The cardioprotective effects of a combination of quercetin and α-tocopherol on isoproterenol-induced myocardial infarcted rats

The present study aims to evaluate the combined protective effects of quercetin and α-tocopherol on isoproterenol-treated myocardial infarcted rats. Male albino Wistar rats were pretreated with a combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) daily for 14 days. After the pretreatment, rats were injected isoproterenol (100 mg/kg) to induce myocardial infarction. Isoproterenol-treated rats showed increased levels of serum troponins and increased intensities of serum lactate dehydrogenase-1 and -2 isoenzyme bands. Isoproterenol treatment also showed significant decreased levels of antioxidant system and significant increased levels of plasma lipid peroxidation, plasma uric acid, and the heart calcium. Furthermore, isoproterenol-treated rat's electrocardiogram showed elevated ST segments. Combined pretreatment with quercetin and α-tocopherol normalized all the biochemical parameters and minimized the alterations in electrocardiogram. Histopathology of myocardium also confirmed the cardioprotective effects of quercetin and α-tocopherol. In vitro studies confirmed the mechanism of action of quercetin and α-tocopherol. Thus, quercetin and α-tocopherol exhibited cardioprotective effects against isoproterenol-induced cardiotoxicity due to their scavenging free radicals, improving antioxidants and maintaining Ca(2+) levels. Our study also showed that combined pretreatment (quercetin and α-tocopherol) was highly effective than single pretreatment (quercetin or α-tocopherol).     

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat’s heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients.     

Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats

The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N-acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect.     

Protective effects of N-acetyl cysteine on membrane-bound adenosine triphosphatases and minerals in isoproterenol-induced myocardial-infarcted rats: an in vivo and in vitro study

The present study was aimed to evaluate the protective effects of N-acetyl cysteine (NAC) on changes in the activities/levels of adenosine triphosphatases and minerals in isoproterenol-induced myocardial-infarcted rats. Male albino Wistar rats were pretreated with NAC (10 mg/kg body weight) daily for a period of 14 days. After pretreatment period, rats were induced myocardial infarction (MI) by isoproterenol (100 mg/kg body weight). The activity of sodium/potassium-dependent adenosine triphosphatase was decreased, and the activities of calcium- and magnesium-dependent adenosine triphosphatases were increased in the heart of isoproterenol-induced myocardial-infarcted rats. Furthermore, the levels of potassium were lowered and the levels of sodium and calcium were increased in the heart of isoproterenol-induced rats. Increased plasma lipid peroxidation was observed in isoproterenol-induced rats. Pretreatment with NAC showed protective effects on adenosine triphosphatases, minerals, and lipid peroxidation. The in vitro study confirmed the reducing property of NAC. The observed effects are due to the membrane-stabilizing and antioxidant effects of NAC. The results of this study will be useful for the prevention of MI.     

Protective Effects of 7‐Hydroxycoumarin on Dyslipidemia and Cardiac Hypertrophy in Isoproterenol‐Induced Myocardial Infarction in Rats

This study evaluates the protective effects of 7‐hydroxycoumarin (7‐HC) on dyslipidemia and cardiac hypertrophy in isoproterenol (ISO) induced myocardial infarction (MI) in rats. Rats were pre‐ and co treated with 7‐HC (16 mg/kg) daily for 8 days. ISO (100 mg/kg) was subcutaneously injected into rats on seventh and eighth days to induce MI. Increased activity/levels of serum creatine kinase‐MB (CK‐MB), troponin‐T, plasma lipid peroxidation products, and altered levels of lipids in the serum and heart and serum lipoproteins were noted in ISO‐induced rats. ISO‐induced myocardial infarcted rats revealed increased hypertrophy (cardiac and left ventricular) and hepatic 3‐hydroxyl 3‐methylglutaryl‐coenzyme‐A reductase (HMG‐CoA reductase) activity. Pre and cotreatment with 7‐HC revealed significant protective effects on all the biochemical parameters evaluated. The in vitro study demonstrated its free radical scavenging property. Thus, 7‐HC protects ISO‐induced MI in rats by its free radical scavenging and antihyperlipidaemic and antihypertrophic properties.     

Pretreatment with a combination of quercetin and α-tocopherol ameliorates adenosine triphosphatases and lysosomal enzymes in myocardial infarcted rats

AimsMembrane bound adenosine triphosphatases (ATPases) and lysosomal enzymes play an important role in the pathology of myocardial infarction. This study was aimed to evaluate the combined preventive effects of quercetin and α-tocopherol on membrane bound ATPases and lysosomal enzymes in isoproterenol induced myocardial infarcted rats.Main methodsMale Wistar rats were pretreated with a combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) daily for 14 days. After the pretreatment period, isoproterenol (100 mg/kg) was injected to rats at an interval of 24 h for two days to induce myocardial infarction. The activities of ATPases and lysosomal enzymes were assayed.Key findingsIsoproterenol treated rats showed decreased levels of heart creatine kinase and lactate dehydrogenase. The activity of sodium potassium adenosine triphosphatase was decreased and the activities of magnesium adenosine triphosphatase and calcium adenosine triphosphatase were increased in isoproterenol treated rats. Also, the activities of β-glucuronidase, β-N-acetylglucosaminidase, β-galactosidase, cathepsin-B and D were increased (serum and heart), but the activities of β-glucuronidase and cathepsin-D were decreased in lysosomal fraction and increased in cytosolic fraction of the heart in isoproterenol treated rats. Furthermore, the heart lipid peroxidation products were increased in isoproterenol treated rats. Combined pretreatment with quercetin and α-tocopherol to isoproterenol treated rats normalized all the biochemical parameters studied. The observed effects are due to their membrane stabilizing property and this property might be due to decreased lipid peroxidation.SignificanceOur study demonstrated that combined pretreatment was better than single pretreatment. This study may have significant impact on myocardial infarcted patients.     

Preventive effect of rutin on lipids, lipoproteins, and ATPases in normal and isoproterenol-induced myocardial infarction in rats

The present study was designed to evaluate the preventive role of rutin on lipids, lipoproteins, and ATPases in normal and isoproterenol (ISO)-induced myocardial infarction in rats. Rutin (40 and 80 mg/kg) was orally administered to rats for a period of 42 days. After that period, isoproterenol (150 mg/kg) was injected subcutaneously to male wistar rats at an interval of 24 h for 2 days. The weight of heart and the concentrations of total cholesterol, triglycerides, and free fatty acids were increased significantly (p < 0.05), and the concentration of phospholipids was decreased significantly (p < 0.05) in the heart of ISO-treated rats. ISO-treated rats also showed a significant increase (p < 0.05) in the levels of total cholesterol, triglycerides, phospholipids, low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) with a significant decrease (p < 0.05) in high-density lipoprotein cholesterol (HDL-C) level in serum. The activities of sodium potassium dependent adenosine triphosphatase (Na(+)/K(+) ATPase) and magnesium-dependent adenosine triphosphatase (Mg(2+) ATPase) were decreased significantly (p < 0.05), and the activity of calcium-dependent adenosine triphosphatase (Ca(2+)ATPase) was increased significantly (p < 0.05) in the heart in ISO-treated rats. Pretreatment with rutin at doses of 40 or 80 mg/kg to ISO-treated rats showed a significant (p < 0.05) effect in all the parameters studied. Oral administration of rutin to normal rats did not show any significant effect. Thus, the results of our study show that pretreatment with rutin maintained the levels of lipids, lipoproteins, and ATPases in ISO-induced myocardial infarcted rats. The observed effects might be due to the antioxidant potential of rutin.     

Chronic effects of platinum(IV) complex and its diamine ligand on rat heart function: comparison with cisplatin

Mitochondrial dysfunction plays crucial role in the pathologenesis of myocardial infarction (MI). The present study evaluated the protective effect of α-bisabolol against isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. Male albino Wistar rats were pre- and co-treated with intraperitoneal injection of α-bisabolol (25 mg/kg body weight) daily for 10 days. To induce experimental MI, ISO (85 mg/kg body weight) was injected subcutaneously to the rats at an interval of 24 h for 2 days (9th and 10th day). ISO-induced MI was indicated by the decreased activities of heart creatine kinase and lactate dehydrogenase in rats. ISO administration also enhanced the concentrations of heart mitochondrial lipid peroxidation products and decreased the activities/concentrations of mitochondrial antioxidants, Kreb’s cycle dehydrogenases and mitochondrial electron transport chain complexes I, II?+?III and IV in rats. Furthermore, ISO triggers calcium overload and ATP depletion in the rat’s heart mitochondria followed by the mitochondrial cytochrome-C release and the activation of intrinsic pathway of apoptosis by upregulating the myocardial pro-apoptotic Bax, P⁵³, APAF-1, active caspase-3, active caspase-9 and down regulating the expressions of anti-apoptotic Bcl-2. α-Bisabolol pre and co-treatment showed considerable protective effects on all the biochemical and molecular parameters studied. Transmission electron microscopic study and mitochondrial swelling assay confirmed our biochemical and molecular findings. The in vitro study on hydroxyl radical also revealed the potent free radical scavenging activity of α-bisabolol. Thus, α-bisabolol attenuates mitochondrial dysfunction and intrinsic pathway of apoptosis in ISO-induced myocardial infarcted rats.

     

Preventive Effects of (–) Epicatechin on Altered Adenosine Triphosphatases and Minerals in Isoproterenol‐Induced Myocardial Infarcted Rats

The present study was aimed to evaluate the preventive effects of (–) epicatechin on alterations in the activities/levels of adenosine triphosphatases and minerals in isoproterenol‐induced myocardial infarcted rats. Male albino Wistar rats were pretreated with (–) epicatechin (20 mg/kg body weight) daily for a period of 21 days. After the pretreatment period, rats were induced myocardial infarction by isoproterenol (100 mg/kg body weight) on 22nd and 23rd day. The activity of sodium/potassium‐dependent adenosine triphosphatase was decreased, and the activities of calcium‐ and magnesium‐dependent adenosine triphosphatases were increased in the heart of isoproterenol‐induced myocardial infarcted rats. In addition, the concentrations of potassium were decreased and the concentrations of sodium and calcium were increased in the heart of isoproterenol‐induced rats. Elevated plasma lipid peroxidation was noted in isoproterenol‐induced rats. Prior treatment with (–) epicatechin significantly prevented the alterations in the activities and concentrations of adenosine triphosphatases, minerals, and plasma lipid peroxidation. The in vitro study confirmed the reducing property of (–) epicatechin. The observed effects in this study are attributed to the membrane‐stabilizing and antioxidant properties of (–) epicatechin. The findings of this study will be beneficial to prevent the occurrence of myocardial infarction. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:516‐521, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21461     

Protective effects of combination of quercetin and α-tocopherol on mitochondrial dysfunction and myocardial infarct size in isoproterenol-treated myocardial infarcted rats: biochemical, transmission electron microscopic, and macroscopic enzyme mapping evidences

Mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. We evaluated the combined protective effects of quercetin and α-tocopherol on mitochondrial damage and myocardial infarct size in isoproterenol-induced myocardia- infarcted rats. Rats were pretreated with quercetin (10 mg/kg) alone, α-tocopherol (10 mg/kg) alone, and combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) orally using an intragastric tube daily for 14 days. After pretreatment, rats were induced myocardial infarction by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Isoproterenol treatment caused significant increase in mitochondrial lipid peroxides with significant decrease in mitochondrial antioxidants. Significant decrease in the activities of isocitrate, succinate, malate, and α-ketoglutarate and NADH dehydrogenases and cytochrome-c-oxidase, significant increase in calcium, and significant decrease in adenosine triphosphate were observed in mitochondria of myocardial infarcted rats. Combined pretreatment with quercetin and α-tocopherol normalized all the biochemical parameters and preserved the integrity of heart tissue and restored normal mitochondrial function in myocardial-infarcted rats. Transmission electron microscopic findings on heart mitochondria and macroscopic enzyme mapping assay on the size of myocardial infarct also correlated with these biochemical parameters. The present study showed that combined pretreatment was highly effective than single pretreatment.     

Effects of gallic acid on brain lipid peroxide and lipid metabolism in streptozotocin-induced diabetic Wistar rats

This study evaluated the protective effects of gallic acid on brain lipid peroxidation products, antioxidant system, and lipids in streptozotocin-induced type II diabetes mellitus. Streptozotocin-induced diabetic rats showed a significant increase in the levels of blood glucose, brain lipid peroxidation products, and lipids and a significant decrease in the activities of brain enzymic antioxidants. Oral treatment with gallic acid (10 mg and 20 mg/kg) for 21 days significantly decreased the levels of blood glucose, brain lipid peroxidation products, and lipids and significantly increased the activities of brain enzymic antioxidants in diabetic rats. Histopathology of brain confirmed the protective effects of gallic acid. Furthermore, in vitro study revealed the free radical scavenging action of gallic acid. Thus, our study shows the beneficial effects of gallic acid on brain metabolism in streptozotocin-induced type II diabetic rats. A diet containing gallic acid may be beneficial to type II diabetic patients.     

Preconditioning with diosgenin and treadmill exercise preserves the cardiac toxicity of isoproterenol in rats

This study was aimed to evaluate the preventive effect of diosgenin and exercise on tissue antioxidant status in isoproterenol-induced myocardial infarction (MI) in male Wistar rats. Levels of lipid peroxides, reduced glutathione (GSH), and the activities of glutathione-dependent antioxidant enzymes (glutathione peroxidise and glutathione reductase) and antiperoxidative enzymes (catalase and superoxide dismutase) in the plasma and the heart tissue of experimental groups of rats were determined. Pretreatment with diosgenin and exercise exerted an antioxidant effect against isoproterenol-induced myocardial infarction by blocking the induction of lipid peroxidation. A tendency to prevent the isoproterenol-induced alterations in the level of GSH, in the activities of glutathione-dependent antioxidant enzymes and antiperoxidative enzymes was also observed. Histopathological findings of the myocardial tissue showed a protective role for combination of diosgenin and exercise in isoproterenol (ISO)-treated rats. Thus, the present study reveals that preconditioning with diosgenin and exercise exerts cardioprotective effect against ISO-induced MI due to its free radical scavenging and antioxidant effects, which maintains the tissue defense system against myocardial damage.     

Preventive effect of caffeic acid on lysosomal dysfunction in isoproterenol‐induced myocardial infarcted rats

We evaluated the preventive effect of caffeic acid (CA) on lysosomal enzymes in isoproterenol (ISO)‐treated myocardial infarcted rats. Male albino Wistar rats were pretreated with CA (15 mg/kg) daily for a period of 10 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. The activity of serum creatine kinase‐MB and lactate dehydrogenase was increased significantly (P < 0.05) in ISO‐induced myocardial infarcted rats. The levels of plasma thiobarbituric acid reactive substances and lipid hydroperoxides were significantly (P < 0.05) increased, and the level of plasma‐reduced glutathione was significantly (P < 0.05) decreased in ISO‐induced myocardial infarcted rats. The activities of lysosomal enzymes (β‐glucuronidase, β‐N‐acetylglucosaminidase, β‐galactosidase, cathepsin‐B and cathepsin‐D) were increased significantly (P < 0.05) in the serum and heart of ISO‐induced myocardial infarcted rats. ISO induction also resulted in decreased stability of membranes, which was reflected by lowered activities of β‐glucuronidase and cathepsin‐D in different fractions except cytosol. Pretreatment with CA (15 mg/kg) to ISO‐treated rats significantly (P < 0.05) prevented the changes in the activities of cardiac marker enzymes, the levels of lipid peroxidation products, reduced glutathione and the activities of lysosomal enzymes in the serum, heart, and subcellular fractions. Oral treatment with CA (15 mg/kg) to normal control rats did not show any significant effect. Thus, the results of our study showed that CA prevented the lysosomal membrane damage against ISO‐induced myocardial infarction. The observed effects of CA are due to membrane‐stabilizing, antilipo peroxidative, and antioxidant effects. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:115–122, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/jbt.20319     

Effect of carnitine administration on levels of lipid peroxides and activities of superoxide dismutase and catalase in isoproterenol-induced myocardial infarction in rats

The effect of carnitine administration on levels of lipid peroxide and activities of superoxide dismutase and catalase was studied in rats administered isoproterenol to induce myocardial infarction. Levels of fatty acid were lower in rats pretreated with carnitine at the peak period and given isoproterenol than the levels in isoproterenoltreated control rats. Lipid peroxides were decreased in the heart at peak infarction in carnitine-treated rats compared to the levels in isoproterenol-treated controls. Activities of superoxide dismutase and catalase showed no change in carnitine-treated animals given isoproterenol compared to those in normal control rats, while they decreased in animals treated with isoproterenol alone.     

Pyrrolidinyl caffeamide against ischemia/reperfusion injury in cardiomyocytes through AMPK/AKT pathways

Background

Coronary heart disease is a leading cause of death in the world and therapy to reduce injury is still needed. The uncoupling of glycolysis and glucose oxidation induces lactate accumulation during myocardial ischemia/reperfusion (I/R) injury. Cell death occurs and finally leads to myocardial infarction. Caffeic acid, one of the major phenolic constituents in nature, acts as an antioxidant. Pyrrolidinyl caffeamide (PLCA), a new derivative of caffeic acid, was synthesized by our team. We aimed to investigate the effect of PLCA on hypoxia/reoxygenation (H/R) in neonatal rat ventricular myocytes (NRVM) and on myocardial I/R in rats.

Results

Cardiomyocytes were isolated and subjected to 6 h hypoxia followed by 18 h reperfusion. PLCA (0.1 to 3 μM) and metformin (30 μM) were added before hypoxia was initiated. PLCA at 1 μM and metformin at 30 μM exerted similar effects on the improvement of cell viability and the alleviation of cell apoptosis in NRVM after H/R. PLCA promoted p-AMPK, p-AKT, and GLUT4 upregulation to induce a cardioprotective effect in both cell and animal model. The accumulation of cardiac lactate was attenuated by PLCA during myocardial I/R, and infarct size was smaller in rats treated with PLCA (1 mg/kg) than in those treated with caffeic acid (1 mg/kg).

Conclusions

AMPK and AKT are synergistically activated by PLCA, which lead facilities glucose utilization, thereby attenuating lactate accumulation and cell death. The cardioprotective dose of PLCA was lower than those of metformin and caffeic acid. We provide a new insight into this potential drug for the treatment of myocardial I/R injury.     

Combined effects of quercetin and α-tocopherol on lipids and glycoprotein components in isoproterenol induced myocardial infarcted Wistar rats

This study was aimed to evaluate the combined effects of quercetin and α-tocopherol on lipid metabolism and glycoprotein components in isoproterenol induced myocardial infarction in Wistar rats. Myocardial infarction in rats was induced by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) were given to rats as pretreatment for 14 days orally using an intragastric tube. Quercetin and α-tocopherol significantly reduced the levels of cholesterol, triglycerides and free fatty acids in the serum and heart and serum phospholipids and significantly increased the levels of heart phospholipids in isoproterenol induced rats. They also significantly decreased the activity of plasma and liver 3-hydroxy-3-methylglutaryl-coenzyme-A reductase and increased the activity of plasma and liver lecithin cholesterol acyl transferase in isoproterenol treated rats. In addition to this, they also significantly reduced the levels of hexose, hexosamine, fucose and sialic acid in the serum and heart of isoproterenol treated rats. Quercetin and α-tocopherol also showed significant decrease in plasma lipid peroxidation products (thiobarbituric acid reactive substances and lipid hydroperoxides). Pretreatment with quercetin alone and α-tocopherol alone showed significant effect in all the biochemical parameters in myocardial infarcted rats. But, combined pretreatment with quercetin and α-tocopherol normalized all the above mentioned biochemical parameters in isoproterenol treated myocardial infarction in rats. Thus, the experiment clearly showed that quercetin and α-tocopherol prevented the accumulation of lipids and glycoprotein components in myocardial infarcted rats by their anti-lipid peroxidative effect. This study also showed that combined pretreatment was better than single pretreatment.     

Protective effect of adenosine against a calcium paradox in the isolated frog heart.

The effect of adenosine on the calcium paradox in the isolated frog heart was studied. Addition of adenosine during calcium depletion protected the frog heart against a calcium paradox. This protective effect was indicated by reduced protein and creatine kinase release, maintenance of electrical activity, and recovery of mechanical activity during reperfusion. Tissue calcium determination results showed that adenosine protected frog myocardial cells by reducing the massive calcium influx during reperfusion possibly through an action on calcium channels. Adenosine exerted its action in a dose-dependent manner; a concentration of 10 microM adenosine provided maximum protection of myocardial cells against the calcium paradox damage. Higher concentrations of adenosine produced side effects on both electrical and mechanical activity. These results are discussed in terms of the possible mechanism involved in the protective effect of adenosine.     

Oxygen radicals in cardiac surgery

Most cardiac surgical procedures require the use of prolonged induced myocardial ischemia. Experimental models of global myocardial ischemia which mimic cardiac surgical techniques have been developed to investigate the possibility of oxygen free radical development during prolonged myocardial ischemia or upon reperfusion. In such experiments, various free radical scavenging agents, including superoxide dismutase, catalase, and mannitol, have been shown to improve the tolerance of the heart to protracted global ischemia. Use of these agents has improved cardiac functional recovery and has attenuated the biochemical and structural changes which occur due to prolonged ischemia and reflow. In a recently developed porcine experimental model, the effects of preexisting regional myocardial ischemia with superimposed global ischemia and reperfusion have been studied, with free radical scavenging agents administered in an attempt to reduce myocardial infarction and improve regional functional recovery. In most such studies completed to date, free radical scavenging agents have resulted in better myocardial preservation, suggesting, at least indirectly, that there may be an oxygen free radical-mediated component of the ischemia-reperfusion injury seen in such models. Techniques for directly measuring myocardial oxygen free radical levels may allow for early clarification of the development of such toxic species in the clinical cardiac surgical setting.     

MCI-186 (edaravone), a novel free radical scavenger, protects against acute autoimmune myocarditis in rats

In this study, we tested the hypothesis that MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one; edaravone), a novel free radical scavenger, protects against acute experimental autoimmune myocarditis (EAM) in rats by the radical scavenging action associated with the suppression of cytotoxic myocardial injury. Recent evidence suggests that oxidative stress may play a role in myocarditis. We administered MCI-186 intraperitoneally at 1, 3, and 10 mg.kg(-1).day(-1) to rats with EAM for 3 wk. The results were compared with untreated rats with EAM. MCI-186 treatment did not affect hemodynamics. MCI-186 treatment (3 and 10 mg.kg(-1).day(-1)) reduced the severity of myocarditis as assessed by comparing the heart-to-body weight ratio and pathological scores. Myocardial interleukin-1beta (IL-1beta)-positive cells and myocardial oxidative stress overload with DNA damage in rats with EAM given MCI-186 treatment were significantly less compared with those of the untreated rats with EAM. In addition, MCI-186 treatment decreased not only the myocardial protein carbonyl contents but also the myocardial thiobarbituric acid reactive substance products in rats with EAM. The formation of hydroxyl radicals in MCI-186-treated heart homogenates was decreased compared with untreated heart homogenates. Furthermore, cytotoxic activities of lymphocytes of rats with EAM treated with MCI-186 were significantly lower compared with those of the untreated rats with EAM. Hydroxyl radicals may be involved in the development of myocarditis. MCI-186 protects against acute EAM in rats associated with scavenging hydroxyl free radicals, resulting in the suppression of autoimmune-mediated myocardial damage associated with reduced oxidative stress state.