1) %, ↓S% and ↓G2+M% |
(1) NR (2) p < 0.05 (3) p < 0.05 (4) p < 0.05 (5) p < 0.05 (6) p < 0.01 (7) p < 0.05 (8) p < 0.05 (9) p < 0.01 |
|||
| Li et al. (2018) | Primary cardiomyocytes of SD neonatal rats | 1, 5 and 10 μM | (1) ↓Ca2+ transient amplitude, ↑Ca2+ transient frequency (2) Enzymatic activities: ↓Ca2+-ATP, ↓Ca2+-Mg2+-ATP and ↓Na+-K+-ATP (3) ↑Na+, ↑Ca2+ and ↓K+ (4) Genes expression: ↓SERCA2 and ↑RyR2 (5) Proteins expression: ↓SERCA2 and ↑RyR2 |
(1) p < 0.01 (2) p < 0.05 (3) p < 0.05 (4) p < 0.05 (5) p < 0.05 |
|||
| Wang (2013) | Primary cardiomyocytes of guinea pig | Undefined multiple concentrations | (1) ↓APD30/90 | (1) p < 0.01 | |||
| Gao (2018) | H9c2 | 50, 100, 150, 200, and 250 μM | (1) ↓Cell viability | (1) p < 0.01 | |||
| (2) ↓Nuclear volume (3) ↑Apoptosis rate (4) ↑ROS (5) ↓Membrane potential (6) ↓ATP (7) Proteins expression: ↓PGC-1α and ↑Bax, ↑caspase-3, ↑cytochrome C, and ↓Bcl-2 |
(2) NR (3) p < 0.001 (4) p < 0.05 (5) p < 0.001 (6) p < 0.001 (7) p < 0.01 |
||||||
| Cui et al. (2018) | Zebrafish embryos | 1, 3, and 10 μM for 1 day | (1) Arrhythmia (2) ↓Stroke volume |
(1) NR (2) p < 0.05 |
|||
| AC-16 | 1 μM | (3) ↑Ca2+ oscillation frequency and ↓Ca2+ oscillation amplitude | (3) p < 0.05 | ||||
| Fu (2007) | Primary cardiomyocytes of SD neonatal rats | Undefined multiple concentrations | (1) ↓Pulse rhythm | (1) NR | |||
| 0.1, 0.25, 0.5, 1, and 3 μM for 0.5, 1, and 2 h | (2) ↓Cell viability (3) ↑LDH |
(2) p < 0.05 (3) p < 0.05 |
|||||
| 0.5, 1, and 3 μM | (4) DNA damage: ↑TL, ↓HDNA% and ↑TDNA% | (4) p < 0.05 | |||||
| 0.5 and 3 μM | (5) Calcium oscillation: ↓amplitude and ↑Ca2+ | (5) p < 0.05 | |||||
| 0.5, 1, and 3 μM for 1 h | (6) Proteins expression: ↑RyR2 and ↑NCX (7) Genes expression: ↑RyR2 and ↑NCX |
(6) p < 0.05 (7) p < 0.05 |
|||||
| Wang (2007) | Primary cardiomyocytes of SD neonatal rats | 3% for 1 min | (1) ↑α1-AR (2) →β1-AR (3) →β2-AR |
(1) p < 0.05 (2) p > 0.05 (3) p > 0.05 |
|||
| 3% for undefined multiple time | (4) ↑Round and smaller cells and ↑contracted pseudopodia | (4) NR | |||||
| 3% for 0.5, 1, and 30 min | (5) ↑IP3 (6) ↑cAMP/cGMP |
(5) p < 0.05 (6) p < 0.01 |
|||||
| Zhang et al. (2018) | H9c2 | 150, 250, 400, 500, and 1,000 μg/ml | (1) ↓Cell viability (2) ↓Cell volume |
(1) p < 0.05 (2) NR |
|||
| (3) ↑LDH (4) ↑Apoptosis |
(3) p < 0.05 (4) p < 0.05 |
||||||
| Hu et al. (2018) | H9c2 | 0.05%, 0.1%, 0.2%, and 0.4% for 0.5, 1, 1.5, and 3 h | (1) ↓Cell viability | (1) p < 0.05 | |||
| (2) ↑Autophagy (3) ↑Apoptosis (4) Proteins expression: ↑LC3B, ↑beclin-1, ↑caspase-3, ↑Bcl-2, and ↑Bax |
(2) NR (3) NR (4) p < 0.05 |
||||||
| Li et al. (2020) | Zebrafish embryos | 1.87, 3.75, 7.5, 15, and 30 μM for 48 h | (1) ↓Survival rate | (1) p < 0.05 | |||
| 2 and 8 μM for 12, 24, 36, and 48 h | (2) ↓Contraction of ventricles and atria | (2) p < 0.05 | |||||
| (3) ↑254 genes and ↓352 genes | (3) NR | ||||||
| H9c2 | Undefined multiple concentrations for 30 min | (4) ↓Survival rate (5) ↑Apoptosis |
(4) p < 0.05 (5) p < 0.01 |
||||
| (6) ↑Ca2+
(7) Proteins expression: ↓TnT, ↓Bcl-2, ↑caspase-3, and ↑Bax |
(6) p < 0.01 (7) p < 0.05 |
||||||
| Gao et al. (2018) | H9c2 | 0–250 μM for 24 h | (1) ↓Cell viability | (1) p < 0.01 | |||
| 0, 100, and 200 μM for 24 h | (2) ↑Cell nuclei shrinkage and chromatin condensation (3) ↑Apoptosis (4) ↓ATP |
(2) NR (3) p < 0.001 (4) p < 0.001 |
|||||
| 0, 100, and 200 μM for 4 h | (5) ↑ROS (6) ↓Mitochondrial transmembrane potential (7) Proteins expression: ↓PGC-1α, ↓Bcl-2, ↑Bax, ↑caspase-3, and ↑cytochrome |
(5) p < 0.05 (6) p < 0.001 (7) p < 0.01 |
|||||
| Sun et al. (2014) | Primary ventricular myocytes of Wistar rats | 1 μM | (1) ↑Beating rhythm (2) ↑Sarcomere shortening (3) ↑Ca2+ transient amplitude and ↑Ca2+ |
(1) NR (2) p < 0.01 (3) p < 0.01 |
|||
| 0.01, 0.04, 0.16, and 0.64 mΜ for 4 h | (4) ↓Cell viability (5) ↑LDH (6) ↑Apoptosis |
(4) p < 0.01 (5) p < 0.05 (6) p < 0.01 |
|||||
| Zhou et al. (2013) | Primary cardiomyocytes of SD neonatal rats | 1 μM | (1) ↑Ca2+
(2) ↑APD50/90 |
(1) p < 0.05 (2) p < 0.01 |
|||
| 1 μM for 48 h | (3) Proteins expression: ↓SERCA2 and ↑NCX | (3) p < 0.05 | |||||
| Liu et al. (2019) | Zebrafish embryos | 1, 2, and 4 μg/L for undefined multiple time | (1) Cardiac function: ↓Heart rate, ↓SV and ↓CO | (1) p < 0.05 | |||
| 2.5 μg/L | (2) ↑Yolk sac hemorrhage and pericardial edema (3) ↑Apoptosis in the brain and eye area (4) Genes expression: ↓Nkx2.5, ↓Tbx5, and ↑caspase-3 |
(2) NR (3) NR (4) p < 0.05 |
|||||
| Ye et al. (2021) | Zebrafish embryos | Undefined multiple concentrations for 2, 10, and 24 h | (1) ↑Heart rate (2) Curvature of the tail spine and enlarged pericardium |
(1) p < 0.05 (2) NR |
|||
| Peng et al. (2020) | H9c2, rat primary cardiomyocytes | Undefined multiple concentrations | (1) ↑503 genes and ↓314 genes (2) ↓Cell viability |
(1) NR (2) p < 0.05 |
|||
| 1 μmol/L | (3) ↑ROS | (3) p < 0.05 | |||||
| 0.5 and 1 μM | (4) ↑Apoptosis (5) Proteins expression: ↑TNF-α and ↑FADD, ↑cytochrome C, ↑caspase-3/8, ↓Bcl-2, ↑RIP1/3, and ↑MLKL |
(4) NR (5) p < 0.05 |
|||||
| Wang et al. (2022a) | H9c2 | 3.125–400 μM for 24 h | (1) ↓Cell viability | (1) p < 0.01 | |||
| 50, 100, and 200 μM for 24 h | (2) ↑LDH (3) Proteins expression: ↑beclin-1, ↑LC3, ↑p-AMPKα/AMPKα, and ↑p-ULK1/ULK1 (4) ↑ROS (5) ↑8-OHdG (6) ↓GSH |
(2) p < 0.01 (3) p < 0.05 (4) p < 0.01 (5) p < 0.01 (6) p > 0.05 |
|||||
| Zhou et al. (2020) | Primary ventricular myocytes of Wistar rats, AC-16 cells | 0–320 μM for 24 h in AC-16 cells | (1) ↓Cell viability (2) ↑Mitochondrial superoxide productions (3) Notch1 signal is activated and then suppressed |
(1) p < 0.05 (2) p < 0.05 (3) p < 0.05 |
|||
| 20 μM for 24 h in AC-16 cells | (4) Unchanged morphological characteristics and ultrastructure | (4) NR | |||||
| NRVMs 0–80 μM for 7 days in NRVMs | (5) →Cell viability (6) Unchanged morphological characteristics and ultrastructure (7) ↑Mitochondrial superoxide productions (8) Notch1 signal is activated and then suppressed |
(5) NR (6) NR (7) p < 0.05 (8) p < 0.05 |
|||||
| (9) ↑Beating rate | (9) p < 0.05 | ||||||
| Yang et al. (2021) | H9c2 | 0.25, 0,5, and 1.0 μM for 24 h | (1) ↑Apoptosis (2) ↑Ca2+ (3) Proteins expression: ↓Bcl-2, ↑Bax, ↑caspase-3, ↑p-p38 and ↑TRPV2 (4) Protein expression: ↑TRPV2 |
(1) p < 0.0001 (2) p < 0.01 (3) p < 0.001 (4) p < 0.05 |
|||
| Wang et al. (2020a) | Zebrafish embryos | 15 mg/L for 48–72 h | (1) ↑Heart rate (2) ↑Pericardial edema, ↑blood cell, and ↑SV-BA distance (3) ↑696 genes and ↓925 genes |
(1) p < 0.0001 (2) NR (3) NR |
|||
| Yu (2015) | Primary cardiomyocytes of SD rats | 0.3, 1, and 3 μM | (1) ↑Ca2+ oscillation amplitude and ↑Ca2+ | (1) p < 0.05 | |||
| Xu (2008) | Primary cardiomyocytes of SD neonatal rats | 0.5, 1, and 3 μM for 15, 30, and 60 min | (1) ↓Cell viability | (1) NR | |||
| 0.5, 1, and 3 μM for 60 min | (2) DNA damage: ↑TDNA% and ↑TM | (2) p < 0.01 | |||||
| (3) ↑ROS | (3) p < 0.01 | ||||||
| Liu (2007) | Primary ventricular myocytes of Wistar rats | 5, 20, 40, 80, 160, 320, 640, and 1,280 μM for 4, 8, and 12 h | (1) ↓Cell viability | (1) p > 0.05 | |||
| 0.1, 0.3, and 0.6 mM for 24 h | (2) ↑LDH | (2) NR | |||||
| 12.5, 25, 50, 100, and 200 μM | (3) Gene expression: ↓Kv4.3 | (3) p < 0.05 | |||||
| Xia et al. (2021) | Zebrafish embryos | 4, 6, 8, 10, 12, 14, 16, and 18 μM | (1) Yolk retention, swim-bladder deficiency, pericardial edema, and curved body shape (2) ↑Malformation rate, ↓body length and ↑SV-BA distance (3) ↑Heart rate |
(1) NR (2) p < 0.05 (3) p < 0.01 |
|||
| 0.73, 2.42, 7.27, and 8.23 μM | (4) ↑ROS (5) ↓SOD (6) ↑MDA (7) ↑Apoptosis (8) Genes expression: ↑JNK, ↓Erk1/2, ↑Bax, ↑Bad, ↑cytochrome C, ↑caspase-3/9, and ↓Bcl-2 |
(4) p < 0.01 (5) p < 0.01 (6) p < 0.01 (7) p < 0.01 (8) p < 0.05 |
|||||
↑: demonstrates increasing trend; ↓: demonstrates decreasing trend; →: demonstrates the unchanging trend; APA, amplitude of action potential; APD, action potential duration; APD30, duration at 30% of repolarization; AR, adrenoceptor; cAMP/cGMP, cyclic adenosine monophosphate/cyclic guanosine monophosphate; CO, cardiac output; GSH, glutathione; HDNA%, head DNA%; IP3, inositol triphosphate; LDH, lactate dehydrogenase; MDA, malondialdenhyde; NADHD, reduce nicotinamide adenine dinucleotide dehydrogenase; NCX, Na+/Ca2+ exchanger; NR, not report; NRVMS, neonatal rat ventricular myocytes; OPTDM, average optical density of myocardial glycogen granules; OTM, olive tail moment; PLB, phospholamban; RPP, rate pressure product; ROS, reactive oxygen species; RyR2, ryanodine receptor; SERCA2, SR Ca2+-ATPase; SDH, succinate dehydrogenase; SD, Sprague–Dawley; SV, stroke volume; SV-BA, sinus venous and bulbus arteriosus; TDNA%, tail DNA%; TL, tail length; TM, tail moment; VDD, average velocity of diastolic spontaneous depolarization; 8-OHdG, 8-hydroxydeoxyguanosine.