Isoproterenol-induced Cardiotoxicity In Rats Research Articles

Beta-glucan protects against isoproterenol-induced cardiac remodeling by regulating the ACE-AT1R axis and attenuates cardiac inflammation and apoptosis

Objective: To investigate the cardioprotective effect of beta-glucan against isoproterenol-induced cardiotoxicity in rats, and elucidate the underlying mechanism. Methods: Rats were orally pretreated with beta-glucan (40 mg/kg body weight) for 30 d, and isoproterenol (20 mg/100 g body weight) was administered on days 31 and 32. The effects of beta-glucan on markers of cardiac injury, hemodynamic changes, production of proinflammatory cytokines, and the corresponding mRNA expressions were evaluated. In addition, histological analysis was performed. Results: Pretreatment with beta-glucan prevented isoproterenol-induced cardiac injury by preserving the structural and functional integrity of the plasma membrane and attenuating the production of proinflammatory cytokines (NF-κB, TNF-α, IL-6, IL-Ιβ, and IFN-γ) in the heart. Moreover, beta-glucan significantly downregulated the mRNA expression of ACE, AT1R, TNF-α, IL-6, NF-κB, caspase-3, TLR-4, and Bax, and upregulated Bcl-2 in the heart. At the same time, pretreatment with beta-glucan alleviated myocardial damage as reflected in a reduction in myonecrosis, edema, and erythrocyte extravasation with almost imperceptible inflammation. Conclusions: Beta-glucan can protect against isoproterenol-induced cardiotoxicity by attenuating cardiac inflammation and apoptosis and regulating the ACE-AT1R axis, thereby preventing cardiac remodeling.

Gallic acid protects against isoproterenol-induced cardiotoxicity in rats.

Gallic acid (GA) is a polyphenolic agent with interesting pharmacological impacts on the cardiovascular system. The present study purposed to study the protective effects of GA at 25 and 50mg/kg against isoproterenol (ISO)-induced cardiac damage in ischemia/reperfusion (I/R) in rats. Male Wistar rats were randomly assigned into six groups: Control, Control treated with GA at 25mg/kg (GA25), Control treated with GA at 50mg/kg (GA50), Hypertrophic rats induced by ISO (ISO), Hypertrophic rats treated with GA at 25mg/kg (ISO+GA25), and Hypertrophic rats treated with GA at 50mg/kg (ISO+GA50). Heart isolation was performed to induce a cardiac I/R injury model. Cardiac hemodynamic parameters were recorded. Serum Lactate Dehydrogenase (LDH) and Creatine Kinase-MB (CK-MB) and cardiac Superoxide dismutases (SOD) levels were evaluated. The gene expression of Sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) was assessed. We found that GA at 50mg/kg was significantly increased cardiac function at post I/R period in ISO-induced hypertrophic hearts. Moreover, it suppressed cardiac hypertrophy, the serum LDH and CK-MB levels in ISO injected rats. Administration of GA at 50mg/kg was significantly increased SOD level and SERCA2a gene expression in the hypertrophic hearts. GA at 50mg/kg could improve cardiac performance possibly by increasing antioxidant defense enzymes, reducing cell damage, and enhancing SERCA2a gene expression in hypertrophic heart induced by ISO in I/R injury conditions.

Suppression of isoproterenol-induced cardiotoxicity in rats by raspberry ketone via activation of peroxisome proliferator activated receptor-α

The peroxisome proliferator-activated receptor-α (PPAR-α) controls the lipid and glucose metabolism and also affects inflammation, cell proliferation and apoptosis during cardiovascular disease. Raspberry ketone (RK) is a red raspberry (Rubusidaeus, Family-Rosaceae) plant constituent, which activates PPAR-α. This study was conducted to assess the cardioprotective action of RK against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups (six rats/group). Rats were orally administered with RK (50, 100 and 200 mg/kg, respectively) and fenofibrate (standard, 80 mg/kg) for 28 days and ISO was administered (85 mg/kg, subcutaneously) on 27th and 28th day. Administration of ISO in rats significantly altered hemodynamic and electrocardiogram patterns, total antioxidant capacity, PPAR-α, and apolipoprotein C-III levels. These myocardial aberrations were further confirmed during infarct size, heart weight to body weight ratio and immunohistochemical assessments (caspase-3 and nuclear factor-κB). RK pretreatment (100 and 200 mg/kg) significantly protected rats against oxidative stress, inflammation, and dyslipidemia caused by ISO as demonstrated by change in hemodynamic, biochemical and histological parameters. The results so obtained were quite comparable with fenofibrate. Moreover, RK was found to have binding affinity with PPAR-α, as confirmed by docking analysis. PPAR-α expression and concentration was also found increased in presence of RK which gave impression that RK probably showed cardioprotection via PPAR-α activation, however direct binding study of RK with PPAR-α is needed to confirm this assumption.

Attenuation of isoproterenol-induced cardiotoxicity in rats by Narirutin rich fraction from grape fruit

BackgroundOxidative 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. PurposeThis 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. MethodsAfter 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. ResultsIsoproterenol 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. ConclusionThus, present study provides evidences for efficacy of NRF against isoproterenol induced myocardial infarction in rats.

Paradoxical effects of atorvastatin in isoproterenol-induced cardiotoxicity in rats: Role of oxidative stress and inflammation

Atorvastatin (ATV) was previously shown to improve oxidative stress, inflammation and endothelial dysfunction in several experimental and clinical studies yet other studies have reported a pro-oxidant and damaging effect upon ATV administration. The present study was directed to investigate the effect of ATV pre- and post-treatment in isoproterenol (ISO)-induced cardiotoxicity in rats. Myocardial damage was induced by ISO (5 mg/kg/day, s.c.) for 1 week. ATV (10 mg/kg/day, p.o.) was given for 2 weeks starting 1 week before or after ISO administration. ISO-treated rats showed significant alterations in electrocardiographic recordings, serum creatine kinase-MB (CK-MB) level as well as oxidative stress and inflammatory biomarkers. Moreover, ISO administration resulted in endothelial dysfunction and significant histopathological damage. Pre-treatment with ATV aggravated ISO-induced cardiotoxicity. On the other hand, ATV post-treatment succeeded to significantly improve oxidative stress and inflammatory biomarkers, endothelial dysfunction and myocardial degeneration. These results suggest that ATV might produce a synergistic pro-oxidant effect if given before or along with another pro-oxidant (ISO). Thus, caution should be applied upon the use of statin as a prophylactic therapy for primary cardiovascular disease prevention.

Cardioprotective Effects of Astaxanthin against Isoproterenol-Induced Cardiotoxicity in Rats

Myocardial infarction (MI) is an important cause of mortality around the world. Isoproterenol (ISO) is a synthetic catecholamine found to cause toxicity leading to severe stress in the myocardium of experimental animals. The aim of the present article is to investigate cardioprotective activity of astaxanthin against ISO-induced cardiotoxicity in adult rats, in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Oral administration of astaxanthin at a concentration of 50 and 100 mg/kg b.wt. daily for 58 days showed a significant protection against-induced alteration in plasma and cardiac SOD, GPx, GSH and CAT as well as CK-MB, LDH, ALT and AST activities. In addition, astaxanthin reduced plasma CK-MB, LDH, ALT and AST as well as cardiac MDA and HP levels as compare to control group. In conclusion, astaxanthin renders resiliency against isoproterenol cardiotoxicity due to its antioxidant and free radical scavenging activity that might serve as novel adjuvant therapy with isoproterenol.

Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity

Cardiovascular diseases (CVDs) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent.

Effect of ginsenoside Rh1 on myocardial injury and heart function in isoproterenol-induced cardiotoxicity in rats

The present study was designed to investigate the effect of ginsenoside Rh1 on myocardial injury and heart function in isoproterenol-induced cardiotoxicity in rats. Sprague–Dawley rats were subcutaneously injected with isoproterenol (20 mg/kg). Cardiac marker enzymes in serum, antioxidative parameters and inflammatory cytokines in left ventricles were measured. Hemodynamic parameters were monitored and recorded as well. Histopathological examination of left ventricles was performed. It was found that creatine kinase-MB (CK-MB) activity and troponin T level in isoproterenol-treated rats were significantly increased. Isoproterenol caused declines of left ventricular systolic pressure, positive and negative maximal values of the first derivative of left ventricular pressure, and an elevation of left ventricular end diastolic pressure. Isoproterenol enhanced the content of malondialdehyde (MDA), tumor necrosis-α (TNF-α), interleukin-1β (IL-1β) and decreased the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) in left ventricles. Ginsenoside Rh1 significantly ameliorated myocardial injury and heart function impairment induced by isoproterenol. The cardioprotective effect of ginsenoside Rh1 was further confirmed by histopathological examination. Ginsenoside Rh1 also partially inhibited the increase of MDA, TNF-α, IL-1β contents and the decrease of SOD, catalase, and GSH-Px activities in left ventricles. The results indicated that ginsenoside Rh1 possessed the effect against isoproterenol-induced cardiotoxicity, and that the mechanism of pharmacological action was related to regulating the activities of SOD, catalase, and GSH-Px and decreasing the contents of TNF-α and IL-1β.

Combined Effects of Quercetin and Atenolol in Reducing Isoproterenol-Induced Cardiotoxicity in Rats: Possible Mediation Through Scavenging Free Radicals

In this investigation, combined effects of quercetin and atenolol in the regulation of isoproterenol (ISO)-induced cardiotoxicity have been evaluated in rats. While ISO administration increased the levels of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (SGPT) as well as cardiac malondialdehyde (MDA); it reduced the activities of superoxide dismutase, catalase, glutathione peroxidase and the level of reduced glutathione. ISO-induced rats also exhibited ST-segment elevation and tachycardia. Oral administration of atenolol (6mg/kg) and quercetin (5mg/kg), along with ISO (5mg/kg, subcutaneously) every day for 10days markedly reduced the serum CK-MB, LDH and SGPT levels. Concomitantly the test drugs improved the status of antioxidative enzymes, decreased the cardiac MDA and nearly normalized the electrocardiogram. Electron paramagnetic resonance study also revealed a decrease in 5,5'-dimethyl-1-pyroline-N-oxide-hydroxyl radicals signal intensity when atenolol and quercetin were administered together to ISO-treated rats. In conclusion, the combined treatment of atenolol and quercetin appears to produce a better cardioprotective effect in ISO-induced animals as compared to their individual treatments, and possibly the beneficial actions are associated with the free radical scavenging action of quercetin.

Seabuckthorn Attenuates Cardiac Dysfunction and Oxidative Stress in Isoproterenol-Induced Cardiotoxicity in Rats

We investigated the effects of seabuckthorn (SBT) oil in isoproterenol (ISO)-induced cardiotoxicity with reference to hemodynamic, antioxidant, histopathological, and ultrastructural parameters. Rats were administered SBT oil (5, 10, and 20 mL/kg per d) or vehicle orally for 30 days along with ISO (85 mg/kg, subcutaneously, at 24-hour interval) on 29th and 30th day. On 31st day, ISO control rats showed cardiac dysfunction, increased lipid peroxidation, depletion of cardiac injury marker enzymes, and antioxidant activities. Myocardial necrosis, edema, and inflammation were evident from the light microscopic and ultrastructural changes. Seabuckthorn oil at the dose of 20 mL/kg per d significantly modulates hemodynamic and antioxidant derangements. The preventive role of SBT oil on ISO-induced cardiotoxicity was reconfirmed by histopathological and ultrastructural examinations. Thus, the present study reveals that SBT oil mitigates myocardial damage in ISO-induced cardiac injury in rats by maintaining hemodynamic, biochemical, histopathological, and ultrastructural perturbations owing to its free radical scavenging and antioxidant activities.

Preventive effect of Crocus sativus L. stigma extract on biochemical, antioxidant and histopathological alterations in isoproterenol-induced cardiotoxicity in rats

Preventive effect of Crocus sativus L. stigma extract on biochemical, antioxidant and histopathological alterations in isoproterenol-induced cardiotoxicity in rats

N-acetylcysteine Offers Cardioprotection by Decreasing Cardiac Lipid Hydroperoxides and 8-Isoprostane Level in Isoproterenol-Induced Cardiotoxicity in Rats

This study investigated the cardioprotective effect of N-acetylcysteine (NAC) on isoproterenol (ISO)-induced cardiotoxicity in rats. Male Sprague-Dawley rats were divided into control, NAC alone (100mg/kg BW orally for 14days), ISO-control (85mg/kg BW), and ISO with NAC (for 14days). Serum creatine kinase-MB and Lactate dehydrogenase were measured. From the heart homogenate lipid hydroperoxides (LPO), superoxide dismutase (SOD), total glutathione (GSH), and 8-isoprostane (IP) were measured. Histopathological examination of the heart was also carried out. There was a significant increase (P<0.05) in LPO and IP levels in ISO-control group and NAC treatment reduced these changes. Antioxidant enzyme, SOD and GSH, level decreased significantly (P<0.05) in ISO-control group, and treatment with NAC was able to reverse these changes significantly (P<0.05). Histopathologically, ISO-control group showed morphological changes suggestive of cardiotoxicity with large areas of coagulative necrosis, with diffused interstitial edema. NAC treatment successfully reduced these histopathological changes. In conclusion, the study proves that NAC has a strong cardioprotective effect against isoproterenol-induced cardiac changes. NAC decreases isoproterenol-induced LPO and IP levels in the heart tissue and prevented free radicals-induced damage to the myocardium.

Effect of Piper betle on cardiac function, marker enzymes, and oxidative stress in isoproterenol-induced cardiotoxicity in rats

The present study was designed to investigate the cardioprotective potential of Piper betle (P. betle) against isoproterenol (ISP)-induced myocardial infarction in rats. Rats were randomly divided into eight groups viz. control, ISP, P. betle (75, 150, and 300 mg/kg) and P. betle (75, 150, and 300 mg/kg) + ISP treated group. P. betle leaf extract (75, 150, or 300 mg/kg) or saline was orally administered for 30 days. ISP (85 mg/kg, s.c.) was administered at an interval of 24 h on the 28th and 29th day and on day 30 the functional and biochemical parameters were measured. ISP administration showed a significant decrease in systolic, diastolic, mean arterial pressure (SAP, DAP, MAP), heart rate (HR), contractility (+LVdP/dt), and relaxation (−LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). ISP also caused significant decrease in myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), and myocyte injury marker enzymes; creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) along with enhanced lipid peroxidation; thiobarbituric acid reacting species (TBARS) in heart. Pre-treatment with P. betle favorably modulated hemodynamic (SAP, DAP, and MAP) and ventricular function parameters (−LVdP/dt and LVEDP). P. betle pre-treatment also restored SOD, CAT, GSH, and GPx, reduced the leakage of CK-MB isoenzyme and LDH along with decreased lipid peroxidation in the heart. Taken together, the biochemical and functional parameters indicate that P. betle 150 and 300 mg/kg has a significant cardioprotective effect against ISP-induced myocardial infarction. Results of the present study suggest the cardioprotective potential of P. betle.

Cardioprotective effect of matrine on isoproterenol-induced cardiotoxicity in rats

This study was designed to explore the effect and mechanism of matrine, an active component of Chinese traditional medicine, on isoproterenol-induced acute cardiotoxicity in rats. Acute myocardial injury was induced in rats by daily subcutaneous injection of isoproterenol (85 mg/kg) for two days. Haemodynamic and biochemical parameters were measured and histopathological examination was performed. Chronic oral administration of matrine (50, 100 or 200 mg/kg per day for 10 days) significantly reduced the release of lactic dehydrogenase, glutamic oxaloacetic transaminase and creatine kinase after isoproterenol-induced myocardial ischaemic injury, improved the left ventricular (LV) dysfunction, including increased LV systolic pressure (LVSP), maximum rate of developed LV pressure (LV dP/dt(max)) and minimum rate of developed LV pressure (LV dP/dt(min)), increased the activity of superoxide dismutase, catalase and glutathione peroxidase, and also decreased the content of the lipid peroxidation product malondialdehyde in plasma and myocardial tissues in rats. Acute oral administration of matrine at a dose of 100 or 200 mg/kg for two days also had a cardioprotective effect on this rat model. The protective role of matrine on isoproterenol-induced myocardial damage was further confirmed by histopathological examination. There were no significant changes in heart rate and blood pressure in all experimental groups. Our results suggest that matrine has a significant cardioprotection against isoproterenol-induced cardiotoxicity through its antioxidant property.

Preventive effect of crocin of Crocus sativus on hemodynamic, biochemical, histopathological and ultrastuctural alterations in isoproterenol-induced cardiotoxicity in rats

We investigated the effects of crocin, a pharmacologically active constituent of Crocus sativus L., in isoproterenol (ISO)-induced cardiotoxicity with reference to hemodynamic, antioxidant, histopathological and ultrastructural parameters. Rats were administered crocin (5, 10 and 20mg/kg/day) or vehicle orally for 21 days along with ISO (85mg/kg, subcutaneously, at 24h interval) on 20th and 21st day. On 22nd day ISO-control rats showed cardiac dysfunction as indicated by lowering of systolic, diastolic and mean arterial blood pressures. In addition, a significant decrease in maximum positive and negative rate of developed left ventricular pressure (+/-LVdp/dt(max)) and an increase in left ventricular end-diastolic pressure (LVEDP) were observed. Furthermore, a marked reduction in the activities of myocardial creatine kinase-MB (CK-MB) isoenzyme, lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) levels along with an increase in content of malondialdehyde (MDA) were observed. Myocardial necrosis, edema and inflammation were evident from the light microscopic and ultrastructural changes. Crocin at the dose of 20mg/kg/day significantly modulated hemodynamic and antioxidant derangements. The preventive role of crocin on ISO-induced MI was reconfirmed by histopathological and ultrastructural examinations. The effect at the dose of 20mg/kg/day of crocin was more pronounced than that of other two doses (5 and 10mg/kg/day). The results suggest that crocin may have cardioprotective effect in ISO-induced cardiac toxicity through modulation of oxidative stress in such a way that maintains the redox status of the cell.

Preventive effect of S-allylcysteine on lipid peroxides and antioxidants in normal and isoproterenol-induced cardiotoxicity in rats: A histopathological study

The consumption of diets rich in plant foods are associated with a reduced risk of cardiovascular diseases. This study was aimed to evaluate the role of S-allylcysteine (SAC) in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Subcutaneous injection of ISO (150 mg/kg) to Wistar rats showed a significant decrease in the activities of marker enzymes such as creatine kinase, lactate dehydrogenase, aspartate and alanine transaminases in heart and a significant increase in the levels of thiobarbituric acid reactive substances and lipid hydroperoxides in plasma and heart. ISO-induced rats also showed a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase in heart and the levels of glutathione and ascorbic acid in plasma and heart. Oral administration of SAC (100 and 150 mg/kg) to ISO-treated rats daily for a period of 45 days caused a significant increase in the activities of marker enzymes and improved the antioxidant status by decreasing lipid peroxidative products and increasing the activities of antioxidant enzymes and the levels of nonenzyomic antioxidants. Administration of SAC to normal rats did not show any significant effect. Histopathological findings of the myocardial tissue showed a protective role of SAC in ISO-treated rats. The effect at a dose of 150 mg/kg of SAC was more pronounced than that of the dose 100 mg/kg and brought back all the parameters to near normal. The effect exerted by 100 mg/kg of SAC was similar to that of α-tocopherol (60 mg/kg). The results of our study show that SAC possesses antioxidant activity in ISO-induced experimental MI.