Effect of abana an ayurvedic formulation,on lipid peroxidation in experimental myocardial infarction in rats

The present study was conducted to elucidate the antioxidant role of an ayurvedic formulation Abana in isoproterenol 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 level were observed. There was also a significant increase in lipid peroxides levels on isoproterenol administration. Activities of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase, glutathione reductase were decreased significantly in heart with isoproterenol-induced myocardial necrosis. Abana, produced a marked reversal of these metabolic changes related to myocardial infarction induced by isoproterenol. In conclusion ayurvedic formulation Abana exerts its effect by modulating lipid peroxidation and enhancing antioxidant and detoxifying enzyme systems.     

Heterogeneity in distribution of cardiac glycogen following isoproterenol infusions in the dog

Synopsis A combined biochemical, histochemical and cytochemical study was made of cardiac glycogen distribution following intravenous infusions of varying doses of isoproterenol in anaesthetized, open-chested dogs. There was a dose-dependent decrease in glycogen levels in biopsies of the posterolateral wall of the left ventricle which also exhibited a transmural gradient with the endocardial third the most severely affected. Periodic acid-Schiff (PAS) histochemical studies also suggested a transmural gradient. There was, however, a marked variability within each layer, particularly the large amounts in the conduction system fibres. The ultrastructural studies exhibited a marked variation in glycogen content from one cell to the next. This was particularly evident in the complete absence of granules in the contraction band lesions of isoproterenol cardiotoxicity yet substantial amounts were retained in neighbouring cells. Isoproterenol, therefore, produces a heterogenous depletion of cardiac glycogen related to the scattered catecholamine-induced myocardial cellular lesions. These relationships have not previously been documented or emphasized.     

Synergistic effect of Nicorandil and Amlodipine on tissue defense system during experimental myocardial infarction in rats

The synergistic protective effect of Nicorandil (K_ATP channel opener) and Amlodipine (calcium channel blocker) on heart tissue antioxidant defense system and lipid profile were examined on isoproterenol induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg^–1 daily, i.p.) for 2 days showed significant changes in antioxidant defense system and lipid profile levels. Pretreatment with Nicorandil (2.5 mg kg^–1 daily, p.o.) and Amlodipine (5.0 mg kg^–1 daily, p.o.) for 3 days significantly prevented these alterations and restored the enzyme activities to near normal. These findings indicate the synergistic protective effect of Nicorandil and Amlodipine on tissue defense system and lipid metabolism during isoproterenol induced cardiac damage.     

Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization

Sympathetic nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and beta-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 micro g.kg(-1).min(-1)) with or without a magnesium infusion (1 mg.kg(-1).min(-1)). The dose response to small doses of isoproterenol (0.025-0.2 micro g.kg(-1).min(-1)) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization.     

Isoproterenol-induced responses in the regional polyamine metabolism of the rat heart

Rats were treated with a single dose of isoproterenol (25 mg/kg s.c.) and the levels of polyamines determined in various parts (right ventricle, basis, medial part and apex of the left ventricle) of the heart 24, 48 and 72 hours after the injection. The isoproterenol treatment produced marked alterations in the concentrations of cardiac polyamines. The most apparent changes were seen in the apex and medial part of the left ventricle where spermidine concentration exhibited a biphasic response with peaks at 24 and 72 hours. In the basis of the heart the spermidine concentration was significantly elevated only at 24 hours. In the right ventricle the spermidine level was significantly higher than control at 72 hours. Spermidine/spermine ratio was augmented in all cardiac tissues examined over the 72-hour period. Results appear to show that the isoproterenol-induced alterations in cardiac polyamine metabolism were not uniformly distributed in the various regions of the heart.     

Alterations in activities of cyclic nucleotide systems and in beta-adrenergic receptor-mediated activation of cyclic AMP-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy.

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoproterenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio(--cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activity ratio half-maximally was higher than controls; the reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the beta-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.     

Effect of Calotropis procera latex on isoproterenol induced myocardial infarction in albino rats.

The alcoholic extract of the latex obtained from Calotropis procera (Asclepidaceae) was evaluated for protection against isoproterenol (20 mg/100 g body wt., s.c.)-induced myocardial infarction in albino rats. The heart damage induced by isoproterenol was indicated by elevated levels of the marker enzymes such as Creatine Kinase-isoenzyme (CK-MB), Lactate dehydrogenase (LDH), Serum Glutamate Oxaloacetic Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) in serum with increased lipid peroxide and reduced glutathione content in heart homogenates. Microscopical examination (histopathology) was also performed on the myocardial tissue. Pretreatment with an ethanolic latex extract of Calotropis procera at a dose of 300 mg/kg body wt., administered orally thrice a day for 30 days, reduced significantly (p < 0.01) the elevated marker enzyme levels in serum and heart homogenates in isoproterenol-induced myocardial infarction. Histopathological observation revealed a marked protection by the extract in myocardial necrotic damage.     

Protective action of aspirin in experimental myocardial infarction induced by isoproterenol in rats and its effect on lipid peroxidation

The protective action of aspirin in experimental myocardial infraction induced by isoproterenol was studied in rats. Aspirin treated rats showed lower mortality rate and smaller changes in the myocardium on histopathological examination when compared to corresponding animals given isoproterenol alone. Changes were also observed in the different lipid fractions studied. The ratio of cholesterol to phospholipids decreased in the heart in aspirin treated animals when compared to control rats given isoproterenol alone. The levels of lipid peroxide also showed a decrease while the activity of superoxide dismutase (SOD) and catalase registered an increase in the aspirin treated animals given isoproterenol when compared to corresponding animals given isoproterenol alone.     

Polyamine levels and diamine oxidase activity in hypertrophic heart of spontaneously hypertensive rats and of rats treated with isoproterenol

Polyamine levels and diamine oxidase (EC 1.4.3.6) activity were studied in hypertrophic heart of spontaneously hypertensive rats as well as in the heart of Wistar rats during the development and regression of cardiac hypertrophy induced by isoproterenol administration. In spontaneously hypertensive rats, putrescine content and diamine oxidase activity were higher than those found in normotensive Kyoto-Wistar control rats. During the development of cardiac hypertrophy induced by isoproterenol, there was an increase in polyamine content and diamine oxidase activity. The administration of cycloheximide or actinomycin D prevented the increase in diamine oxidase activity during the first 24 h after isoproterenol administration, demonstrating that the rise in diamine oxidase activity was due to synthesis of new enzyme. Following the cessation of isoproterenol treatment, cardiac hypertrophy regressed and polyamine levels and diamine oxidase activity diminished toward control values. The administration of aminoguanidine to isoproterenol-treated rats caused in the heart an inhibition of diamine oxidase activity that led to an increase in putrescine level beyond the values found in animals given isoproterenol alone. The results suggest that the enhancement of diamine oxidase activity plays a role in the regulation of putrescine level in hypertrophic heart.     

Role of Arogh, a polyherbal formulation to mitigate oxidative stress in experimental myocardial infarction

Antioxidant role of Arogh in isoproterenol induced myocardial infarction in rats has been studied. The activity of heart tissue antioxidants like glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase were significantly decreased in isoproterenol administered group. The activity of ceruloplasmin and levels of glutathione, vitamins E and C were also found to be substantially decreased in serum with a concomitant rise in lipid peroxide levels after isoproterenol exposure to rats. The synergistic effect of Arogh pretreatment, significantly suppressed the alterations induced by isoproterenol alone in rats.     

Lipid composition of the rat liver nuclear matrix as affected by hydrocortisone

It has been found that the rat liver nuclear matrix contains a small amount of phospholipids (2%) and neutral lipids (1.6%). The injection of hydrocortisone increased the nuclear matrix phospholipid content and reduced its neutral lipid levels. A marked increase in sphingomyelin content observed was accompanied by the reduction in phosphatidylcholine level. The decrease in neutral lipid content took place mainly at the expense of a sharp lowering of triglyceride and cholesterol ether levels. The latter may turn into free cholesterol, thus increasing its content. The data obtained testify to steroid hormone influence on lipid metabolism in intranuclear structures. The observed changes in lipid composition may be related to specific hydrocortisone-induced activation of genome.     

Regulation of fat specific protein 27 by isoproterenol and TNF-α to control lipolysis in murine adipocytes

The lipid droplet-associated fat specific protein 27 (FSP27) suppresses lipolysis and thereby enhances triglyceride accumulation in adipocytes. We and others have recently found FSP27 to be a remarkably short-lived protein (half-life, 15 min) due to its rapid ubiquitination and proteasomal degradation. Thus, we tested the hypothesis that lipolytic agents such as tumor necrosis factor-α (TNF-α) and isoproterenol modulate FSP27 levels to regulate FFA release. Consistent with this concept, we showed that the lipolytic actions of TNF-α, interleukin-1β (IL-1β), and IFN-γ are accompanied by marked decreases in FSP27 expression and lipid droplet size in mouse adipocytes. Similar depletion of FSP27 using short interfering RNA (siRNA) mimicked the lipolysis-enhancing effect of TNF-α, while maintaining stable FSP27 levels using expression of hemagglutinin epitope-tagged FSP27 blocked TNF-α-mediated lipolysis. In contrast, we show the robust lipolytic action of isoproterenol is paradoxically associated with increases in FSP27 levels and a delayed degradation rate corresponding to decreased ubiquitination. This catecholamine-mediated increase in FSP27 abundance, probably a feedback mechanism for restraining excessive lipolysis by catecholamines, is mimicked by forskolin or 8-bromo-cAMP treatment and is prevented by the protein kinase A (PKA) inhibitor KT5720 or by PKA depletion using siRNA. Taken together, these data identify the regulation of FSP27 as an important intermediate in the mechanism of lipolysis in adipocytes in response to TNF-α and isoproterenol.     

Alterations in activities of cyclic nucleotide systems and in β-adrenergic receptor-mediated activation of cyclic amp-dependent protein kinase during progression and regression of isoproterenol-induced cardiac hypertrophy

Initial and transient increases in the basal levels of cyclic GMP in the heart were noted prior to cardiac hypertrophy in rats administered isoprotenol. Increased levels of cyclic AMP-phosphodiesterase (in both the soluble and particulate fractions) and stimulatory modulator of cyclic GMP-dependent protein kinase, however, were associated with the progression, or the state, of cardiomegaly, with their levels returning to the control values upon regression of the hypertrophy. The levels of cyclic GMP phosphodiesterase in the soluble fraction were lower, whereas those in the particulate fraction were higher, in the hypertrophied heart than the control. In cardiac hypertrophy, the maximal activity ratio (?cyclic AMP/+cyclic AMP) of cyclic AMP-dependent protein kinase in the incubated minced heart caused by isoproterenol was lower, whereas the concentration of isoproterenol required to increase the activit ratio half-maximally was higher than controls; The reduced responsiveness to the drug, however, was reversed when the hypertrophy regressed. These observations, taken collectively, appear to suggest that the desensitization of the β-adrenergic mechanism seen in the cardiac hypertrophy produced by repeated administration of isoproterenol is associated with adaptive modifications in certain parameters of the cyclic nucleotide systems.     

Role of beta-adrenergic agonists in the control of vascular capacitance

The role of beta-adrenergic agonists, such as isoproterenol, on vascular capacitance is unclear. Some investigators have suggested that isoproterenol causes a net transfer of blood to the chest from the splanchnic bed. We tested this hypothesis in dogs by measuring liver thickness, cardiac output, cardiopulmonary blood volume, mean circulatory filling pressure, portal venous, central venous, pulmonary arterial, and systemic arterial pressures while infusing norepinephrine (2.6 micrograms.min-1.kg-1), or isoproterenol (2.0 micrograms.min-1.kg-1), or histamine (4 micrograms.min-1.kg-1), or a combination of histamine and isoproterenol. Norepinephrine (an alpha- and beta 1-adrenergic agonist) decreased hepatic thickness and increased mean circulatory filling pressure, cardiac output, cardiopulmonary blood volume, total peripheral resistance, and systemic arterial and portal pressures. Isoproterenol increased cardiac output and decreased total peripheral resistance, but it had little effect on liver thickness or mean circulatory filling pressure and did not increase the cardiopulmonary blood volume or central venous pressure. Histamine caused a marked increase in portal pressure and liver thickness and decreased cardiac output, but it had little effect on the estimated mean circulatory filling pressure. Isoproterenol during histamine infusions reduced histamine-induced portal hypertension, reduced liver size, and increased cardiac output. We conclude that the beta-adrenergic agonist, isoproterenol, has little influence on vascular capacitance or liver volume of dogs, unless the hepatic outflow resistance is elevated by agents such as histamine.     

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.     

Effect of carnitine on malondialdehyde, taurine and glutathione levels in heart of rats subjected to myocardial stress by isoproterenol

The effect of carnitine on free fatty acid, malondialdehyde, taurine and glutathione levels in myocardium was studied in rats administered isoproterenol to induce a stress in the myocardium resulting in myocardial ischaemia. Carnitine decreased the levels of free fatty acid and malondialdehyde (an index of lipid peroxidation) when compared to control rats given isoproterenol alone. Taurine and glutathione also registered a fall in the carnitine treated animals when compared to rats treated with isoproterenol alone. The results indicate that carnitine by decreasing the levels of these parameters helps the myocardium to survive from the stress induced by isoproterenol.     

13-Propylberberine reduces response of guinea-pig myocardium to inotropic interventions including changes in extracellular Ca2+

Berberine has been shown to increase developed tension in cardiac muscle but its derivatives have been reported to inhibit the catalytic subunit of adenylate cyclase. In the present study, the cardiac actions of the most potent derivative, 13-propylberberine, were examined. It produced a transient increase followed by a sustained decrease in developed tension in paced left atrial muscle preparations isolated from guinea-pig heart. In the presence of 13-propylberberine, isoproterenol caused only a transient increase in developed tension; marked desensitization to the positive inotropic effect of isoproterenol occurred within 20 min. After washout of isoproterenol and an additional 15-min incubation in the presence of 13-propylberberine, the muscle lost its sensitivity to isoproterenol. Moreover, the positive inotropic effect of ouabain or effects of decrease or increase in extracellular Ca2+ concentration on the force of muscle contraction were markedly attenuated. Isoproterenol-induced elevation of tissue cyclic AMP concentration was inhibited by 13-propylberberine; however, 13-propylberberine did not alter the basal cyclic AMP concentration and its effects on inotropic actions of ouabain or extracellular Ca2+ appear unrelated to tissue cyclic AMP concentration.     

Synergistic interactions of Ferulic acid with Ascorbic acid: Its cardioprotective role during isoproterenol induced myocardial infarction in rats

Studies on the lipid peroxidation and antioxidant changes and their significance during myocardial injury have provided a new insight into the pathogenesis of heart disease. The heart failure subsequent to myocardial infarction may be associated with an antioxidant deficit as well as increased myocardial oxidative stress. The present study was designed to evaluate the effect of the combination of ferulic acid and ascorbic acid on antioxidant defense system and lipid peroxidation against isoproterenol (ISO)-induced myocardial infarction in rats. Induction of rats with isoproterenol (150 mg/kg body weight daily, i.p.) for 2 days resulted in a marked elevation in lipid peroxidation, serum marker enzymes (LDH, CPK, GOT, and GPT), and a significant decrease in activities of endogenous antioxidants (SOD, GPx, GST, CAT, and GSH). Pre-co-treatment with the combination of ferulic acid (20 mg/kg body weight/day) and ascorbic acid (80 mg/kg body weight/day) orally for 6 days, significantly attenuated these changes when compared to the individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. Thus, ferulic acid and ascorbic acid significantly counteracted the pronounced oxidative stress effect of ISO by the inhibition of lipid peroxidation, restoration of antioxidant status, and myocardial marker enzymes levels. In conclusion, these findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on lipid peroxidation and antioxidant defense system during ISO-induced myocardial infarction and associated oxidative stress in rats.     

miR-29a attenuates cardiac hypertrophy through inhibition of PPARδ expression

Although cardiac hypertrophy is widely recognized as a risk factor that leads to cardiac dysfunction and, ultimately, heart failure, the complex mechanisms underlying cardiac hypertrophy remain incompletely characterized. The nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) is involved in the regulation of cardiac lipid metabolism. Here, we describe a novel PPARδ-dependent molecular cascade involving microRNA-29a (miR-29a) and atrial natriuretic factor (ANF), which is reactivated in cardiac hypertrophy. In addition, we identify a novel role of miR-29a, in which it has a cardioprotective function in isoproterenol hydrochloride-induced cardiac hypertrophy by targeting PPARδ and downregulating ANF. Finally, we provide evidence that miR-29a reduces the isoproterenol hydrochloride-induced cardiac hypertrophy response, thereby underlining the potential clinical relevance of miR-29a in which it may serve as a potent therapeutic target for heart hypertrophy treatment.     

Experimental myocardial necrosis in rats: Role of arjunolic acid on platelet aggregation,coagulation and antioxidant status

Arjunolic acid, a new triterpene and a potent principle from the bark of Terminalia arjuna, has been shown to provide significant cardiac protection in isoproterenol induced myocardial necrosis in rats. To further explore the mechanism of action of arjunolic acid, antiplatelet activity, anticoagulant assays, electrocardiographic changes, serum marker enzymes, antioxidant status, lipid peroxide and myeloperoxidase (MPO) have been measured and the results are compared with a potent cardioprotective drug, acetyl salicylic acid (ASA). Administration of isoproterenol produces electrocardiographic changes such as decreased R amplitude and increased ST segment elevation and has resulted in an increase in serum marker enzyme levels as well as a decrease in enzymatic and nonenzymatic antioxidant levels. Arjunolic acid at an effective dosage of 15 mg/kg body weight (pre and post treatment),when administered intraperitoneally (i.p.), effects a decrease in serum enzyme levels and the electrocardiographic changes get restored towards normalcy. Arjunolic acid treatment is also shown to prevent the decrease in the levels of superoxide dismutase, catalase, glutathione peroxidase, ceruloplasmin, -tocopherol, reduced glutathione (GSH), ascorbic acid, lipid peroxide, MPO and the cardioprotection is confirmed by the histopathological studies.This study shows that the cardioprotection of arjunolic acid pre and post treatment could possibly be due to the protective effect against the damage caused by myocardial necrosis.