Interleukin-37 has A Promising Cardioprotective Effect on Isoproterenol-Induced Myocardial Infarction / La Interleucina-37 tiene un Efecto Cardioprotector Prometedor sobre el Infarto de Miocardio Inducido por Isoproterenol

SUMMARY: The main cause of mortality and disability globally is myocardial infarction (MI). Isoproterenol (ISO), a β-adrenoceptor agonist, has been used to induce rat myocardial necrosis. Whereas interleukin-37 (IL-37) has anti-inflammatory and cytoprotective properties. The study aimed to investigate the potential protective effects of IL-37 administration on cardiac architecture, oxidative stress, and inflammatory markers during ISO-induced MI in rats. Three groups of adult male rats were used in this study, the normal control group (n=8), ISO-induced MI group (n=8) that received isoproterenol hydrochloride (ISO) (100 mg/kg/day, SC, for the first 2 consecutive days), and IL-37-treated group (ISO+IL-37) (n=8) that received recombinant human IL-37 (40 µg/kg /day, intraperitoneally, for 2 weeks during and after ISO injections. Heart rate (HR.) and ECG changes were monitored. Some oxidative stress markers such as superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) tissue levels in the tissue homogenate were assayed. Interleukin- 6 (IL-6), tumor necrosis factor- α (TNF-α), caspase-8, P53, and C- reactive protein (CRP) were among the inflammatory markers examined. In addition, serum levels of creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) were analyzed to evaluate the myocardial injury. For histological analysis, tissues were sectioned, fixed in paraffin, and stained with hematoxylin and eosin (H&E), Masson Trichrome and, immunohistochemical against NF-kB, TNF-α, and Caspase-9. IL-37 improved ECG changes, cardiac enzyme markers, and some inflammatory markers of oxidative stress in ISO-induced MI. It also improved the histopathological and immunohistochemical changes in MI. In conclusion: IL-37 might be a promising therapeutic modality in myocardial infarction.

La principal causa de mortalidad y discapacidad a nivel mundial es el infarto de miocardio (IM). El isoproterenol (ISO), un agonista de los receptores adrenérgicos β, se ha utilizado para inducir necrosis miocárdica en ratas. Mientras que la interleucina-37 (IL-37) tiene propiedades antiinflamatorias y citoprotectoras. El estudio tuvo como objetivo investigar los posibles efectos protectores de la administración de IL-37 en la arquitectura cardíaca, el estrés oxidativo y los marcadores inflamatorios durante el infarto de miocardio inducido por ISO en ratas. En este estudio se utilizaron tres grupos de ratas macho adultas, el grupo control normal (n=8), el grupo con IM inducido por ISO (n=8) que recibió clorhidrato de isoproterenol (ISO) (100 mg/kg/día, SC, durante los primeros 2 días consecutivos) y el grupo tratado con IL-37 (ISO+IL- 37) (n=8) que recibió IL-37 humana recombinante (40 µg/kg/día, por vía intraperitoneal, durante 2 semanas durante y después de las inyecciones de ISO. Se monitorearon la frecuencia cardíaca (FC) y los cambios en el ECG. Se analizaron algunos marcadores de estrés oxidativo como la superóxido dismutasa (SOD), el óxido nítrico (NOx), el malondialdehído (MDA) y los niveles tisulares de glutatión (GSH) en el homogeneizado de tejido. La interleucina-6 (IL-6), el factor de necrosis tumoral-α (TNF-α), la caspasa-8, la P53 y la proteína C reactiva (CRP) se encontraban entre los marcadores inflamatorios examinados. Se analizaron los niveles de creatinoquinasa (CK-MB) y lactato deshidrogenasa (LDH) para evaluar la lesión miocárdica; para el análisis histológico se seccionaron los tejidos, se fijaron en parafina y se tiñeron con hematoxilina y eosina (H&E), Tricromo de Masson e inmunohistoquímica contra NF-kB, TNF-α y Caspasa-9. IL-37 mejoró los cambios de ECG, los marcadores de enzimas cardíacas y algunos marcadores inflamatorios de estrés oxidativo en el IM inducido por ISO. Además mejoró los cambios histopatológicos e inmunohistoquímicos en MI. En conclusión: la IL-37 podría ser una modalidad terapéutica prometedora en el infarto de miocardio.

Shexiang Tongxin Dropping Pill Allieviates Heart Failure via Extracellula Matrix-Receptor Interaction Pathways Based on RNA-Seq Transcriptomics and Experimental Studies / 中国结合医学杂志

OBJECTIVE@#To investigate the protective mechanisms of Chinese medicine Shexiang Tongxin Dropping Pills (STDP) on heart failure (HF).@*METHODS@#Isoproterenol (ISO)-induced HF rat model and angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast (CFs) model were used in the present study. HF rats were treated with and without STDP (3 g/kg). RNA-seq was performed to identify differentially expressed genes (DEGs). Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson's stainings were taken to assess cardiac fibrosis. The levels of collagen I (Col I) and collagen III (Col III) were detected by immunohistochemical staining. CCK8 kit and transwell assay were implemented to test the CFs' proliferative and migratory activity, respectively. The protein expressions of α-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), MMP-9, Col I, and Col III were detected by Western blotting.@*RESULTS@#The results of RNA-seq analysis showed that STDP exerted its pharmacological effects on HF via multiple signaling pathways, such as the extracellular matrix (ECM)-receptor interaction, cell cycle, and B cell receptor interaction. Results from in vivo experiments demonstrated that STDP treatment reversed declines in cardiac function, inhibiting myocardial fibrosis, and reversing increases in Col I and Col III expression levels in the hearts of HF rats. Moreover, STDP (6, 9 mg/mL) inhibited the proliferation and migration of CFs exposed to Ang II in vitro (P<0.05). The activation of collagen synthesis and myofibroblast generation were markedly suppressed by STDP, also the synthesis of MMP-2 and MMP-9, as well as ECM components Col I, Col III, and α-SMA were decreased in Ang II-induced neonatal rats' CFs.@*CONCLUSIONS@#STDP had anti-fibrotic effects in HF, which might be caused by the modulation of ECM-receptor interaction pathways. Through the management of cardiac fibrosis, STDP may be a compelling candidate for improving prognosis of HF.

Cardio-Protective Effect of the Leaf Extract of Andrographis paniculata in Isoproterenol-Induced Myocardial Infarction

Background: Nowadays, myocardial infarction has been regarded as one of the chronic diseases with increasing mortality rate worldwide. The use of medicinal plants in the treatment of this chronic disease is gaining wide acceptance globally. Materials and Methods: This study was carried out to evaluate the cardio-protective effect of the leaf extract of A. paniculata in isoproterenol-induced myocardial infarction. Fresh green leaves of A paniculata were collected from the Faculty of Agriculture farmland, Nnamdi Azikiwe University, Awka, Nigeria. The plant was identified and authenticated at the Department of Botany, Nnamdi Azikiwe University and a voucher specimen was deposited at the herbarium accordingly. The shredded, air-dried sample was then pulverized and weighed. Solvent-solvent (ethanol and water) (7:3) was used for extraction via maceration for 72 hr. The filtrate was evaporated to dryness to obtain the ethanol extract which was used for further bioassay study. The bioactive constituents of the plant extract were quantitatively analyzed by Gas chromatography mass spectrometry (GC-MS). The animals were administered with the extract of A. paniculata orally for seven days at a divided dose of 100 mg/kg, 200 mg/kg and 400 mg/kg body weights. On the eight day, myocardial infarction was induced through subcutaneous administration of isoproterenol at a dose of 150 mg/kg/day diluted in 2 ml of saline on two consecutive days. Subsequently, the blood pressures were monitored and blood collected for bioassay studies. Results: The results of the study showed that the leaf extract of A. paniculata was rich in 2,5-Octadecadiynoic acid, methyl ester (28.21%); 1,2,3,5-Cyclohexanetetrol,(1à,2á,3à,5á)- (15.10 %) and 10-12-Pentacosadiynoic acid (13.05%). The findings also showed a significant decrease (p>0.05) in the Mean arterial blood pressure, heart rate, aspartate transaminase, alanine transaminase, creatinine kinase and lactate dehydrogenase activities of the treatment group compared with the untreated control group while the antioxidant (superoxide dismutase, catalase and glutathione) activities were significantly increased in the treatment group, compared with the untreated control group. Conclusion: The findings of this work have shown that leaf of A. paniculata was rich in bioactive compounds which could be synthesized to produce plant based products to combat cardiovascular diseases especially myocardial infarction.

Canagliflozin reduces the contractile response of isolated heart of normal adult rats / Canagliflozin reduce la respuesta contráctil del corazón aislado de ratas adultas normales

SUMMARY: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent a unique class of glucose-declining renal-targeted drugs. The SGLT2i Canagliflozin (CANA) is an anti-hyperglycemic drug that reduces various cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. This study aimed to explore the potential effects of CANA on the isolated healthy adult rat hearts to show if CANA has positive inotropic or cardiac depressant effects via analyzing the amplitude and frequency of cardiac contractions. In isolated normal adult rat hearts, the effects of CANA on cardiac contractility were examined. In a dose-response curve, CANA led to a significant cardiac depressant effect in a dose-dependent manner. This cardiac depressant effect of CANA (10-6 M) was not prevented by atropine. However, this cardiac depressant effect was partially antagonized by both Isoproterenol (10-5 M) and Calcium chloride (10-6 M), suggesting beta-adrenoceptor and calcium channel blocking actions. In addition, the cardiac depressant effect of CANA (10-6 M) was mitigated in part by Nitric oxide synthase inhibitor, L-NAME, suggesting that its action probably depends to some extent on the accumulation of nitric oxide, which decreases the rise of intracellular Calcium. Data from this study demonstrate that CANA has a significant cardiac relaxant effect in isolated hearts of healthy adult rats by different possible mechanisms. This inhibitory effect on cardiac contractility may help improve the diastolic ventricular filling providing a therapeutic potential to help the other cardioprotective mechanisms of CANA in the prevention and treatment of heart failure.

RESUMEN: Los inhibidores del cotransportador de sodio- glucosa 2 (SGLT2i) representan una clase única de fármacos dirigidos a los riñones que disminuyen la glucosa. El SGLT2i Canagliflozin (CANA) es un fármaco antihiperglucémico que reduce varios resultados cardiovasculares y renales en pacientes con diabetes mellitus tipo 2. Este estudio tuvo como objetivo explorar los efectos potenciales de CANA en corazones aislados de ratas adultas sanas para indicar si CANA tiene efectos inotrópicos o depresores cardíacos positivos mediante el análisis de la amplitud y la frecuencia de las contracciones cardíacas. En corazones aislados de ratas adultas normales, se examinaron los efectos de CANA sobre la contractilidad cardíaca. En una curva de dosis-respuesta, CANA condujo a un efecto depresor cardíaco significativo de manera dependiente de la dosis. Este efecto depresor cardíaco de CANA (10-6 M) no fue impedido por la atropina. Sin embargo, este efecto depresor cardíaco fue parcialmente antagonizado tanto por el isoproterenol (10-5 M) como por el cloruro de calcio (10-6 M), lo que sugiere acciones bloqueadoras de los receptores beta adrenérgicos y de los canales de calcio. Además, el efecto depresor cardíaco de CANA (10-6 M) fue mitigado en parte por el inhibidor de la sintasa de óxido nítrico, L-NAME, lo que sugiere que su acción probablemente depende en cierta medida de la acumulación de óxido nítrico, lo que disminuye el aumento de calcio intracelular. Los datos de este estudio demuestran que CANA tiene un efecto relajante cardíaco significativo en corazones aislados de ratas adultas sanas por diferentes mecanismos posibles. Este efecto inhibitorio sobre la contractilidad cardíaca puede ayudar a mejorar el llenado ventricular diastólico proporcionando un potencial terapéutico para ayudar a los otros mecanismos cardioprotectores de CANA en la prevención y tratamiento de la insuficiencia cardíaca.

Impaired tricarboxylic acid cycle flux and mitochondrial aerobic respiration during isoproterenol induced myocardial ischemia is rescued by bilobalide / 药物分析学报

There is an urgent need to elucidate the pathogenesis of myocardial ischemia (MI) and potential drug treatments.Here,the anti-MI mechanism and material basis of Ginkgo biloba L.extract (GBE) were studied from the perspective of energy metabolism flux regulation.Metabolic flux analysis (MFA) was performed to investigate energy metabolism flux disorder and the regulatory nodes of GBE components in isoproterenol (ISO)-induced ischemia-like cardiomyocytes.It showed that[U-13C]glucose derived m+2 isotopologues from the upstream tricarboxylic acid (TCA) cycle metabolites were markedly accu-mulated in ISO-injured cardiomyocytes,but the opposite was seen for the downstream metabolites,while their total cellular concentrations were increased.This indicates a blockage of carbon flow from glycolysis and enhanced anaplerosis from other carbon sources.A Seahorse test was used to screen for GBE components with regulatory effects on mitochondrial aerobic respiratory dysfunction.It showed that bilobalide protected against impaired mitochondrial aerobic respiration.MFA also showed that bilobalide significantly modulated the TCA cycle flux,reduced abnormal metabolite accumulation,and balanced the demand of different carbon sources.Western blotting and PCR analysis showed that bilobalide decreased the enhanced expression of key metabolic enzymes in injured cells.Bilobalide's efficacy was verified by in vivo experiments in rats.This is the first report to show that bilobalide,the active ingredient of GBE,protects against MI by rescuing impaired TCA cycle flux.This provides a new mechanism and potential drug treatment for MI.It also shows the potential of MFA/Seahorse combi-nation as a powerful strategy for pharmacological research on herbal medicine.

Effects of PNU 282987 on Improving Cardiac Remodeling and JAK 2/STAT3 Signaling Pathway / 中国药房

OBJECTIVE：To st udy the effects of α7 nicotinic acetylcholine receptor agonists （PNU282987）on improving cardiac remodeling of mice and Janus kinase 2/signal transducer and activator of transcription 3（JAK2/STAT3）signaling pathway. METHODS：Male Kunming mice were randomly divided into normal control group ，model group ，propranolol group （positive control，i.g. 40 mg/kg）and PNU 282987 low-dose，medium-close and high-dose groups （intraperitoneal injection of 0.5，1.0，3.0 mg/kg），with 10 mice in each group. Except for the normal control group ，mice in the other groups were given isoproterenol （ISO，30 mg/kg） subcutaneously for 7 days to induce the cardiac remodeling model. After 30 minutes of ISO injection ， administration groups were given relevant liquid ，once a day ，for 7 consecutive days. Twelve hours after last administration ，the left ventricular ejection fraction （EF）and left ventricular short axis shortening rate （FS）of mice in each group were measured ，and the whole heart mass index （HMI）was calculated ；the pathological changes of myocardium were observed. The serum contents of lactate dehydrogenase （LDH），creatine kinase （CK），tumor necrosis factor α（TNF-α），interleukin 6（IL-6），the protein expression of intercellular adhesion molecule 1（ICAM-1）and adhesion molecule 1（VCAM-1）were also determined. The ratios of p-JAK2/JAK2，p-STAT3/STAT3 in myocardial tissue were detected. RESULTS ：Compared with normal control group ，EF and FS of model group were significantly reduced ，HMI，the contents of LDH，CK，TNF-α and IL-6，the protein expression of ICAM- 1 and VCAM- 1，the ratio of p-JAK 2/JAK2 and p-STAT 3/STAT3 were increased significantly （P＜0.05 or P＜0.01）； blue collagen deposition in the interstitium of myocardium was obvious，and the degree of fibrosis was severe. Compared with model group ， the EF and FS of the mice in the medium-dose and high-dose groups were increased significantly ， HMI （except for PNU 282987 medium-dose group ），the contents of LDH （except for PNU 282987 medium-dose group ），CK，TNF-α and IL-6，the protein expression of ICAM- 1 and VCAM- 1，the ratio of p-JAK 2/JAK2 and p-STAT 3/STAT3 were decreased significantly （P＜0.05 or P＜ 0.01）；blue collagen deposition in the myocardial interstitium was significantly reduced ，and the degree of myocardial fibrosis was significantly reduced. There was no significant difference in the comparison of the above indicators in PNU 282987 low-dose group （P＞0.05）. CONCLUSIONS ：PNU282987 can improve cardiac remodeling of mice ，the mechanism of which may be associated with inhibiting JAK 2/STAT3 signaling pathway.

Huoxin Pill () Attenuates Cardiac Fibrosis by Suppressing TGF-β1/Smad2/3 Pathway in Isoproterenol-Induced Heart Failure Rats / 中国结合医学杂志

OBJECTIVE@#To evaluate the effects of Huoxin Pill (, HXP) on cardiac fibrosis and heart failure (HF) in isoproterenol (ISO)-induced HF rats.@*METHODS@#Thirty Wistar rats were randomly divided into 5 groups including control, HF, isosorbide mononitrate (ISMN), HXP low (HXP-L), and HXP high (HXP-H) groups (n=6 for each group) according to the complete randomization method. Rats were pretreated with ISMN (5 mg/kg daily), low concentration of HXP (10 mg/kg daily) or high concentration of HXP (30 mg/kg daily) or equal volume of saline by intragastric administration for 1 week, followed by intraperitoneal injection of ISO (10 mg/kg, 14 days), and continually intragastric administrated with above medicines or saline for additional 6 weeks. The effects of HXP treatment on the cardiac function, heart weight index (HWI), pathological changes, and collagen content were further assessed. Moreover, the role of HXP on activation of transforming growth factor- β 1 (TGF-β 1)/Smads pathway was further explored using immunohistochemistry (IHC) and Western-blot assay.@*RESULTS@#HXP treatment significantly alleviated the decrease of ejection fraction (EF) and fractional shortening (FS), while decreased the elevation of left ventricular end-systolic volume (LVESV) in ISO-induced HF rats (P<0.05). Moreover, HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB (CK-MB, P<0.05), as well as pathological changes in ISO-induced HF rats. Further determination indicated that HXP treatment alleviated the elevation of collagen I and collagen III protein expression in cardiac tissues of ISO-induced HF rats. Furthermore, HXP treatment significantly down-regulated the increase of TGF-β 1 and p-Smad2/3 protein expression in cardiac tissues of HF rats (P<0.05), while did not affect the expression of total Smad2/3.@*CONCLUSIONS@#HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β 1/Smad2/3 pathway.

A conglomeration of preclinical models related to myocardial infarction

Cardiovascular diseases are the main source of death and morbidity in developed and developing nations. Animal models are required to propel our understanding of the pathogenesis, increase our knowledge, disease progress, and mechanism behind cardiovascular disorder, providing new approaches focused to improve the diagnostic and the treatment of these pathological conditions and additionally to test various therapeutic ways to deal with tissue regeneration and re-establish heart working following damage. A perfect model framework ought to be reasonable, effectively controlled, reproducible, and physiologically illustrative of human disease, show cardinal signs and pathology that resembles after the human ailment and ethically stable. The decision of selection of animal model should be considered precisely since it influences exploratory results and whether results of the research can be sensibly matched with the human. In this way, no specific technique splendidly reproduces the human disease, and relying upon the model, extra cost burden, resources, infrastructure and the necessity for technical hands, should also be kept under consideration. Here we have discussed and compiled various methods of inducing myocardial infarction in animals, basically by surgery, chemicals and through genetic modification, this may benefit the researchers in getting a complied data regarding various methods through which they can induce myocardial infarction in animals.

Feasibility of assessing left ventricular myocardial morphology and function in acute and chronic myocardial hypertrophy rat models with ultrasound biomicroscopy / 中国医学影像技术

Objective: To investigate the feasibility of assessing left ventricular myocardial morphology and function in acute and chronic myocardial hypertrophy rat models induced by isoproterenol (ISO) with ultrasound biomicroscopy (UBM). Methods: Totally 40 SD rats were randomly divided into 4 groups (each n=10). Rats in acute myocardial hypertrophy model group (acute model group) were given subcutaneous injection with ISO 85 mg/kg once a day for 2 days, and those in acute control group were given equal amount saline with subcutaneous injection for equal course. Rats in chronic myocardial hypertrophy model group (chronic model group) were given subcutaneous injection with ISO 5 mg/kg once a day for 7 days, and those in chronic control group were given equal amount saline with subcutaneous injection for equal course. The following parameters, including left ventricular anterior wall diameter (LVAWD), left ventricular posterior wall diameter (LVPWD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) and left ventricular myocardial mass were measured with UBM. Then the rats were sacrificed, the left ventricular myocardial masses were accurately weighed. Results: Compared with acute control group, LVAWD and LVPWD increased in acute model group (both P<0.05). Compared with chronic control group, LVAWD, LVPWD, LVESD and LVESV increased in chronic model group, while LVEF and LVFS decreased (all P<0.05). Compared with acute model group, LVEDD, LVESD, LVEDV and LVESV of chronic model group increased, but LVEF and LVFS decreased (all P<0.05). Left ventricular myocardial masses measured with UBM were higher than anatomical accurate weighing in all 4 groups (all P<0.05). Left ventricular myocardial masses of acute model group measured with both Methods: were all lower than those of chronic model group (both P<0.05). The left ventricular myocardial masses measured with UBM were positively correlated with the value measured by anatomical accurate weighing in all 4 groups (all P<0.05). Conclusion: UBM can non-invasively evaluate left ventricular morphology and function in rats with acute and chronic myocardial hypertrophy induced by ISO.

Inhibitory effects of adenosine a1 receptor stimulation on rat myocardial hypertrophy induced by isoproterenol through tgf-β1/smad3 signal pathways / 中国药学杂志

OBJECTIVE: To observe the inhibitiory effect of adenosine A1 receptor stimulation on myocardial hypertrophy by TGF-β1/Smad3 signal pathways and myocardial energy metabolism in rats and discuss its related mechanism. METHODS: High dose isoproterrnol was subcutaneously injected into rats to establish myocardial hypertrophy model. Forty Sprague-Dawley rats were randomly divided into four groups with ten rats for each group:blank control group,isoproterenol model group, CCPA(150 μg·kg-1·min-1) treatment group.From second day after modeling,rats in CCPA group and in propranolol group were injected continuosly for eight weeks. Then the heart mass index (HMI)and left ventricular mass index (LVMI) were measured, the myocardial cells were observed under the light microscope by HE staining. The free fatty acids (FFA), lactic acids (LAC) and adenosine triphosphate (ATP) contents in myocardial tissue of rats were detected. The relative expression of TGE-β1 and Smad3 protein were determined by Western blotting. RESULTS: Compared with model group, in CCPA group, the HMI and LVMI were reduced, the conetent of FFA and LAC were decreased, the content of ATP was increased,and the relative expression of TGF-β1/Smad3 of CCPA group was decreased. CONCLUSION: When the adenosine A1 receptor was stimulated, it can improve the energy metabolism of myocardial hypertrophy, and restrain TGF-β1/Smad3 signal pathway, thus it play a protective role in the myocardial cells by reducing the expression of TGF-β1 and Smad3 protein.

Protective effect of luteolin on DNA damage of peripheral blood lymphocytes of isoproterenol-induced heart failure rats / 西安交通大学学报(医学版)

Objective: To explore the effects of luteolin on DNA damage of peripheral blood lymphocytes of isoproterenol-induced heart failure rats by using comet assay and micronucleus assay. Methods: Male SD rats aged 6-7 weeks were randomly divided into heart failure group (HF, n=10) and control group (Ctrl, n=10). The heart failure model was established through intraperitoneal injection of isoproterenol (50 mg/kg) for 10 consecutive days. Echocardiography was conducted to confirm HF model construction. Blood was taken from the abdominal aorta from rats in both groups using EDTA-anticoagulate tubes. Peripheral blood lymphocytes were separated bylymphocyte isolation kit within two hours after the blood was taken. Comet assay was carried out to test the short-run damage of DNA. Then those lymphocytes were treated with 5, 10, 20, and 50 μmol/L of luteolin and comet assay was carried out again after 30 min to test DNA damage. The lymphocytes were treated with 50 μmol/L of luteolin to culture new peripheral blood for micronucleus assay. Optic microscopy detected long-term DNA damage of the cells. Results: Compared with those in Ctrl group, the mean ejection fraction of left ventricle (EF%) of HF group was decreased; left ventricular fraction shortening, left ventricular end-systolic diameter, and left ventricular end-diastolic diameter significantly increased. These indicated that the heart failure model was established successfully. Compared with Ctrl group, the ratio of Tail DNA in HF group increased (P<0.05). Compared with that in HF group, Tail DNA decreased in 50 μmol/L luteolin-treated HF group (P<0.05). The micronuleus assay results were in accordance with comet assay results. Basically, the number of micronucleus in 1000 cells increased in HF group compared with Ctrl group, but decreased when treated with 50 μmol/L of luteolin. Conclusion: Luteolin can significantly reduce DNA damage on peripheral blood lymphocytes of HF rats.

Role of the alkylglycerone phosphate synthase in isoproterenol-induced cardiac hypertrophy / 国际生物医学工程杂志

Objective To research the effect of alkylation of glycerol phosphate synthase (AGPS) in isoproterenol (ISO) induced rat cardiac hypertrophy. Methods The pathological cardiac hypertrophy rat model was constructed by ISO intraperitoneal injection. Twelve healthy Sprague-Dawley rats (120～150 g) were divided into ISO group and control group randomly. In the ISO group, rats were injected with ISO (3 mg/kg) per day for two consecutive weeks. In the control group, rats were injected with normal saline (3 mg/kg) per day for two consecutive weeks. Changes of left ventricular diastolic diameter, left ventricular posterior wall thickness, left ventricular ejection fraction, left ventricular short-axis shortening rate and left ventricular mass were detected by echocardiography. The cross-sectional area of myocardial cells in rats was measured by hematoxylin-eosin staining. The expression of hypertrophic factors [atrial natriuretic peptide (ANP), myosin light chain-2V (MLC-2V), α-myosin heavy chain (α-MHC)] and AGPS were detected by Western Blot and real-time quantitative PCR (qPCR). Results The results of echocardiography showed that the cardiac hypertrophy rat model was successfully constructed. The results of hematoxylin-eosin staining showed that the myocardial cross-sectional area in the ISO group was significantly larger than that of the control group. The Western Blot and qPCR results indicated that the relative expression of protein and mRNA of hypertrophic factor and AGPS in the ISO group were both up-regulated comparing with that of the control group, and the differences were statistical significance (all P<0.05). Conclusions The rat model of pathological cardiac hypertrophy with up-regulated AGPS expression was successfully constructed providing a theoretical basis for further study on the role of AGPS in pathogenesis of pathological cardiac hypertrophy.

Experimental study on Yiqifumai mixture in treatment of arrhythmia induced by isoproterenol / 中国中西医结合急救杂志

Objective To evaluate the effect of Yiqifumai mixture on ventricular arrhythmia induced by isoproterenol. Methods Forty spontaneous hypertensive rats (SHR) were randomly divided into a control group and a Chinese medicine (TCM) group with 20 rats in each group. The control group was given distilled water 3.48 mL·kg-1·d-1, and the TCM group was given Yiqifumai mixture (composition: Codonopsis pilosula, Rhizoma coptidis, Pinellia ternate, Euonymus alatus, Rhizome of chuanxiong, Salvia miltiorrhiza, Radix paeoniae rubra, Radix paeonia alba, Licorice, Zizyphus jujuba, Polygala tenuifolia) 3.48 mL·kg-1·d-1, both groups were administered continuously for 7 days. Arrhythmia was induced by subcutaneous injection of isoproterenol 100 mg/kg into the neck 1 hour after the last administration in both groups. ECG telemetry was carried out for 2 hours to record whether single premature ventricular contraction (SP), paired premature ventricular contraction (PP) and ventricular tachycardia (VT) occurred in the control group and the TCM group, and the incidences, numbers and times of their occurrences were registered. Results There were no statistical significant differences in SP incidence (SPR), PP incidence (PPR), VT incidence (VTR) between the control group and TCM group at 1 hour and 2 hours [1 hour SPR was 90% (18/20) vs. 80% (16/20), PPR was 65% (13/20) vs. 65% (13/20), VTR was 45% (9/20) vs. 40% (8/20); 2 hours SPR was 100% (20/20) vs. 100% (20/20), PPR was 75% (15/20) vs. 75% (15/20), VTR was 65% (13/20) vs. 60% (12/20); all P > 0.05]. After 1 hour of ECG telemetry, the number of SP in the TCM group was significantly lower than that in the control group [numbers: 10.00 (4.00, 11.00) vs. 16.00 (8.50, 42.50), P < 0.05]; after 2 hours of ECG telemetry, the numbers of SP, PP and VT in the TCM group were significantly lower than those in the control group [SP (numbers), 27.00 (15.50, 38.00) vs. 37.50 (24.00, 74.50), PP (numbers), 5.00 (3.00, 8.00) vs 7.00 (5.00, 11.00), VT (numbers), 2.50 (1.25, 4.00) vs. 7.00 (4.50, 11.00), all P <0.05]. After 1 hour and 2 hours of ECG telemetry, the occurrence times of SP, PP and VT were slightly longer than those in cintrol group, but there were no significant differences between the two groups [1 hour: SP (minutes) was 4.35 (3.65, 9.90) vs. 3.66 (1.12, 9.52), PP (minutes) was 35.56 (26.78, 46.42) vs. 23.39 (11.74, 43.42), VT (minutes) was 22.31 (6.25, 30.02) vs. 14.27 (8.79, 31.38); 2 hours: SP (minutes) was 7.06 (3.65,12.29) vs. 4.09 (1.38, 14.11), PP (minutes) was 46.40 (33.88, 71.39) vs. 33.81(14.54, 46.20), VT (minutes) was 75.49 (59.37, 96.63) vs. 60.55 (24.65, 86.48), all P > 0.05]. Conclusion Yiqifumai mixture has the effect of anti-arrhythmia induced by isoproterenol and its effect in longer term use is more significant.

Effects of heme oxygenase-1 upregulation on isoproterenol-induced myocardial infarction

The present study was designed to examine the effect of heme oxygenase-1 (HO-1) induction by cobalt protoporphyrin (CoPP) on the cardiac functions and morphology, electrocardiogram (ECG) changes, myocardial antioxidants (superoxide dismutase [SOD] and glutathione [GSH]), and expression of heat shock protein (Hsp) 70 and connexin 43 (Cx-43) in myocardial muscles in isoproterenol (ISO) induced myocardial infarction (MI). Thirty two adult male Sprague Dawely rats were divided into 4 groups (each 8 rats): normal control (NC) group, ISO group: received ISO at dose of 150 mg/kg body weight intraperitoneally (i.p.) for 2 successive days; ISO + Trizma group: received (ISO) and Trizma (solvent of CoPP) at dose of 5 mg/kg i.p. injection 2 days before injection of ISO, with ISO at day 0 and at day 2 after ISO injections; and ISO + CoPP group: received ISO and CoPP at a dose of 5 mg/kg dissolved in Trizma i.p. injection as Trizma. We found that, administration of ISO caused significant increase in heart rate, corrected QT interval, ST segment, cardiac enzymes (lactate dehydrogenase, creatine kinase-muscle/brain), cardiac HO-1, Hsp70 with significant attenuation in myocardial GSH, SOD, and Cx-43. On the other hand, administration of CoPP caused significant improvement in ECG parameters, cardiac enzymes, cardiac morphology; antioxidants induced by ISO with significant increase in HO-1, Cx-43, and Hsp70 expression in myocardium. In conclusions, we concluded that induction of HO-1 by CoPP ameliorates ISO-induced myocardial injury, which might be due to up-regulation of Hsp70 and gap junction protein (Cx-43).

Influence of Hawthorn (Crataegus oxyacantha) Leaves Extract Administration on Myocardial Infarction Induced by Isoproterenol in Rats

Aims: To investigate the influence of ethanolic hawthorn leaves extract (EHLE) oral administration (200 mg / kg body weight /day) on isoproterenol (ISO) induced- myocardial infarction (MI) in rats and its bioactive constituents. Methods: Healthy adult male albino rats (Sprague-Dawely strain) were divided into five groups (10 rats /group); MI was induced in rats by ISO at a dose of {85 mg/kg body weight/day subcutaneously (S.C.,)} on two consecutive days with a 24 hours interval. Results: Pre-and post-treatment with EHLE significantly (p≤0.05) lowered the elevated serum cardiac enzyme marker activities namely, creatine kinase (CK), creatine kinase MB (CK- MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and specific MI markers level of galectin-3(Gal-3), cardiac troponin I (cTnI). Also, significantly (p≤0.05) ameliorated oxidant/ antioxidant status by decreasing oxidative stress biomarkers [tissue nitric oxide (NO), serum and tissue malondialdehyde (MDA)], and increasing antioxidant status [glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH)] in ISO-injected rats. Microscopic examination of heart tissues confirmed these results. Conclusion: Our results demonstrated that EHLE has a cardioprotective effect against ISO-induced MI in rats due to its high antioxidant properties, inhibition of lipid peroxidation and restoration of cardiac enzyme activities.

Intraoperative awareness as an example of the influence of cardiac output on anesthetic dosing: case report / Despertar intraoperatorio como ejemplo de la influencia del gasto cardíaco en la dosificación anestésica. Reporte de caso

Abstract A case of intraoperative awareness during ablation of pulmonary veins-one of the most widely used techniques in interventional cardiology-is discussed. An infusion of isoproterenol was administered following the ablation of ectopic foci. A few seconds after the infusion the patient experienced increased heart rate and intraoperative awareness manifested as an abrupt patient movement and bispectral index elevation. This has been described in similar procedures, following the administration of isoproterenol. In our opinion, the isoproterenol infusion caused the increased heart rate and subsequent abrupt rise in cardiac output. As an inversely proportional relationship between the propofol concentrations and cardiac output has been described, we believe that this rise in cardiac output could have favored the decline in the concentrations of propofol, leading to an intraoperative awareness episode.

Resumen Presentamos un caso de despertar intraoperatorio durante la ablación de venas pulmonares, una de las técnicas más empleadas por los cardiólogos intervencionistas. Tras la ablación de focos ectópicos se procede a la infusión de isoproterenol. Segundos después de la infusión se produce un aumento de la frecuencia cardíaca seguido de un despertar intraoperatorio traducido como un movimiento brusco del paciente y un aumento en el índice bi-espectral (BIS). Esto ha sido descrito en procedimientos similares tras la administración de isoproterenol. En nuestra opinión, la infusión de isoproterenol provocó un aumento de la frecuencia cardiaca y secundariamente del gasto cardíaco de forma brusca. Dado que se ha descrito una relación inversamente propocional entre las concentraciones de propofol y el gasto cardíaco, pensamos que este aumento del gasto cardíaco pudo condicionar un descenso de las concentraciones de propofol y esto causar el episodio de despertar intraoperatorio.

Isoproterenol accelerates the movement of the orthodontic tooth in rats / 医学研究生学报

ObjectiveIsoproterenol (ISO) stimulates the β2-adrenoceptor to enhance osteoclast formation, thus accelerating bone resorption. This study was to explore the effect of β-adrenoceptor agonist ISO on orthodontic tooth movement in rats.MethodsForty healthy 8-week-old SD male rats with the upper right first molar moved proximally by 50 g force application were randomly divided into an ISO and a control group and injected intraperitoneally with ISO at 5 mg/kg/d and the same amount of saline, respectively. Five rats were sacrificed in each group after 0, 7, 14 and 21 days of orthodontic force application and the upper right maxillary harvested for measuring the distance of movement of the upper right first molar, observing the changes in the periodontal tissue by HE staining, and counting the osteoclasts by tartrate-resistant acid phosphatase staining (TRAP).ResultsAt 7, 14 and 21 days of orthodontic force application, the tooth movement distance was significantly larger in the ISO group (\[0.52±0.04\], \[0.84±0.05\] and \[1.11±0.15\] mm) than in the control (\[0.40±0.07\], \[0.62±0.06\] and \[0.85±0.07\] mm) (P<0.05). On HE staining, the alveolar bone resorption at the pressure side was the most significant at 14 days, and obvious new bone formation was observed in the alveolar bone at 21 days. At 7, 14 and 21 days, TRAP staining showed remarkably larger numbers of osteoclasts in the ISO group (13.8±3.3, 24±6.3 and 18.8±2.6) than in the control (9.6±1.9, 14.6±3.7, 10.4±3.1) (P<0.05).ConclusionIsoproterenol can increase the number of osteoclasts and accelerate the movement of the orthodontic tooth in rats.

Expression Alteration of PLP2 in the Process of Cardiac Remodeling / 医学研究杂志

Objective To investigate the expression of PLP2 protein in the process of cardiac remodeling.Methods Mice were subjected to left anterior descending coronary artery ligation to induce cardiac remodeling model.Mice were subjected to isoproterenol (ISO) subcutaneous injection for 2 weeks to establish acute cardiac injury model.Mice were subjected to aortic banding (AB) surgery to establish a myocardial hypertrophy model.Cardiac myocytes hypertrophy model was induced by phenylephrine (PE) stimulation.Transforming growth factor (TGF) beta was used to stimulate cardiac fibroblasts.The PLP2 transcription level was detected by RT-PCR.Results PLP2 expression was significantly increased in 2 weeks after myocardial infarction (P ＜ 0.05),as well as in acute cardiac injury induced by ISO injection (P ＜ 0.05).After 1 week of AB surgery,the PLP2 expression began to increase (P ＜ 0.05),peaked at 2 weeks post AB (P ＜ 0.05),preserved to 8 weeks after AB (P ＜ 0.05).The expression of PLP2 in PE stimulated cardiomyocytes was increased as well as TGFβ stimulated fibroblast.Conclusion The expression of PLP2 were dynamically changed significantly in different cardiac remodeling model,suggesting that it may be involved in the occurrence and development of cardiac remodeling.

Nigella sativa protects against isoproterenol-induced myocardial infarction by alleviating oxidative stress, biochemical alterations and histological damage

Objective To evaluate the cardioprotective effect of Nigella sativa L. (N. sativa) in isoproterenol-induced myocardial infarction (MI). Methods Groups were treated with different doses of ethanol extract of N. sativa (EENS) and N. sativa oil alone and along with enalapril for 28 days. MI was induced by subcutaneous administration of isoproterenol (85 mg/kg) in two consecutive doses. Levels of cardiac biomarkers and antioxidant enzymes such as creatine kinase–N-acetyl-L-cysteine, lactate dehydrogenase, aspartate aminotransferase, malondialdehyde, superoxide dismutase, reduced glutathione and catalase were evaluated along with gross histopathological examination. Results Isoproterenol (85 mg/kg) induced MI by causing the significant (P < 0.01) reduction in the activity of cardiac biomarkers (creatine kinase–N-acetyl-L-cysteine, lactate dehydrogenase, aspartate aminotransferase) and antioxidant markers (superoxide dismutase, catalase, glutathione) along with significant (P < 0.01) increase in the level of malondialdehyde. Furthermore, histopathological evaluation also confirmed the isoproterenol-induced MI. Pretreatment with EENS (800 mg/kg) and combination of EENS (800 mg/kg) with enalapril (1 mg/kg) significantly (P < 0.01) prevented the development of these alteration and restored activity of cardiac biomarkers as well as antioxidant markers almost near to normal levels. Histopathological evaluation of cardiac tissue further confirmed the restoration of biochemical activity. Conclusions Experimental findings thus indicate that EENS (800 mg/kg) demonstrated cardioprotective effect against isoproterenol-induced MI by restoring cardiac biomarkers and antioxidant status.

Protective Effect of Trimetazidine on Myocardial Injury in Mice / 医学研究杂志

Objective To study the protective effect of Trimetazidine on myocardial injury in mice.Methods 6 to 7 week-old male BALB/c mice were randomly divided into 3 groups at twelve for each group:normal saline (NS) group,ISO group and TMZ group,N.S group for blank control group,ISO group for damage group,TMZ as treatment group.After 4 weeks,cardiac index (HW/BW) was calculated,serum lactate dehydrogenase (LDH) activity were measured by enzyme standard method.Malondialdehyde(MDA) was detected by thiobarbituric acid method(TBA).Superoxide dismutase (SOD) activity were determined by WST-1 method.The concentrations of serum Klotho were measured by ELSIA.The cardiac muscular tissue was imbedded with paraffin and colored with HE,Massion and caspase-3.Results The experiment model meets the requirements.In TMZ groups' HW/BW,LDH activity and MDA level were significantly lower than those of the ISO group(P ＜ 0.01).SOD energy,concentration of Klotho was significantly higher than those of the ISO group(P ＜ 0.01).HE color results showed that the myocardial cell diameter of ISO group was obviously larger than that of NS group,combined with disordered muscle fibers and hyperplastic myocardial interstitial fibroblasts.The cardiomyocytes diameter of TMZ groups was much smaller than that of the ISO group.Masson color results showed that the level of collagen fiber distribution in the myocardial interstitial and hemal wall of TMZ group was lower than that of ISO group.Caspase 3 color results showed that the number of tan dye distribution was significantly lower in TMZ group than that of the ISO group(Color positive results showed obvious practical color distribution).Conclusion Trimetazidine could prevent myocardial injury and its mechanism might be related to raised Klotho level.