RESUMEN
Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose ß-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of ß-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid.
Asunto(s)
Isoproterenol/toxicidad , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/prevención & control , Rosuvastatina Cálcica/farmacología , Transducción de Señal/efectos de los fármacos , Tretinoina/farmacología , Agonistas Adrenérgicos beta/toxicidad , Animales , Anticolesterolemiantes/farmacología , Antineoplásicos/uso terapéutico , Peso Corporal/efectos de los fármacos , Corazón/anatomía & histología , Corazón/efectos de los fármacos , Masculino , Tamaño de los Órganos , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Fuziline, an aminoalcohol-diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)-induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO-induced apoptosis. Meanwhile, fuziline significantly decreased the production of ROS, maintained mitochondrial membrane potential (MMP) and blocked the release of cytochrome C, suggesting that fuziline could play the cardioprotective role through restoring the mitochondrial function. Fuziline also could suppress ISO-induced endoplasmic reticulum (ER) stress via the PERK/eIF2α/ATF4/Chop pathway. In addition, using ROS scavenger NAC could decrease ISO-induced apoptosis and block ISO-induced ER stress, while PERK inhibitor GSK2606414 did not reduce the production of ROS, indicating that excess production of ROS induced by ISO triggered ER stress. And fuziline protected against ISO-induced myocardial injury by inhibiting ROS-triggered ER stress. Furthermore, fuziline effectively improved cardiac function on ISO-induced myocardial injury in rats. Western blot analysis also showed that fuziline reduced ER stress-induced apoptosis in vivo. Above these results demonstrated that fuziline could reduce ISO-induced myocardial injury in vitro and in vivo by inhibiting ROS-triggered ER stress via the PERK/eIF2α/ATF4/Chop pathway.
Asunto(s)
Alcaloides/farmacología , Diterpenos/farmacología , Estrés del Retículo Endoplásmico , Regulación de la Expresión Génica/efectos de los fármacos , Isoproterenol/toxicidad , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Aconitum/química , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Agonistas Adrenérgicos beta/toxicidad , Animales , Apoptosis , Masculino , Daño por Reperfusión Miocárdica/inducido químicamente , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
CALB-3, a purified acidic hetero-polysaccharide isolated from Fructus aurantii, has been shown to exert cardioprotective effects in vitro. Recently, we investigated the protective effects of CALB-3 on myocardial injury and its possible mechanisms of action using a rat model of myocardial ischemia. In this study, a myocardial ischemia model was established via intragastric administration of 2â¯mg/kg isoproterenol (ISO) to male Sprague-Dawley rats (200-220â¯g) daily for 3â¯days. We found that pretreatment with CALB-3 (50, 100, and 200â¯mg/kg, i.g.) daily for 21â¯days prevented ISO-induced myocardial damage, including improvement in electrocardiographic parameters, and decrease in serum cardiac enzymes, heart vacuolation, and TUNEL-positive cells. We used western blotting to identify the underlying mechanisms and determine the possible signal pathways involved. We found that CALB-3 pretreatment prevented apoptosis, increased the expression of antioxidant enzymes, and enhanced the binding of Nrf2 to the antioxidant response element. In addition, CALB-3 activated the phosphorylation of PI3K/Akt and ERK to increase the cytoprotective effect. Overall, our results show that CALB-3 is a promising polysaccharide for protecting against myocardial injury induced by ISO.
Asunto(s)
Cardiotónicos/farmacología , Citrus/química , Isoproterenol/toxicidad , Isquemia Miocárdica/prevención & control , Estrés Oxidativo , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Agonistas Adrenérgicos beta/toxicidad , Animales , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Masculino , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Oxidative stress is one of the major mechanism involved in pathogenesis of myocardial infarction. Use of natural products as therapeutic approach for ischemic myocardial injury is gaining attention worldwide. PURPOSE: This study was designed to investigate efficacy of Narirutin rich fraction (NRF), obtained from grape fruit peel, in the treatment of isoproterenol induced myocardial infarction in rats. METHODS: After 3-days pretreatment with NRF (100⯠mg/kg and 200⯠mg/kg, p.o.) myocardial injury was induced by subcutaneous administration of isoproterenol (85⯠mg/kg) for 2 days. Hemodynamic parameters, biochemical parameters, histological and ultrastructural changes were observed. RESULTS: Isoproterenol induced myocardial injury was evidenced by significant alterations in ECG, mean arterial pressure and left ventricular functions. Myocardial creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level were reduced while MDE levels were increased. Histological findings also showed severe changes. Treatment with NRF significantly attenuated these parameters in dose dependent manner. CONCLUSION: Thus, present study provides evidences for efficacy of NRF against isoproterenol induced myocardial infarction in rats.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Cardiotoxicidad/etiología , Citrus paradisi/toxicidad , Disacáridos/toxicidad , Flavanonas/toxicidad , Isoproterenol/toxicidad , Infarto del Miocardio/inducido químicamente , Estrés Oxidativo/efectos de los fármacos , Animales , Citrus paradisi/química , Corazón/fisiopatología , Masculino , Ratas , Ratas WistarRESUMEN
Myocardial infarction (MI) is the most prevalent cause of cardiovascular death. A possible way of preventing MI maybe by dietary supplements. The present study was thus designed to ascertain the cardio-protective effect of a formulated curcumin and nisin based poly lactic acid nanoparticle (CurNisNp) on isoproterenol (ISO) induced MI in guinea pigs. Animals were pretreated for 7 days as follows; Groups A and B animals were given 0.5 mL/kg of normal saline, group C metoprolol (2 mg/kg), groups D and E CurNisNp 10 and 21 mg/kg respectively (n = 5). MI was induced on the 7th day in groups B-E animals. On the 9th day electrocardiogram (ECG) was recorded, blood samples and tissue biopsies were collected for analyses. Toxicity studies on CurNisNp were carried out. MI induction caused atrial fibrillation which was prevented by pretreatment of metoprolol or CurNisNp. MI induction was also associated with increased expressions of cardiac troponin I (CTnI) and kidney injury molecule-1 (KIM-1) which were significantly reduced in guinea pig's pretreated with metoprolol or CurNisNp (P < 0.05). The LC50 of CurNisNp was 3258.2 µg/mL. This study demonstrated that the formulated curcumin-nisin based nanoparticle confers a significant level of cardio-protection in the guinea pig and is nontoxic.
Asunto(s)
Cardiotónicos/farmacología , Curcumina/farmacología , Sistemas de Liberación de Medicamentos , Infarto del Miocardio/prevención & control , Nanopartículas/administración & dosificación , Nisina/farmacología , Poliésteres/química , Agonistas Adrenérgicos beta/toxicidad , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Cardiotónicos/administración & dosificación , Cardiotónicos/química , Curcumina/administración & dosificación , Curcumina/química , Quimioterapia Combinada , Cobayas , Isoproterenol/toxicidad , Masculino , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/patología , Nanopartículas/química , Nisina/administración & dosificación , Nisina/químicaRESUMEN
There is increasing evidence for a beneficial effect of ginseng on cardiac pathology. Here, we determined whether North American ginseng can modulate the deleterious effects of the ß-adrenoceptor agonist isoproterenol on cardiac hypertrophy and function using in vitro and in vivo approaches. Isoproterenol was administered for 2 weeks at either 25 mg/kg per day or 50 mg/kg per day (ISO25 or ISO50) via a subcutaneously implanted osmotic mini-pump to either control rats or those receiving ginseng (0.9 g/L in the drinking water ad libitum). Isoproterenol produced time- and dose-dependent left ventricular dysfunction, although these effects were attenuated by ginseng. Improved cardiac functions were associated with reduced heart masses, as well as prevention in the upregulation of the hypertrophy-related fetal gene expression. Lung masses were similarly attenuated, suggesting reduced pulmonary congestion. In in vitro studies, ginseng (10 µg/mL) completely suppressed the hypertrophic response to 1 µmol/L isoproterenol in terms of myocyte surface area, as well as reduction in the upregulation of fetal gene expression. These effects were associated with attenuation in both protein kinase A and cAMP response element-binding protein phosphorylation. Ginseng attenuates adverse cardiac adrenergic responses and, therefore, may be an effective therapy to reduce hypertrophy and heart failure associated with excessive catecholamine production.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Cardiomegalia/prevención & control , Extractos Vegetales/uso terapéutico , Saponinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Disfunción Ventricular Izquierda/prevención & control , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/diagnóstico por imagen , Relación Dosis-Respuesta a Droga , Isoproterenol/toxicidad , Masculino , Panax , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas , Ratas , Ratas Sprague-Dawley , Saponinas/aislamiento & purificación , Transducción de Señal/fisiología , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
Myocardial oxidative stress leading to apoptosis and remodeling is the major consequence of ischemic heart disease. In the present study, we investigated the effect of Lagerstroemia speciosa L. leave (LS) extract containing 1 % corosolic acid in the context of cardiovascular disorder by using isoproterenol (ISO)-induced myocardial injury mouse model. Serum was analyzed for specific cardiac injury biomarkers. Cardiac tissue was examined for lipid peroxidation, protein carbonyl content, antioxidant (GSH, GR, GPx, GST, SOD, CAT, NQO1, and HO-1), and apoptosis (cleaved caspase-3, Bax, Bcl-2, p53, and DNA fragmentation) status. Myocardial protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in different experimental groups was evaluated. Pathological changes in heart tissue and activities of matrix metalloproteinases (MMPs) were also analyzed. Our results demonstrated that LS pretreatment augmented myocardial antioxidant status and attenuated myocardial oxidative stress. Myocardial apoptosis as well as MMPs activities was significantly prevented by LS pretreatment in ISO-induced mice. In addition, the immunoblot of Nrf2 revealed that LS pretreatment enhanced the nuclear protein expression of Nrf2 when compared to ISO control group. Thus, the overall results indicate that LS has cardioprotective effect and may prevent the myocardial stress by suppressing apoptosis through up-regulation of myocardial antioxidant levels.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Hemo-Oxigenasa 1/metabolismo , Isoproterenol/toxicidad , Lagerstroemia/química , Proteínas de la Membrana/metabolismo , Isquemia Miocárdica/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/sangre , Western Blotting , Masculino , Ratones , Modelos Animales , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/metabolismo , Extractos Vegetales/química , Triterpenos/farmacologíaRESUMEN
This study assessed the effects of mumie (shilajit) pre-treatment, a traditional drug which is well known in the ancient medicine of both east and west, on cardiac performance of rats subjected to myocardial injury. Animals were divided into control, M250, and M500 (received mumie at dosages of 250 and 500 mg/kg/day, orally for 7 days, respectively) main groups each consisting of two subgroups-with and without heart injury. On the 6th and 7th days, isoproterenol (ISO) (85 mg/kg i.p.) was injected (s.c.) to half of the animal subgroups to induce myocardial damage. On the 8th day, after hemodynamic parameter recordings, hearts were removed for further evaluation. Mumie pre-treatment had no significant effects on hemodynamic and cardiac indices of normal animals. When the cardiac injury was induced, mumie maintained the ±dp/dt maximum, attenuated the serum cardiac troponin I, and reduced the severity of cardiac lesions. Despite the mild positive effects of mumie on total antioxidant capacity and lipid proxidation index, no significant difference was observed among animal groups. The findings suggest the prominent cardioprotective effect of mumie against destructive effects of ISO. It seems that other mechanisms than reinforcements of antioxidant system are involved in this beneficial effect.
Asunto(s)
Cardiotónicos/farmacología , Minerales/farmacología , Infarto del Miocardio/prevención & control , Resinas de Plantas/farmacología , Agonistas Adrenérgicos beta/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Isoproterenol/toxicidad , Medicina Tradicional de Asia Oriental , Infarto del Miocardio/sangre , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/patología , Ratas , Ratas Wistar , Troponina I/sangreRESUMEN
OBJECTIVE: The objective of this study is to evaluate the effect of ethanolic extract of Urtica parviflora Roxb. in isoproterenol (ISO) induced myocardial infarction (MI) in rats. MATERIALS AND METHODS: U. parviflora Roxb. (350 mg/kg and 500 mg/kg, p.o) was administered for 15 days in rats. MI was induced with a single dose of ISO (200 mg/kg, s.c.) on the 14(th) and 15(th) day. At the end of the experimental period (i.e., on the day 16), serum and heart tissues were collected and total cholesterol (TC), high density lipoprotein, triglyceride and malondialdehyde, superoxide dismutase, catalase (CAT), reduced glutathione (GSH) and body weight were determined. RESULTS: Administration of ISO in control rats showed a significant (P < 0.001) increase serum cholesterol alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and low density lipoprotein (LDL). There was a significant increase (P < 0.01) in the levels of heart tissues as compared with respective control groups. Rats treated with U. parviflora significantly (P < 0.01) decreased ALT, AST, ALP, LDL and TC. Moreover, there was an increased CAT and GSH levels in rat treated with U. parviflora Roxb. as compared with the control group. CONCLUSION: U. parviflora (350 and 500 mg/kg p.o.) is effective in controlling serum LDL levels and reduced cardiac complication in experimentally induced MI in rats.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Isoproterenol/toxicidad , Infarto del Miocardio/prevención & control , Extractos Vegetales/uso terapéutico , Urticaceae/química , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Etanol/química , Femenino , Masculino , Infarto del Miocardio/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
Cardiac hypertrophy occurs in response to increased workload, such as hypertension or valvular heart disease. Oxidative stress has been implicated in cardiac hypertrophy and in its transition to heart failure. This study was taken up with the objective to evaluate the role of oxidative stress in cardiomyoblast hypertrophy and its modulation by Desmodium gangeticum (DG) that has been traditionally used in Ayurveda, an Indian system of medicine. The methanolic root extract was analyzed for total phenolic content and tested for antioxidant potential. Hypertrophy was induced by exposing H9c2 cell line to ß-adrenergic receptor agonist, isoproterenol (ISO), for 96 hours. Analyses of reactive oxygen species (ROS) generation, mitochondrial transmembrane potential ([INCREMENT]Ψm), and integrity of permeability transition were performed in ISO as well as Desmodium and ISO-cotreated cells. The results demonstrated potent free radical scavenging activity of DG. Cell line studies showed significant increase in ROS generation, dissipation of [INCREMENT]Ψm, and permeability transition pore opening in ISO-treated cells. Desmodium was found to attenuate ISO-induced hypertrophy by reduction of ROS generation, restoration of [INCREMENT]Ψm, and prevention of permeability transition pore opening. This study is the first documentation of the modulatory effect of DG on cardiac hypertrophy.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Antioxidantes/farmacología , Cardiomegalia/prevención & control , Fármacos Cardiovasculares/farmacología , Isoproterenol/toxicidad , Mitocondrias Cardíacas/efectos de los fármacos , Mioblastos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Antioxidantes/química , Cardiomegalia/metabolismo , Cardiomegalia/patología , Fármacos Cardiovasculares/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fabaceae , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Mioblastos Cardíacos/metabolismo , Mioblastos Cardíacos/patología , Fenoles/análisis , Extractos Vegetales/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Factores de TiempoRESUMEN
Nerium oleander Linn (NOL) an evergreen shrub belonging to the Apocynaceae family has been reported to have a wide spectrum of bioactivities. In in vitro study, the free radical scavenging potential of the hydroethanolic extract of N oleander Linn (ENO) flower and its fractions (glycosidic and nonglycosidic) were studied using 2, 2(')-azino-di [3-ethylbenzthiazoline sulphonate] (ABTS(*+) ) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH*) scavenging assay. ENO exhibited better radical scavenging activities than its fractions. Furthermore, the cardioprotective role of ENO (10, 30, 100 mg/kg, per oral [po]) was tested against isoproterenol-induced myocardial toxicity (ISO, 120 mg/kg per day, subcutaneously [sc], for 2 days at 48 hours interval) in experimental rats when compared to propranolol (5 mg/kg, po) which was the standard. Pretreatment with ENO (10, 30, and 100 mg/kg) and propranolol for 2 weeks followed by ISO challenge in rats prevented the elevation of marker enzymes such as lactate dehydrogenase (LDH), γ-glutamyl transferase (GGT), creatine kinase (CK-MB and creatine phosphokinase [CPK]), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in plasma. In addition, pretreatment with ENO and propranolol significantly attenuated the lipid peroxidation by maintaining the levels of enzymatic (superoxide dismutase and glutathione peroxidase) and nonenzymatic antioxidants (reduced glutathione and nitrite), which was also confirmed histologically. Taken together, the current study indicates that the hydroalcoholic extract of N oleander Linn flowers aid in cardioprotection probably by improving the antioxidant defense system during experimental myocardial necrosis.
Asunto(s)
Cardiotónicos/uso terapéutico , Flores/química , Corazón/efectos de los fármacos , Miocardio/patología , Nerium/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Agonistas Adrenérgicos beta/toxicidad , Animales , Biomarcadores/sangre , Cardiotónicos/aislamiento & purificación , Cardiotónicos/farmacología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/aislamiento & purificación , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Isoproterenol/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/prevención & control , Necrosis , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Artemisiaafra Jacq. ex Willd. is a widely used medicinal plant in South Africa for the treatment of various diseases. In this study, the effect of the herb on isoproterenol (ISO)-induced myocardial injury in rats was investigated. Pretreatment with the aqueous leaf extract of the plant at 100 and 200 mg/kg body weight for 30 days prevented the elevation of serum marker enzymes namely lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) in myocardial injured rats. ISO-induced animals exhibited decreased levels of glutathione reductase (GR), glutathione peroxides (GPx), superoxide dismutase (SOD) and glutathione (GSH) in the heart, which were restored to near normal levels following treatment with the herb. The extract also attenuated lipid peroxidation (LPO) in the heart and improved the imbalance in lipid profile caused by ISO. The effect was more prominent at 200 mg/kg body weight. These findings revealed the cardioprotective effect of A. afra against isoproterenol-induced myocardial injury.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Artemisia/química , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Isoproterenol/antagonistas & inhibidores , Isoproterenol/toxicidad , Sustancias Protectoras , Animales , Antioxidantes/metabolismo , Enzimas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Miocardio/enzimología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Ratas , Ratas WistarRESUMEN
The aim of the present study was to evaluate the efficacy of pre-supplementation with pomegranate (Punica granatum L.) juice (PJ) on heart weight, infarct size, plasma marker enzymes of cardiac damage, lipid peroxidation, endogenous enzymatic and non-enzymatic antioxidants, cardiac ATPases and histopathology of isoproterenol (IP)-induced cardiac necrosis (CN) in rats. Rats treated with IP (85 mg/kg, s.c.) for 2 days at an interval of 24 h caused significant (P < 0.05) infarct in myocardium and increase in heart weight, lipid peroxidation (LPO), activity levels of Ca(+2) ATPase and plasma marker enzymes, while there was significant (P < 0.05) decrease in endogenous enzymatic and non-enzymatic antioxidants and Na(+)-K(+) and Mg(+2)ATPases. Pre-supplementation with PJ for 30 consecutive days and treated with IP on days 29th and 30th showed significantly (P < 0.05) lesser increase in heart weight, infarct size, plasma marker enzymes, lipid peroxidation, Ca(+2) ATPase and a significant protective effect in endogenous enzymatic and non-enzymatic antioxidants, Na(+)-K(+) and Mg(+2) ATPases compared to IP alone treated group. Present study provides first scientific report on protective effect of supplementation of Pomegranate juice against IP-induced CN in rats.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Bebidas , Suplementos Dietéticos , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Isoproterenol/antagonistas & inhibidores , Isoproterenol/toxicidad , Lythraceae/química , Adenosina Trifosfatasas/metabolismo , Animales , Antioxidantes/metabolismo , Creatina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Cardiopatías/patología , L-Lactato Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Infarto del Miocardio/patología , Miocardio/enzimología , Miocardio/patología , Necrosis , Tamaño de los Órganos , Ratas , Ratas WistarRESUMEN
An extensive toxicology programme on salmeterol hydroxynaphthoate (Serevent), a marketed long-acting beta(2)-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged beta( 2)-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Albuterol/análogos & derivados , Carcinógenos/toxicidad , Mutágenos/toxicidad , Administración Oral , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/clasificación , Albuterol/administración & dosificación , Albuterol/clasificación , Albuterol/toxicidad , Animales , Animales Endogámicos , Carcinógenos/administración & dosificación , Carcinógenos/clasificación , Perros , Evaluación Preclínica de Medicamentos , Femenino , Hipertrofia/inducido químicamente , Hipertrofia/patología , Exposición por Inhalación , Laringe/efectos de los fármacos , Laringe/patología , Masculino , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Mutágenos/administración & dosificación , Mutágenos/clasificación , Conejos , Ratas , Reproducción/efectos de los fármacos , Sistema Respiratorio/efectos de los fármacos , Xinafoato de Salmeterol , Taquicardia/inducido químicamente , Taquicardia/fisiopatología , Pruebas de ToxicidadRESUMEN
The aim of this study was to investigate (1) whether Rhodobryum roseum, a traditional Chinese medicine used to treat cardiac disease, can protect myocardium damage due to isoproterenol-induced injury, (2) whether the cardioprotective effect of the R. roseum extract is related to its antioxidant activity, and (3) to identify the active components of R. roseum using the oxidant-mediated injury in cardiomyocytes. R. roseum was extracted with 95% EtOH (RE-95), 50% EtOH (RE-50) and water (Re-H2O) and the rats were treated orally for 11 days at doses of 250 mg and 63 mg/kg respectively after cardiac necrosis was induced by administering ISO subcutaneously at a dose of 85 mg/kg body weight. Levels of marker enzymes (LDH, GOT and CK) were assessed in serum whilst the antioxidant parameters, superoxide dismutase (SOD), and malondialdehde (MDA) were assayed in heart homogenate. Significant myocardial necrosis, depletion of endogenous antioxidants and an increase in serum levels of marker enzymes was observed in ISO-treated animals when compared with the normal animals. The RE-50 elicited a significant cardioprotective effect by lowering the levels of serum marker enzymes, lipid peroxidation (MDA). To extend this work, we sought to investigate the antioxidant effects of the components of R. roseum, using the neonatal rat cardiomyocytes model of H2O2-induced oxidant injury. Among the four major components, piperine and methyl piperate significantly reduced the medium level of CK and LDH at a variety of dosages. Moreover, piperine and methyl piperate significantly attenuated 2',7'-dichlorofluorescein (DCF) fluorescence by 63.9% and 52.6%, respectively. The present findings demonstrate that the cardioprotective effects of extracted R. roseum in ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of the membranes. Moreover, its components piperine and methyl piperate exert significant protectective effects on cardiac myocytes.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Antioxidantes/farmacología , Briófitas/química , Cardiomiopatías/inducido químicamente , Cardiomiopatías/prevención & control , Isoproterenol/toxicidad , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Aspartato Aminotransferasas/sangre , Cardiomiopatías/patología , Supervivencia Celular/efectos de los fármacos , Creatina Quinasa/metabolismo , Dioxolanos/farmacología , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/toxicidad , Radical Hidroxilo/metabolismo , Isoproterenol/antagonistas & inhibidores , L-Lactato Deshidrogenasa/sangre , Miocitos Cardíacos/efectos de los fármacos , Oxidantes/metabolismo , Oxidantes/toxicidad , Piperidinas/farmacología , RatasRESUMEN
AIMS: Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of G gamma subunits. We examined whether atorvastatin exerts similar effects in vivo and protects the rat heart from harmful effects of catecholamines. METHODS AND RESULTS: Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H(2)O for 14 days per gavage. All three animal groups were subjected to restraint stress on day 10 and to infusions of isoprenaline (ISO; 1 mg/kg x day) or NaCl via minipumps for the last 4 days. Heart rate was measured by telemetry, left ventricular atrial natriuretic peptide (ANP) transcript levels by RT-PCR, and left atrial contractile function in organ baths. Heart rate was similar in all six study groups. In animals pre-treated with water, infusion of ISO induced an increase in heart-to-body weight ratio (HW/BW) by approximately 20%, an increase in ANP mRNA by approximately 350%, and a reduction in the inotropic effect of isoprenaline in left atrium by approximately 50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were approximately 40, 50, and 40% smaller, respectively. Low dose atorvastatin had similar, albeit smaller effects. Atorvastatin treatment of NaCl-infused rats had only marginal effects. In cardiac homogenates from atorvastatin-treated rats (both NaCl- and ISO-infused), G gamma and G alpha(s) were partially translocated from the membrane to the cytosol. CONCLUSION: In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane G gamma and G alpha(s) to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.
Asunto(s)
Agonistas Adrenérgicos beta/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Isoproterenol/toxicidad , Contracción Miocárdica/efectos de los fármacos , Pirroles/farmacología , Agonistas Adrenérgicos beta/administración & dosificación , Animales , Atorvastatina , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/prevención & control , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Ritmo Circadiano , Citosol/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Corazón/fisiopatología , Bombas de Infusión Implantables , Isoproterenol/administración & dosificación , Masculino , Miocardio/metabolismo , Transporte de Proteínas , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
Curcumin (diferuoylmethane) is the active ingredient of turmeric (curcuma longa). There has been a surge of research in its anti-inflammatory and antioxidative properties, and its cardiovascular effects. A host of studies in in vitro and in vivo models of cardiac injury show that curcumin treatment reduces reactive oxygen species generation, monocyte adhesion to activated endothelial cells, and phosphorylation of c-Jun N-terminal kinase, p38 mitogen activated protein kinase and signal transducer and activator of transcription-3, and subsequent downstream signals. These alterations lead to preservation of myocardial function following ischemic or biochemical insult to the heart. Recent studies in models of pressure overload show that curcumin can reduce cardiac remodeling by altering reninangiotensin-system-transforming growth factor beta1 and collagen axis. Studies need to be done in humans to define the potential of curcumin in limitation of cardiac injury and preservation of cardiac function following ischemia.
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Curcumina/uso terapéutico , Cardiopatías/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Agonistas Adrenérgicos beta/toxicidad , Animales , Antibióticos Antineoplásicos/toxicidad , Doxorrubicina/toxicidad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Cardiopatías/inducido químicamente , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Isoproterenol/toxicidad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The protective effects of Ginkgo biloba Phytosomes (GBP) in isoproterenol (ISO)-induced cardiotoxicity and the antioxidant activity involved in this protection were investigated in rats. Myocardial infarction was produced in rats with 65, 85, 120 and 200mg/kg of ISO administered subcutaneously (sc) twice at an interval of 24h. An ISO dose of 85mg/kg was selected for the present study as this dose offered significant alteration in biochemical parameters and moderate necrosis in heart. Effect of GBP oral treatment for 21 days at two doses (100mg and 200mg/kg body weight) was evaluated against ISO (85mg/kg, sc)-induced cardiac necrosis. Levels of marker enzymes (AST, LDH and CPK) were assessed in serum and heart, antioxidant parameters viz., reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) and malondialdehde (MDA) were assayed in heart homogenate. Significant myocardial necrosis, depletion of endogenous antioxidants and increase in serum levels of marker enzymes were observed in ISO-treated animals when compared with the normal animals. GBP elicited a significant cardioprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPx and GR. The present findings have demonstrated that the cardioprotective effects of GBP in ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of membrane.
Asunto(s)
Ginkgo biloba , Isquemia Miocárdica/prevención & control , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Agonistas Adrenérgicos beta/toxicidad , Animales , Ginkgo biloba/química , Corazón/efectos de los fármacos , Isoproterenol/toxicidad , Infarto del Miocardio/inducido químicamente , Miocardio/patología , Necrosis/inducido químicamente , Necrosis/prevención & control , Ratas , Ratas WistarRESUMEN
Altered membrane integrity and inflammation play a key role in cardiovascular damage. We investigated the salubrious effect of exogenously administered alpha-mangostin against beta-adrenergic cathecolamine-induced cardiovascular toxicity with special reference to membrane ATPases, lysosomal hydrolases and inflammatory mediators TNF-alpha and Cyclooxygenase-2 (COX-2) expressions in albino rats. Induction of rats with isoproterenol (150mg/kg body wt, i.p.) for 2 days resulted in a significant increase in the activities of serum and cardiac lysosomal hydrolases (beta-d-glucuronidase, beta-d-galactosidase, beta-d-N-acetylglucosaminidase, acid phosphatase and cathepsin-D). A significant increase in cardiac levels of sodium, calcium with a decrease in the level of potassium paralleled by abnormal activities of membrane-bound phosphatases (Na(+)-K(+) ATPase, Ca(2+) ATPase and Mg(2+) ATPase) were observed in the heart of ISO-administered rats. Cardiac TNF-alpha and COX-2 expressions were assessed by Western blotting. Cardiac TNF-alpha and COX-2 expressions were significantly elevated in ISO-intoxicated rats. Pre-co-treatment with alpha-mangostin (200mg/kg body wt.) orally for 8 days significantly attenuated these abnormalities and restored the levels to near normalcy when compared to ISO intoxicated group of rats. In conclusion, alpha-mangostin preserves the myocardial membrane integrity and extenuates anomalous TNF-alpha and COX-2 expressions by mitigating ISO-induced oxidative stress and cellular damage effectively. Restoration of cellular normalcy accredits the cytoprotective role of alpha-mangostin.
Asunto(s)
Ciclooxigenasa 2/efectos de los fármacos , Garcinia mangostana , Isquemia Miocárdica/prevención & control , Fitoterapia , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Xantonas/farmacología , Agonistas Adrenérgicos beta/toxicidad , Animales , Western Blotting , Ciclooxigenasa 2/biosíntesis , Garcinia mangostana/química , Corazón/efectos de los fármacos , Hidrolasas/análisis , Hidrolasas/efectos de los fármacos , Isoproterenol/toxicidad , Masculino , Isquemia Miocárdica/inducido químicamente , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
This study was designed to investigate the effect of oral curcumin pretreatment (200 mg/kg) on isoproterenol-induced myocardial injury in rats. Isoproterenol (85 mg/kg, s.c., in two divided doses at 24 h intervals) administration induced a statistically significant increase (P < 0.01) in serum lactate dehydrogenase, creatine kinase, aspartate transaminase, and alanine transaminase activities and significant increase (P < 0.01) in myocardial lipid peroxides levels as compared to vehicle control rats. Furthermore, significant depletion (P < 0.01) of myocardial endogenous antioxidants viz. superoxide dismutase, catalase, and tissue glutathione levels were also found in the pathogenic control group, that is, isoproterenol only treated animals. Curcumin (200 mg/kg) pretreatment for 20 days in isoproterenol treated rats significantly lowered (P < 0.01) the serum lactate dehydrogenase, creatine kinase, aspartate transaminase, alanine transaminase, and myocardial lipid peroxides levels and increased the levels of myocardial endogenous antioxidants (superoxide dismutase, catalase, and tissue glutathione) as compared to pathogenic control rats. Furthermore, histological examination of rat's heart section confirmed myocardial injury with isoproterenol administration and near normal pattern with curcumin pretreatment. The results of our study provide clear evidence that the curcumin pretreatment enhances the antioxidant defense against isoproterenol-induced oxidative myocardial injury in rats and exhibit cardioprotective property.