Isoprenaline-induced Myocardial Injury Research Articles

Effect of folic acid on isoprenaline-induced myocardial injury in rats.

Isoprenaline (ISO), a synthetic catecholamine and a β-adrenoceptor agonist, is widely used to develop an experimental model of myocardial injury (MI) in rats. The leading hypothesis for ISO-induced MI in rats is that it results from catecholamine overstimulation, oxidative stress, inflammatory responses, and development of cardiomyopathy during ISO administration. Folic acid (FA) reduces oxidative stress, improves endothelial function and prevents apoptosis, thereby contributing to cardiovascular protection. This study aimed to investigate the potentially protective effect of FA pretreatment on ISO-induced MI in rats. For 7 days, adult male Wistar albino rats were pretreated with 5 mg/kg/day of FA. On the sixth and seventh days, MI in rats was induced by administering 85 mg/kg/day of ISO. Prooxidant markers in plasma samples, antioxidant capacity in erythrocyte lysates, cardiac damage markers, lipid profile, electrocardiography (ECG) and histopathological analysis were evaluated. FA pretreatment significantly alleviated changes induced by ISO; it decreased the homocysteine and high-sensitivity troponin I level. FA moderately decreased the reactive oxygen species (ROS) levels (superoxide anion radical, hydrogen peroxide and thiobarbituric acid reactive substances) and improved the antioxidant activities of catalase, superoxide dismutase and reduced glutathione. ISO reduced the nitrite level and FA significantly alleviated this change. It can be concluded that FA, as a mild antioxidant, could be an appropriate cardioprotective substance in the rat model of ISO-induced MI.

Molecular mechanisms mediate roflumilast protective effect against isoprenaline-induced myocardial injury

BackgroundMyocardial necrosis is one of the most common cardiac and pathological diseases. Unfortunately, using the available medical treatment is not sufficient to rescue the myocardium. So that, we aimed in our model to study the possible cardioprotective effect of roflumilast (ROF) in an experimental model of induced myocardial injury using a toxic dose of isoprenaline (ISO) and detecting the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/ sirtuin1 (cGMP/cAMP/SIRT1) signaling cascade.Materials and methodsAnimals were divided into five groups; control, ISO given group (150 mg/kg) i.p. on the 4th and 5th day, 3 ROF co-administered groups in different doses (0.25, 0.5, 1 mg/kg/day) for 5 days.ResultsOur data revealed that ISO could induce cardiac toxicity as manifested by significant increases in troponin I, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and cleaved caspase-3 with toxic histopathological changes. Meanwhile, there were significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, eNOS, cGMP, cAMP and SIRT1. However, co-administration of ROF showed significant improvement and normalization of ISO induced cardiac damage.ConclusionWe concluded that ROF successfully reduced ISO induced myocardial injury and this could be attributed to modulation of PDE4, VEGF/eNOS and cGMP/cAMP/SIRT1 signaling pathways with antioxidant, anti-inflammatory, and anti-apoptotic properties.

Cardioprotective effects of liraglutide pretreatment on isoprenaline-induced myocardial injury in rats.

Type 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease, especially myocardial injury. Due to their hypoglycemic effects, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are efficiently used for T2DM management. GLP-1RAs also have anti-inflammatory and antioxidative effects and can improve cardiac function. The aim of this study was to investigate the cardioprotective effects of liraglutide, a GLP-1RA, on isoprenaline-induced myocardial injury in rats. The study included four groups of animals. They were pretreated with saline for 10 days + saline on days 9 and 10 (control), saline for 10 days + isoprenaline on days 9 and 10 (isoprenaline group), liraglutide for 10 days + saline on days 9 and 10 (liraglutide group), and liraglutide for 10 days, and on days 9 and 10 isoprenaline was administered. This study evaluated ECG, myocardial injury markers, oxidative stress markers, and pathohistological changes. The results showed that liraglutide mitigated the isoprenaline-induced cardiac dysfunction recorded by ECG. Liraglutide reduced serum markers of myocardial injury such as high-sensitive troponin I, aspartate aminotransferase, alanine aminotransferase, reduced thiobarbituric acid reactive substances, increased catalase and superoxide dismutase activity, increased reduced glutathione level, and improved lipid profile. Liraglutide induced antioxidative protection and alleviated isoprenaline-induced myocardial injury.

S-Allylcysteine limits cardiac structural changes via antioxidant status in ovariectomized rats with induced myocardial injury

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Higher Education, Malaysia (Fundamental Research Grant Scheme) Background Cardiovascular disease is the primary cause of death in Malaysia. Past studies have shown the incidence of cardiovascular diseases among post-menopausal women increased where their estrogen level is deficient. Thus, there is growing interest in investigating alternative approach in which to limit cardiovascular injury for post-menopausal women. S-Allylcysteine (SAC) is one of the aged garlic extract compounds that has shown its cardioprotective effect through mitochondrial preservation and CSE/hydrogen sulfide pathway. Purpose Hence, this study was aimed to investigate the effect of SAC in ovariectomized rats with isoprenaline-induced myocardial injury. Methods Ovariectomy surgery (ovary removal) was done onto 32 female Wistar rats, whereas eight rats had the same surgery without ovary removal (Sham). After three weeks of recovery, all rats received subcutaneous administration of either normal saline (Sham, OVX) or isoprenaline 85 mg/kg (OVXIM, 2x) to induce myocardial injury. Then, oral gavage of either distilled water (Sham, OVX, OVXIM) or SAC 100 mg/kg (OVXS, OVXIMS) were given to the rats for one week. Finally, the rats were anesthetized before the hearts were cannulated on Langendorff isolated heart system for cardiac function measurement. Results The rat models were validated by decreased estrogen level, while cardiac injury was from the increased ST elevation on electrocardiogram and plasma Troponin T level. Systolic blood pressure in OVXS (142.45±5.17 mmHg vs 120.53±6.75 mmHg) showed significant decrease after receiving SAC. Although SAC did not reduce oxidative stress product TBARS in OVXIM, but it increased GSH (OVX: 0.0291±0.002 vs. OVXMIS: 0.0644±0.005 nmol/mg protein) and SOD (OVX: 0.7148±0.039 vs OVXMIS: 0.4991±0.068 E/mg protein/min) antioxidants in the treatment group. This is probably due to the allyl and cysteine group in the SAC molecule that has antioxidative property which protects vascular tissue, thus contributes to the lowering of blood pressure. Histological observation showed that SAC treatment was able to limit hypertrophy and collagen deposition in OVXIM group. This suggests that SAC antioxidant action may be able to limit the cell injury from oxidative stress, thus decreasing fibrosis effect (OVXIM: 5.41 ± 1.15 vs. OVXIMS: 2.31 ± 0.42%) and preserving cardiomyocyte size (OVXIM: 5.41 ± 1.15 vs. OVXIMS: 2.31 ± 0.42 µm2). Despite the histological alteration, the Langendorff-perfused hearts of the treated rats showed similar function as Sham. CSE enzyme activity and protein expression in OVXS tended to return to the same level as Sham. Conclusion In summary, this study showed SAC’s potential in preserving cardiac structure in estrogen-deficient condition, but in-depth study is warranted to further understand antioxidant and CSE enzyme signalling pathway.

The cardioprotective effect of astaxanthin against isoprenaline-induced myocardial injury in rats: involvement of TLR4/NF-κB signaling pathway.

Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality around the world. Nuclear transcription factor kappa B (NF-κB) represents a factor that plays a major role in the pathogenesis of CVDs. The current study aims to investigate the modulatory effects of astaxanthin and its molecular mechanismsin rats with isoprenaline-induced myocardial infarction. Rats were pretreated with astaxanthin daily for 14 days prior to inducing myocardial infarction with isoprenaline in the final two days. Blood and heart tissue samples were collected 24 hours after the last dose of isoprenaline was injected for biochemical and histological analysis. Isoprenaline-induced myocardial injury was demonstrated with histopathological examination of heart tissue and the significantly elevated serum troponin-I. Isoprenaline caused an increase in oxidative stress and a decrease in antioxidants. Toll-like receptor-4 (TLR4), NF-κB and tumor necrosis factor-α (TNF-α) expression levels were significantly higher in infarcted rats. Astaxanthin pretreatment had a significant preventive effect on all of the biochemical and molecular parameters tested in myocardial infarcted rats. Astaxanthin's cardioprotective effect has been linked to the inhibition of the TLR4/NF-κB signaling pathway. This inhibits the release of inflammatory cytokines, which can cause myocardial cell death. Because of its antioxidant and anti-inflammatory properties, astaxanthin is a promising cardioprotective agent.

Cardioprotective effect of ranolazine in nondiabetic and diabetic male rats subjected to isoprenaline-induced acute myocardial infarction involves modulation of AMPK and inhibition of apoptosis.

Diabetes increases the sensitivity of myocardium to ischemic damage and impairs response of the myocardium to cardioprotective interventions. The present study aimed to elucidate the potential cardioprotective effect provided by ranolazine during myocardial infarction in nondiabetic and diabetic male rats. As AMP-activated protein kinase (AMPK) has been shown to be involved in the cellular response to ischemic injury, in this context, the present animal study evaluated the modulating role of ranolazine in the AMPK expression in isoprenaline-induced myocardial ischemic rat model. Male rats were divided into 2 experiments: experiment I and II (nondiabetic and diabetic rats) and assigned to normal control, saline control for isoprenaline, isoprenaline control, and ranolazine-treated groups. Ranolazine administration revealed effectiveness in attenuating the severity of isoprenaline-induced myocardial injury in both nondiabetic and diabetic rats as revealed by ECG signs, histopathological score, and apoptotic markers via abrogating the increments in the inflammatory and oxidative stress markers and modulating AMPK expression. Therefore, the current cardioprotective effect of ranolazine was, at least in part, mediated through inhibition of apoptosis and modulation of AMPK expression, encouraging considering the utility of ranolazine in protection from acute myocardial infarction.

Pretreatment with β-glucan attenuates isoprenaline-induced myocardial injury in rats.

What is the central question of this study? The study was designed to assess whether pretreatment with β-glucan could exert any protective action against isoprenaline-induced myocardial injury in rats. What is the main finding and its importance? β-Glucan pretreatment could reduce myocardial injury by restoring cardiac biomarkers, antioxidant status, apoptosis and histopathological changes. Therefore, β-glucan might have the potential to be used in the prevention and/or treatment of myocardial infarction. This study was designed to investigate the cardioprotective effect of pretreatment with β-glucan, the glucose polymer derived from the yeast Saccharomyces cerevisiae, against isoprenaline (ISO)-induced myocardial injury in rats by studying biochemical cardiac markers, antioxidant parameters, apoptosis, ECG and histopathological changes. Male Sprague-Dawley rats were randomly divided into four treatment groups, namely control, β-glucan, isoprenaline and β-glucan+isoprenaline. The β-glucan treatment group received β-glucan (50mgkg-1 day-1 , p.o.) for 10 days. Myocardial injury was induced by ISO administration (100mgkg-1 , s.c.) twice, at an interval of 24h, on the 9th and 10th days. Isoprenaline administration resulted in a marked increase in heart rate, ST segment elevation, myocardial malondialdehyde content, cardiac marker levels (lactate dehydrogenase, creatine kinase-MB and high-sensitivity cardiac troponinT) and apoptotic index, and a significant decrease in R-wave amplitude and myocardial superoxide dismutase, catalase and glutathione peroxidase activities. In addition, apoptosis, congestion, necrosis, inflammatory cell infiltration and myofibrillar disorganization were observed histologically in myocardial tissue sections. The oral pretreatment with β-glucan prevented almost all the parameters of isoprenaline-induced myocardial injury in rats, and these findings were confirmed by the histopathological analysis. These findings provide evidence that β-glucan could protect rat myocardium against ISO-induced myocardial injury, and this was attributed to its antioxidant and anti-apoptotic properties.

Identification of Pharmacokinetic Markers for Guanxin Danshen Drop Pills in Rats by Combination of Pharmacokinetics, Systems Pharmacology, and Pharmacodynamic Assays.

This paper reported a feasibility study strategy of identifying pharmacokinetic (PK) markers for a cardiovascular herbal medicine, Guanxin Danshen drop pill (GDDP). First, quantification analysis revealed the constituent composition in the preparation by high-performance liquid chromatography (HPLC). Subsequently, physiochemical property calculation predicted the solubility and intestinal permeability of the constituents in the preparation. Furthermore, HPLC–MS analysis ascertained the absorbable ingredients and their PK properties in rat plasma. The main effective substances from the ingredients absorbed into blood and their cardiovascular effects were also predicted by systems pharmacology study, and were further confirmed by in vivo protective effects on isoprenaline-induced myocardial injury in mice. Finally, the ingredients with high content, representative structure feature, favorable PK properties, high relevant degree to myocardial ischemia (MI) issues, and validated therapeutic effects were considered as the PK markers for the preparation. Ginsenosides Rg1, Rb1, and tanshinone (TS) IIA were identified originally as PK markers for representing PK properties of GDDP. In addition, integrated PK studies were carried out according to previous reports, viz. drug concentration sum method and the AUC weighting method, to understand the in vivo process of GDDP comprehensively. The present study maybe provide a reference approach to identify PK markers for cardiovascular herbal medicines.

Protective Role of N-Acetylcysteine on Isoprenaline-Induced Myocardial Injury: Histological, Immunohistochemical and Morphometric Study.

Several researchers studied the protective effect of the N-acetylcysteine (NAC) when it was given before the induction of myocardial infarction (MI). Other researchers studied such protective effect when it was before done and after done of the MI. The missing data are the comparison between the protective effect of NAC before myocardial injury with its protective effect both before and after myocardial injury. The aim of the study was to compare the cardioprotective effect of NAC on the isoprenaline-induced myocardial injury before the isoprenaline (ISP) injection with its protective effect both before and after the ISP injection. This study was applied over both short and long time periods. A total of 90 male adult Wistar albino rats were used in the study. The rats were divided into four groups: control group, ISP-treated group, NAC-pretreated group and NAC-pre-& posttreated group. Based on the duration of the experiment, the second and third groups were further subdivided into a and b groups. Histological, immunohistochemical and histomorphometric analysis were used. The myocytes in the ISP-treated groups were fragmented, disrupted with karyolysis. The blood vessels were dilated, congested and associated with blood extravasation, interstitial edema and cellular inflammatory infiltration. Much improvement was observed in the NAC-pretreated group. Focal degeneration was detected in the muscle fibers. The capillaries were normal. Minimal blood extravasation and cellular infiltration were seen. The cardiac muscle fibers in the NAC-pre-& posttreated group were regularly arranged. The mean collagen fiber area percent of the ISP-treated groups was significantly higher by 8.3-folds and 10.1-folds as compared with that of the control group and was also higher by 5.5-folds and 6.8-folds as compared with that of the NAC-pre-&posttreated groups. The α-SMA area percent in the ISP-treated groups was significantly higher by 12.2-folds and 23.9-folds as compared with that of the control group and was higher by 7.5-folds and 15-folds as compared with that of the NAC-pre-& posttreated groups. The mean PCNA area percent of the ISP-treated groups was significantly higher by 126.2 and 164.8% as compared with that of the control group and was higher by 106.3 and 141.5% as compared with that of NAC-pre-& posttreated groups. ISP had deleterious effects on the heart. Administration of NAC before ISP injection could largely reduce the ISP-induced short- and long-term alterations. The protection was maximum with the use of NAC before the ISP injection and continued after the injection for 12days.

Evaluation of cardioprotective effect of aqueous extract of Allium cepa Linn. bulb on isoprenaline-induced myocardial injury in Wistar albino rats.

To investigate the cardioprotective potential of the aqueous extract of Allium cepa Linn. bulb in isoprenaline-induced myocardial injury in Wistar albino rats. In vitro total phenolic, total flavonoid content and 2, 2’-diphenyl-1-picrylhydrazyl hydrate radical scavenging activity was measured. Isoprenaline-induced myocardial injury model was used to evaluate in vivo effect of aqueous extract of A. cepa in Wistar albino rats. Seventy two rats were randomly divided in 6 groups. Rats were treated with A. cepa 400 mg/kg and 800 mg/kg doses for 30 days and myocardial injury was produced by subcutaneous injection of isoprenaline (ISO) 85 mg/kg on day 28 and 29. Carvedilol 1 mg/kg for 30 days served as active control. Electrocardiogram parameters, cardiac injury markers, oxidative stress markers and histopathological changes were evaluated in each group and compared using appropriate statistical tests. In vitro evaluation of aqueous extract of A. cepa showed significant antioxidant property. ISO produced significant myocardial injury as compared to normal control group (P < 0.05). Administration of A. cepa in the dose of 400 mg/kg significantly recovered the altered parameters (Troponin-I, Creatine kinase-MB, glutamate-pyruvate transaminase, HR, R-R interval, and oxidative stress markers) compared to disease control group (P < 0.05) while A. cepa in the dose 800 mg/kg recovered the altered parameters (HR, heart weight/body weight ratio, and superoxide dismutase level) compared to disease control group. Histopathological parameters did not recover in the doses of 400 and 800 mg/kg (P > 0.05). The aqueous extract of A. cepa 400 mg/kg was found to be cardioprotective against myocardial injury while A. cepa 800 mg/kg did not show significant cardioprotective activity. So, we presume that A. cepa might be effective within certain dose range only.

Blockers of sulfonylureas receptor 1 subunits may lead to cardiac protection against isoprenaline-induced injury in obese rats

Recent studies have found that blockers of sulfonylureas receptor 1(SUR1) might have cardiac ischemic protective effects. We evaluated the effects of a selective SUR1 blocker gliclazide on cardiac function and arrhythmia after isoprenaline-induced myocardial injury in obese rats. Diet-induced obese rats received isoprenaline or saline shots subcutaneously. Gliclazide or saline was given q12h for 48h to rats received isoprenaline. We measured ECG and hemodynamic parameters and collected blood samples for CK-MB, glucose and lipid profile determination, and then harvested hearts for water content, histological and immunohistochemical analysis and infarct size measurements. The obese rats’ hearts receiving isoprenaline-induced myocardial injury showed up-regulated SUR-1 expression in the peri-microvascular area. Obese rats receiving gliclazide lavage had less severe arrhythmia (ASI: 4.00±0.61 vs. 2.14±0.39, P<0.05) and myocardial edema (water percentage: 85.16±0.46% vs. 81.56±0.57%, P<0.05). Less infarct size (47.6±12.8% vs. 32.7±9.1%, P<0.05) and improved diastolic function (LVEDP: 6.86±0.85% vs. 2.51±1.09%, P<0.05;−(dp/dt)max: −1663.6±387.91mmHg/s vs. −2834.8±290.76mmHg/s, P<0.05) were also observed in rats receiving gliclazide lavage. Blocking of the SUR1 thus exerts a protective effect on the isoprenaline-induced myocardial injury in obese rats. That SUR1 blocker leads to ischemic protection suggesting a critical biological role of SUR1 in regulating the function of the cardiovascular system than previously recognized under pathophysiological conditions.

Protective effects of Carthamus tinctorius injection on isoprenaline-induced myocardial injury in rats

Context: Carthamus tinctorius injection (CTI) is a traditional Chinese medicine (TCM) specifically used for the treatment of cerebral ischemia and myocardial ischemia.Objective: This study evaluated the protective effects of CTI on isoprenaline-induced acute myocardial ischemia (AMI) in rats and explored the underlying mechanisms.Materials and methods: (i) Sprague-Dawley rats were randomly divided into 5 groups: control, myocardial ischemia model, and high-, low-dose of CTI groups (2.5 and 0.625 g/kg, respectively, i.p. for 5 days), and Xiang-Dan (20 g/kg) group (n = 10 in each group). AMI was induced by isoproterenol (5 mg/kg) by intraperitoneal injection. Assessment of electrocardiograms (ECG) was carried out. (ii) Another 40 rats were randomly divided into 5 groups, the concentration of IL-6 and TNF-α in serum were measured by radioimmunological assay; Bcl-2 and Bax protein expression were measured by immunohistochemistry.Results: CTI (2.5 and 0.625 g/kg) significantly inhibited the typical ECG S-T segment elevation, reduced concentration of IL-6 and TNF-α in serum, suppressed overexpression of Bax protein and also inhibited the reduction of Bcl-2 expression and markedly depressed the Bax/Bcl-2 ratio.Discussion and conclusion: These findings demonstrate that CTI is cardioprotective against AMI in rats and is likely to related to decrease inflammatory response mediated by TNF-α and IL-6, down-regulate protein level of Bax and up-regulate that of Bcl-2 in the heart tissue.

Apelin reduces myocardial reperfusion injury independent of PI3K/Akt and P70S6K

Apelin peptides are endogenous ligands of the apelin receptor (APJ) and are expressed in endothelial cells and adipocytes. Apelins regulate vascular tone, cardiac contractility and have been reported to protect from isoprenaline-induced myocardial injury. Furthermore, apelin peptides activate components of the reperfusion injury salvage kinase (RISK) pathway such as PI3K/Akt and P70S6 kinase (P70S6K) in transgenic cell based assays. We therefore hypothesised that apelin peptides may protect the post-ischaemic myocardium from reperfusion injury via activation of the RISK pathway and tested this hypothesis in a rat isolated heart model of ischaemia and reperfusion.

Effects of Thalidomide on Isoprenaline‐Induced Acute Myocardial Injury: A Haemodynamic, Histopathological and Ultrastructural Study

In the present study, we investigated the cardioprotective effects of thalidomide in a rat model of acute myocardial injury, induced by subcutaneous injection of isoprenaline hemisulphate (85 mg/kg per day for 2 days). Thalidomide (75/150/300 mg/kg) or vehicle (dimethylsulphoxide) or saline (0.9% NaCl) was administered orally for 14 days and isoprenaline injection on the 12th and 13th days. Cardiovascular responses (arterial and left ventricular haemodynamic parameters and heart rate) were obtained in anaesthetized rats on the 14th day. Histopathological and electronmicroscopical analysis of myocardial injury was done. The results showed that thalidomide 300 mg/kg per day orally caused significant improvement in isoprenaline-induced reduction of cardiac function with increases in maximum rate of pressure development (+LVdP/dt, P < 0.001) and maximum rate of pressure decline (-LVdP/dt, P < 0.001) and decreases in left ventricular end-diastolic pressure (P < 0.01), systolic arterial pressure (P < 0.001), diastolic arterial pressure (P < 0.001), mean arterial pressure (P < 0.001) and heart rate (P < 0.001). The myocardial injury caused by isoprenaline was significantly reduced by thalidomide treatment as judged by the reduction of myocardial necrosis, ultrastructural changes such as mitochondria and myofibril damage, 300 mg/kg being the most effective dose. In conclusion, oral administration of thalidomide is able to ameliorate isoprenaline-induced myocardial injury and impaired myocardial function in spite of decreases in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure, which may be due to its depressant effect on the sino-atrial node and sedative action.

Protective effect of taurine against isoprenaline-induced myocardial damage.

The effect of the sulfur amino acid, taurine, was examined on histological and biochemical changes induced by a toxic dose of isoprenaline in chick hearts. Isoprenaline treatment (80 or 240 mg/kg id twice daily for 4 days) caused a dose-dependent increase in heart weight and decrease in myocardial ATP. Isoprenaline administration (240 mg/kg id twice daily) produced necrotic changes in hearts, such as eosinophilic degeneration, myolysis, interstitial oedema, fibrosis, and inflammatory cell infiltration. Substantial accumulation of calcium was also observed. Taurine content of the heart was not significantly decreased. Parenteral administration of taurine (200 mg/day for 7 days) partially protected against these necrotic changes induced by isoprenaline. It is suggested that the protective effect of taurine against isoprenaline-induced myocardial injury might be due in part to the prevention of the massive overloading with calcium which is thought to cause myocardial cell necrosis.