Isoproterenol-induced Myocardial Necrosis Research Articles

Arglabin: A mediator of inflammasome modulated and independent myocardial injury (PARA-AMI study)

BackgroundArglabin is a plant alkaloid (sesquiterpene lactone) that is used as an anticancer drug. It has potential anti-diabetic and anti-atherogenic effects. PurposeArglabin has drawn particular attention because of its therapeutic effects as an anti-inflammatory agent in multiple diseases. Since arglabin inhibits Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, concerns for cardiotoxic effects are valid. The present study was designed to investigate the protective effects of arglabin on the myocardium. Study designThis study was designed to evaluate the effect of arglabin on the myocardium in an experimental model of myocardial necrosis in rats. Different doses of arglabin (2.5, 5, and 10 μg/kg) were investigated as pre-treatment for 21 days in the isoproterenol (ISO) model of myocardial necrosis groups and per se groups. MethodsOn the 22nd day, hemodynamic, histopathological, electron microscopy, oxidative stress markers, inflammatory mediators, apoptotic markers, inflammasome mediators, and Western blot analysis were performed to evaluate the effects of arglabin. ResultsArglabin pre-treatment showed improvement in hemodynamic parameters and histopathological findings at low doses in isoproterenol-induced myocardial necrosis model of rats. Arglabin administration altered myocardial structure and modulated myocardial function via activation of NFκB/MAPK pathway that led to myocardial injury with an increase in dose. ConclusionArglabin imparted partial cardio-protection via an inflammasome-dependent pathway and mediated injury through the inflammasome-independent pathway.

Cardioprotective effects of Callicarpa tomentosa leaf extract in Wistar albino rats against isoproterenol-induced myocardial necrosis: Phytochemical analysis and in vitro antioxidant study

BackgroundGlobally, cardiovascular disease (CVD) remains the foremost cause of mortality. Conventional medications are associated with several complications, necessitating an alternative, safe and efficacious medicine. Therefore, the study was planned to assess the cardioprotective efficacy of Callicarpa tomentosa (CT) leaf extract against isoproterenol (ISO)-induced myocardial failure in experimental rats. Materials and methodsCT leaf extract was subjected to phytochemical analysis, total phenolic and flavonoid content measurement, and in vitro antioxidant evaluation. Additionally, the protection from myocardial injury was evaluated based on the estimation of biomarkers including CK-MB, CKNAC, and LDH in both the low-dose (200 mg/kg) and high-dose (400 mg/kg) groups of rats. We measured endogenous antioxidants in heart tissue to estimate the antioxidant potential. Histopathological analysis confirmed the biochemical results. ResultsThe findings of this study indicated that the CT leaf extract contained several phytoconstituents such as alkaloids, flavonoids, steroids and triterpenoids, cardiac glycosides, carbohydrates, phenols, saponins, and tannins. The CT's total phenol content was 33.3 ± 0.14 mg GAE (Gallic Acid Equivalent) per gram of extract, while its total flavonoid concentration was 76.5 ± 1.2 mg QUE (Quercetin Equivalent). In the DPPH assay, CT had a mean inhibitory effect of 60.06 ± 1.358 g/ml, whereas its IC50 in the H2O2 radical scavenging activity assay was 102.85 ± 0.194 g/ml. The electrocardiograms of the treated animals demonstrated considerable recovery from ISO-induced electrophysiological abnormalities as well and the amount of endogenous biomarkers was significantly reduced in animals that receivedCT treatment. Additionally, the use of CT reversed the effects of ISO administration on SOD activity, increased GSH levels, and lowered LPO levels. The damage to the heart tissues was significantly reduced, with the tissue architecture appearing closer to normal in groups that received high doses of CT. ConclusionThese results suggest that C. tomentosa leaf extract has potent antioxidant activity and provides protection against isoproterenol-induced cardiac necrosis in Wistar albino rats. The cardioprotectivebenefits are attributed to the presence of active components in the extract, which aid in the restoration of antioxidant equilibrium and the reduction of damage caused by oxidative stress.

Protective role of wild garlic on isoproterenol-induced myocardial necrosis in wistar rats

Ethnopharmacological relevanceTulbaghia violacea Harv. (TVL) is a folk medicine, native to South Africa which has previously shown antioxidant, anti-hypertensive and anti-diabetic effects. The Aim of the study: The aim of the current study was to investigate the protective role of wild garlic or TVL on isoproterenol (ISO)-induced myocardial necrosis in rats. Materials and methodsAnimal (n = 6 each group) were pre and co-treated with TVL (60 mg/kg body weight) daily for 30 days. Myocardial necrosis was administrated by subcutaneous injection of ISO (85 mg/kg body weight) into rats on 29th and 30th day. On the 31st day, rats were anaesthetized and blood, heart samples were obtained for the biochemical, histopathological and molecular study. The specific protein target analysis from TVL was done by reverse docking study (reverse pharmacophore mapping) using PharmMapper. ResultsThe levels of cardiac markers, lipid peroxidation products, and heart rate were considerably increased in ISO-induced myocardial necrosis in rats whilst plasma enzymatic antioxidants were significantly decreased. Myocardial necrotic mRNA genes were increased in ISO-induced myocardial necrosis in rats compared to controls. Pre and co-treatment with TVL and ramipril of myocardial necrosis in rats showed significant effects on all the biochemical and molecular studies evaluated. TVL reduced heart rate, prevented oxidative stress and downregulated the Fas-receptor and caspase-mediated apoptosis-signaling pathway, and heart muscle damage in myocardial necrosis in rats. The specific target protein [disulfide, bis (2-sulfhydrylethyl] from TVL mediates the protective effects. ConclusionWild garlic or TVL extract has shown a protective effect on ISO-induced myocardial necrosis in rats by increasing antioxidant production confirmed with docking studies.

Inhibition of PKCβ Mediates Cardioprotective Activity of Ambrex against Isoproterenol-Induced Myocardial Necrosis: in vivo and in silico Studies

Aims and objectives: The current study characterized the morphology of Ambrex formulation by Scanning Electron Microscopy and assessed its cardioprotective activity against Isoproterenol (ISPH)-induced myocardial necrosis in rats by biochemical and histopathological evaluations, and also attempted to predict the prospective protein-targets of Ambrex and the signaling pathway that mediates this activity through molecular docking approach. Materials and methods: Sprague–Dawley male rats (4 groups, 6 rats per group) chosen for the current study were acclimatized to the laboratory conditions for 7 days prior to actual treatment; they were pretreated with Ambrex (40 mg/kg b.wt/day, p.o) everday for 21 days and then intoxicated with ISPH (85 mg/kg b.wt, s.c) on day-20 and 21 to experimentally induce myocardial necrosis. The extent of ISPH-induced myocardial necrosis was quantified in terms of the serum levels of two cardiac biomarkers: creatine kinase-MB and lactate dehydrogenase. The extent of ISPH-induced oxidative stress was quantified in terms of the tissue levels of five oxidative stress biomarkers: superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase and lipid peroxidation. Results and discussion: The Scanning Electron Microscopy image of Ambrex formulation showed the formation of nanoparticles with thickness of 65 nm, making Ambrex a unique metal-deficient Siddha-medicine based polyherbal nano-formulation characterized and evaluated in India. Pretreatment with Ambrex attenuated the extent of ISPH-induced oxidative stress, lipid peroxidation and generation of reactive oxygen species as reflected by biochemical evaluations, and also ameliorated the degree of ISPH-induced myocardial necrosis and membrane damage as reflected by histopathological evaluations. The results of molecular docking revealed that Withaferin-A and Methyl Commate-A (the key metabolites of Withania somnifera and Ambrex respectively) inhibit Protein KinaseC Beta, and renders Ambrex its cardioprotective activity by maintaining the intracellular antioxidant homeostasis and myocardial membrane architecture.

Cardioprotective effect of Vitex negundo on isoproterenol-induced myocardial necrosis in wistar rats: A dual approach study

Cardiovascular diseases (CVDs) are becoming the major cause of deaths worldwide, and their treatment demands novel therapeutic strategies. In this connection, we have identified p21 activated kinase 1 (PAK1) as a novel therapeutic target for the treatment of myocardial infarction (MI), where its expression is decreased when MI is induced with isoproterenol (ISO), which was brought back normal with pretreatment of Vitex negundo leaf ethanolic extract (VNE). These results were also supported by histopathological studies, cardiac markers, antioxidants, and inflammatory cytokines (NF-κB and IL-1β). Further studies with GC–MS analysis of VNE and in silico experiments confirmed 5,7-dihydroxy-6,4′,-dimethoxy flavonone and 3′,5-dihydroxy-6,7,4′,-trimethoxyflavone are responsible for either maintaining or inducing the expression of PAK1 to protect from MI. Our findings for the first time revealed the use of phytoconstituents in the treatment of MI.

Cardioprotective effect of vincristine on isoproterenol-induced myocardial necrosis in rats

This study investigated the protective effect of vincristine (VCR) on isoproterenol (ISO)-induced cardiac necrosis (CN) in rats. Animals (n=7 in each group) were pretreated with vincristine (25µg/kg) intraperitoneal (i.p.) daily in 5-day cycles with 2 days pause between cycles using a 5-day-on, 2-day-off schedule for two weeks and then intoxicated with isoproterenol (100mg/kg, s.c., for 2 consecutive days). ISO-induced myocardial damage was indicated by changes in electrocardiographic (ECG) patterns, increased activities of marker enzymes such as creatine kinase-MB, serum glutamate pyruvate transaminase and lactate dehydrogenase and the levels of troponin-T in the serum. The levels of lipid peroxide products, (thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (HP)) were increased with a parallel decrease in the activities of antioxidants (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione) in ISO-induced rats. Furthermore, ISO-induced rats showed increase in the activities of membrane bound enzymes such as Ca2+-ATPase and Mg2+-ATPase with a decreased activity of Na+/K+-ATPase. Triphenyl tetrazolium chloride (TTC) staining of the heart section showed increased area of necrosis in ISO-induced rats. Pretreatment with VCR (25µg/kg) eliminated all ISO-induced biochemical and histopathological changes, and decreased the myocardial necrosis to a greater extent. Transmission electron microscopic findings on the structure of the heart mitochondria confirmed the protective effects of VCR. Present study provides first scientific report on protective effect of vincristine against ISO-induced cardiac damage in rats.

Cardioprotective effect of ritonavir, an antiviral drug, in isoproterenol induced myocardial necrosis: a new therapeutic implication

BackgroundRitonavir is a HIV protease inhibitor. In addition to its antiviral effect, Ritonavir directly inhibits the insulin-regulated glucose transporter GLUT4 and blocks glucose entry into fat and muscle cells. However, the effect of Ritonavir on cardiac GLUT4 inhibition during myocardial necrosis is not investigated. In the present study, we evaluated the role of Ritonavir in isoproterenol-induced myocardial necrosis in vivo and compared the effect with Phlorizin, a nonslective SGLTs inhibitor.MethodsIsoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) was administered to mice to cause myocardial necrosis. Phlorizin (400 mg/kg/day i.p twice daily for 2 days) and Ritonavir (10 mg/kg/day i.p twice daily for 2 days) were administered in two different groups of mice before isoproterenol administration.Results and discussionIsoproterenol (ISO) (150 mg/kg/day, i.p for 2 consecutive days) administration caused significant (p < 0.05) increase in heart/body weight ratio, and myocardial necrosis as evident by significant (p < 0.05) increase in serum markers i.e. SGOT and CK; and cardiac histopathological changes. Significant (p < 0.05) reduction in myocardial SOD and catalase activities, and GSH level along with a significant (p < 0.05) rise in myocardial TBARS and nitric oxide levels were observed after ISO administration. However, administration of phlorizin, a SGLT1 inhibitor has been found to exhibit partial protection in ISO induced myocardial necrosis, as observed by significant decrease in heart/body weight ratio and myocardial nitric oxide level; significant increase in myocardial SOD and catalase activities along with no histopathological alterations. On the other hand, administration of ritonavir, a nonspecific GLUT inhibitor has been found to exhibit complete protection as observed by normalisation of heart/body weight ratio, serum markers, antioxidant enzymes activities and histopathological alterations. In vitro study with heart homogenate confirmed no antioxidant effect of ritonavir and phlorizin in the absence and presence of isoproterenol.ConclusionsOur study concluded that ritonavir, a nonspecific GLUT inhibitors showed complete protection in catecholamine induced myocardial necrosis.

Formulation and evaluation of transdermal patches of papaverine hydrochloride

Transdermal patches of papaverine hydrochloride were prepared by the solvent casting method using ethyl cellulose: PVP, PVA: PVP and Eudragit RL-100: Eudragit RS-100 using different ratios. The physicochemical parameters such as flexibility, thickness, smoothness, weight variation, moisture content, hardness and tensile strength were evaluated for the prepared patches. The formulation exhibited flexibility, uniform thickness and weight, smoothness, good drug content (92 to 96%), and little moisture content. The in vitro diffusion studies were carried out using modified Keshery-Chein cell using cellophane as the diffusion membrane and the formulation followed the Higuchi diffusion mechanism. The formulation containing PVA: PVP as polymers showed faster release rate (hydrophilic polymers) compared to Eudragit RL-100: Eudragit RS-100 (hydrophobic polymers) or combination of hydrophilic and hydrophobic polymers (ethyl cellulose and PVP). The stability studies indicated that all the patches maintained good physicochemical properties and drug content after storing the patches in different storage conditions. Compatibility studies indicated that there was no interaction between the drug and polymers. In vivo studies showed that papaverine hydrochloride helps in decreasing the effect of isoproterenol-induced myocardial necrosis. Hence, the aim of the present study was to prepare the sustained release formulation (Transdermal patches) of the drug using different blend of polymers. The formulated patches containing the hydroplilic polymers showed best release rate of drug. Key words: Eudragit RL-100, eudragit RS-100, in vivo study, papaverine hydrochloride, transdermal patch

Mitigation of mitochondrial dysfunction and regulation of eNOS expression during experimental myocardial necrosis by alpha-mangostin, a xanthonic derivative from Garcinia mangostana

Oxidative stress can play a key role in myocardial necrosis. The present study was designed to investigate the effect of alpha-mangostin (an antioxidant phytonutrient) on mitochondrial dysfunction and endothelial nitric oxide synthase (eNOS) expression during isoproterenol-induced myocardial necrosis in rats. Induction of rats with isoproterenol (ISO) (150 mg/kg body weight, intraperitoneally) for 2 days resulted in a significant decrease in the activities of respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase), tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase), mitochondrial antioxidants (GPx, GST, SOD, CAT, and GSH), mitochondrial cytochromes (b, c, c1, and aa3), and adenosine triphosphate level. A marked elevation in mitochondrial lipid peroxidation was also observed in ISO-intoxicated rats. Pretreatment with alpha-mangostin (200 mg/kg body weight) orally for 8 days significantly attenuated these functional abnormalities and restored normal mitochondrial function, when compared to the ISO-intoxicated group of rats. Cardiac eNOS expression was assessed by Western blot. Cardiac eNOS expression and NO level were significantly suppressed in ISO-intoxicated rats. Pretreatment with alpha-mangostin extenuated ISO-induced diminution of eNOS expression and NO level. Transmission electron microscopic observations also correlated with these biochemical parameters. Hence, these findings conclude the ameliorative potential of alpha-mangostin against ISO-induced biochemical and morphological changes in mitochondria, which might be mediated through the NO pathway and by its ability at quenching free radicals.

Cardioprotective effect of ‘Khamira Abresham Hakim Arshad Wala’ a Unani formulation in isoproterenol-induced myocardial necrosis in rats

The present study was designed to investigate whether Khamira Abresham Hakim Arshad Wala (KAHAW), a preparation of Unani System of Medicine, is able to attenuate the isoproterenol (ISO)-induced myocardial necrosis on the basis of its effects on hemodynamic, antioxidant, histopathological and ultrastructural parameters. Male Wistar albino rats were administered KAHAW (200, 400 and 800 mg/kg/day, orally) or vehicle for 14 days with concurrent ISO administration (85 mg/kg, subcutaneously, 2 doses at 24 h interval) on 13th and 14th day. On the 15th day, vehicle+ISO-treated rats exhibit cardiac dysfunctions as indicated by decrease in systolic, diastolic, and mean arterial pressures, reduction in both maximum positive and maximum negative rates of developed left ventricular pressure (±LVdp/dt) and an increase in left ventricular end-diastolic pressure (LVEDP). Biochemical analysis of their heart homogenate presented reduced levels of enzymes viz., superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) isoenzyme. A marked reduction in reduced glutathione (GSH) levels along with increase in levels of thiobarbituric acid reactive substances (TBARS) was also observed in rat myocardium. Myocardial necrosis, edema and inflammation were evident from the light microscopic and ultrastructural changes. KAHAW at dose of 800 mg/kg/day significantly reversed majority of hemodynamic and antioxidant derangements. The protective role of KAHAW on ISO-induced myocardial necrosis was further confirmed by histopathological and ultrastructural examination. There was no significant change in heart rate in all experimental groups. KAHAW per se groups showed no significant change when compared with vehicle control group. The study results thus demonstrated the cardioprotective potential of KAHAW against ISO-induced myocardial necrosis and associated oxidative stress.

Cardioprotective activity of Ginkgo biloba Phytosomes in isoproterenol-induced myocardial necrosis in rats: A biochemical and histoarchitectural evaluation

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 200 mg/kg of ISO administered subcutaneously (sc) twice at an interval of 24 h. An ISO dose of 85 mg/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 (100 mg and 200 mg/kg body weight) was evaluated against ISO (85 mg/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.

Temporal Gene Expression Profiling Indicates Early Up-regulation of Interleukin-6 in Isoproterenol-induced Myocardial Necrosis in Rat

Gene expression was evaluated in the myocardium of male Wistar rats after a single subcutaneous administration of 0.5 mg of isoproterenol, a beta-adrenergic agonist that causes acute tachycardia with subsequent myocardial necrosis. Histology of the heart, clinical chemistry, and hematology were evaluated at 9 time points (0.5 hours to 14 days postinjection). Myocardial gene expression was evaluated at 4 time points (1 hour to 3 days). Contraction bands and loss of cross-striation were identified on phosphotungstic acid-hematoxylin-stained sections 0.5 hours postdosing. Plasma troponin I elevation was detected at 0.5 hours, peaked at 3 hours, and returned to baseline values at 3 days postdosing. Interleukin 6 (Il6) expression spiked at 1 to 3 hours and was followed by a short-lived, time-dependent dysregulation of its downstream targets. Concurrently and consistent with the kinetics of the histologic findings, many pathways indicative of necrosis/apoptosis (p38 mitogen-activated protein kinase [MAPK] signaling, NF-kappaB signaling) and adaptation to hypertension (PPAR signaling) were overrepresented at 3 hours. The 1-day and 3-day time points indicated an adaptive response, with down-regulation of the fatty acid metabolism pathway, up-regulation of the fetal gene program, and superimposed inflammation and repair at 3 days. These results suggest early involvement of Il6 in isoproterenol-induced myocardial necrosis and emphasize the value of early time points in transcriptomic studies.

Cardioprotective response to chronic administration of vitamin E in isoproterenol induced myocardial necrosis: Hemodynamic, biochemical and ultrastructural studies

The present study evaluated the cardioprotective potential of vitamin-E by studying its effect on hemodynamic parameters, lipid peroxidation, myocyte injury marker and ultrastructural changes in model of isoproterenol-induced myocardial necrosis in rats. Wistar albino male rats (150-200 g) were randomly divided into saline, ISP control, and vit E groups. Vitamin E group was administered vitamin E at a dose of 100mg/kg/day while saline and ISP control groups received saline orally for one month. On 29(th) and 30(th) day, ISP (85 mg/kg, sc) was administered at an interval of 24 h to vit E and ISP control rats. On 31(st) day, rats of all groups were anesthetized and hemodynamic parameters were recorded. At the end of experimentation, animals were sacrificed; hearts were excised and processed for biochemical and ultrastructural studies. ISP administration produced marked cardiac necrosis as evidenced by significant decrease in my ocardial creatine kinase-MB as well as increase in malonaldialdehyde levels. ISP-induced myocardial necrosis resulted in myocardial dysfunction as evidenced by significant depression in heart rate and mean arterial pressure in the ISP control group as compared to saline control. Salient ultrastructural changes including extensive loss of myofibrils, muscle necrosis, loss of mitochondria, and formation of several intracytoplasmic vacuoles and lipid droplets further confirmed the ISP-induced myocardial damage. However, subsequent to ISP challenge, vit E treatment significantly preserved the myocardium by restoring myocardial CK-MB activity, inhibiting the ISP-induced lipid peroxidation and ultrastructural changes. Additionally, pre-and co-treatment of vit E prevented the deleterious ultrastructural changes caused by ISP. These beneficial effects of chronic vit E treatment also translated into significant restoration of the altered hemodynamic parameters. The present study clearly demonstrated the cardioprotective potential of vit E at dose of 100 mg/kg in ISP-induced model of myocardial necrosis in rats. The significant restoration of altered hemodynamic parameters, myocardial CK-MB activity, prevention of ISP-induced rise in lipid peroxidation and ultrastructural changes may confirm its cardioprotective effect.

Dietary palm olein oil augments cardiac antioxidant enzymes and protects against isoproterenol-induced myocardial necrosis in rats

Wistar rats, 150-200 g, of either sex, were fed daily with commercial rat diet supplemented with palm olein oil in two doses (5% v/w (n = 16) and 10% v/w (n = 16) of diet) for 30 days. Control rats (n = 16) were fed with normal diet. On the 29(th) and 30(th) days, 8 rats from each group were administred isoproterenol (85 mg/kg, s.c., 24-h interval). On the 31(st) day, all rats were sacrificed and myocardial tissues were studied for thiobarbituric acid reactive substances (TBARS), antioxidant enzymes and light microscopic changes, along with the ferric-reducing ability of plasma (FRAP). A significant rise in myocardial superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activity and FRAP level were observed in rats fed with palm olein oil. Isoproterenol caused an increase in myocardial oxidative stress in control rats, as evidenced by an increase in myocardial TBARS level, reduction in FRAP and myocardial SOD, catalase and GPx activity, along with focal necrosis of cardiac muscle fibres on light microscopy. The rise in myocardial TBARS and depletion of SOD and catalase activity following isoproterenol administration were prevented in palm-olein-oil-supplemented diet-fed rats at both doses. Isoproterenol-induced myocardial light-microscopic changes were also prevented in the treated groups. The results suggest that dietary palm olein oil caused augmentation of myocardial antioxidant enzymes and protected against isoproterenol-induced myocardial necrosis and associated oxidative stress.

Chronic oral administration of Ocimum sanctum Linn. augments cardiac endogenous antioxidants and prevents isoproterenol-induced myocardial necrosis in rats

Wistar rats (200-250 g) of either sex were fed with fresh leaf homogenate of Ocimum sanctum by oral gavage in two different doses, 50 mg kg-1(Os 50) and 100 mg kg-1 (Os 100), daily for 30 days. This was followed by isoproterenol administration (85 mg kg-1 s.c. two doses at 24h intervals) in both control and 0. sanctum-fed rats to induce myocardial necrosis. Hearts were isolated for estimation of endogenous myocardial antioxidants (superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and glutathione peroxidase (GPx) and myocardial lipid peroxidation) and light microscopic study. Increased basal myocardial antioxidant SOD (9.3 +/- 1.2 vs 3.7 +/- 0.7 units mg-1 protein; P<0.05) and catalase activities (34.3 +/- 5.4 vs 17.9 +/- 5.1 units mg-1 protein; P< 0.05) were observed in the Os 50 group only without any evidence of cellular injury in both the groups. In control rats, isoproterenol administration caused significant depletion of myocardial SOD (1.7 +/- 0.2 units mg-1 protein) and GPx (104 +/- 2mU mg-1 protein) activities and increase in GSH (551.7 +/- 30.9, microg g-1 wet weight of tissue) level, with evidence of myocardial necrosis. Isoproterenol-induced changes in myocardial SOD, GPx and GSH were prevented by both the doses of 0. sanctum, however cellular injury was minimal only with 50mg kg-1. The results indicate that long-term feeding of 0. sanctum offered significant protection against isoproterenol-induced myocardial necrosis through a unique property of enhancement of endogenous antioxidants.

Effect of garlic ( Allium sativum) on lipid peroxidation in experimental myocardial infarction in rats

The present study was conducted to elucidate the antioxidant role of garlic oil in isoproterenol (IPL)-induced myocardial infarction in rats. In myocardial necrosis induced by isoproterenol, a significant increase in serum iron content with a significant decrease in plasma iron binding capacity, ceruloplasmin activity and glutathione (GSH) level were observed. There was also a significant increase in lipid peroxides levels on isoproterenol administration. Activities of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione- S-transferase (GST) and glutathione reductase (GRD) were decreased significantly in heart with isoproterenol-induced myocardial necrosis. Garlic oil produced a marked reversal of these metabolic changes related to myocardial infarction induced by isoproterenol. In conclusion, garlic oil exerts its effects by modulating lipid peroxidation and enhancing antioxidant and detoxifying enzyme systems.

Chronic oral administration of raw garlic protects against isoproterenol-induced myocardial necrosis in rat

Wistar albino rats (150–200 g) were fed raw garlic homogenate orally in three different doses (125, 250, 500 mg/kg/day) for 30 days. Isoproterenol (85 mg/kg, s.c. 2 doses at 24-h interval, animals sacrificed after 24 h of last injection) induced myocardial necrosis in control rats and after 30 days of garlic feeding. Myocardial oxidative stress was evident following isoproterenol administration by reduction in myocardial superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities along with a rise in plasma thiobarbituric acid reactive substances (TBARS). Myocardial necrosis was evident from the light microscopic and ultrastructural changes, along with a rise in plasma lactate dehydrogenase (LDH). Significant preservation of myocardial SOD activity was observed in all the garlic-fed rats. However, there was no significant change in myocardial reduced glutathione level and GPx activity in any of the treated groups. Significant reduction in plasma TBARS and LDH levels was observed in the 500 mg/kg garlic treated group. Isoproterenol-induced myocardial morphological changes were least in the 250 and 500 mg/kg garlic treated groups. The results suggest that chronic oral administration of raw garlic offered protection against isoproterenol-induced myocardial necrosis and associated oxidative stress.

Effect of D-003 on isoproterenol-induced myocardial necrosis in rats.

D-003 is a mixture of high-molecular-weight aliphatic primary acids purified from sugar cane wax with antiplatelet and cholesterol-lowering effects. Cardiac lesions induced by isoproterenol (ISO) are characterized by myocardial necrosis and exudative infiltration. The objective of this study was to determine whether D-003 shows protective effects against ISO-induced myocardial necrosis in rats. Effects of orally administered single doses of D-003 (25-400 mg/kg) and acetylsalicylic acid (ASA, 30 mg/kg), as well as repeated doses of D-003 (5-200 mg/kg), on characteristic markers of ISO-induced myocardial necrosis in rats were investigated. D-003 administered as single doses dose-dependently decreased necrosis area, percent of infarct area, and the presence of polymorphonuclear cells (PMNs) in myocardial tissue, but only the reductions induced by 200 and 400 mg/kg were significant. Oral acute treatment with ASA also decreased necrosis area and percent of infarct area, but the occurrence of PMNs was unchanged. D-003 administered repeatedly for 10 days also decreased all myocardial necrosis indicators in a dose-dependent manner, with results effective from 25 mg/kg to the highest dose tested, indicating that the repeated dose scheme was more effective to prevent the damage. It is concluded that D-003 shows a protective effect on the myocardial necrosis induced by ISO in rats.

Antioxidant Potential of a Novel Tetrapeptide Derivative in Isoproterenol-Induced Myocardial Necrosis in Rats

A novel tetrapeptide derivative Boc-Lys(Boc)-Arg-Asp-Ser(tbu)-OtBu (PEP1261) has been tested in vivo in isoproterenol (ISO) hydrochloride (HCl)-induced myocardial necrosis in rats. ISO·HCl induces myocardial necrosis in rats which is accompanied by the distinct increase in heart weight, marked electrocardiographic changes, increase in the levels of serum marker enzymes and lipid peroxides and decrease in the levels of antioxidants. PEP1261 (5 mg/kg body weight i.p.) pre- and post-treatment effectively decreases serum marker enzyme levels, while the electrocardiographic changes get restored towards normalcy. PEP1261 also inhibits the action of the free radicals toxicity by increasing the levels of antioxidants and histological studies confirm the above findings. This study shows that PEP1261 could serve as an excellent cardioprotective agent possessing membrane-stabilizing action.

Effect of left ventricular sphericity on the evolution of ventricular dysfunction in rats with diffuse isoproterenol-induced myocardial necrosis

Background: Previous studies in heart failure have suggested that increased left ventricular (LV) sphericity is a precursor to hemodynamic deterioration, although these studies have predominantly used models with segmental damage due to coronary vessel occlusion and have only made baseline assessments of LV function. The purpose of this study was to examine the relationship between LV geometry and hemodynamic compromise through time in heart failure due to graded, diffuse myocardial injury with a patent coronary circulation.Methods and Results: Rats received two injections of either 0,85, 170, or 340 mg/kg isoproterenol. At 2, 6, and 16 weeks after injection, baseline hemodynamics, peak pressure-generating (aortic occlusion) and flow-generating (Tyrode's volume loading) capacities, and ventricular pressure-volume curves, dimensions, and histological scoring were measured. Increased LV sphericity preceded deterioration in baseline cardiac output, although it was the most powerful correlate of the dose-dependent decreases in peak cardiac output and ejection fraction. Time-dependent increases in pressure-generating capacity at a given volume were also due to compensatory increases in LV sphericity. The extent of right ventricular damage was also a strong correlate of peak flow-generating capacity.Conclusions: This study demonstrates that isoproterenol-induced myocardial necrosis resulted in progressive hemodynamic dysfunction of the left ventricle which most closely correlated with alterations in LV geometry. Although increases in LV sphericity preceded decrements in baseline function, techniques that assessed peak LV function demonstrated that increased LV sphericity was directly correlated with decreased peak flow-generating capacity, underscoring the clinical importance of these geometric alterations.