Subcutaneous Administration Of Isoproterenol Research Articles

Gentisic acid protects Sprague-Dawley rats from myocardial infarction through reversing electrocardiographical, biochemical and histopathological abnormalities.

Gentisic acid (GA), a cytochrome P450 metabolite of the antiplatelet drug aspirin, exhibits smooth muscle relaxant, antiatherogenic, and antioxidant activities. It also has a protective role in hypertrophic heart failure, suggesting its role in the management of myocardial infarction (MI). This study aimed to explore the protective activity of GA in isoproterenol (ISO)-induced MI in Sprague-Dawley (SD) rats in-vivo, followed by mechanistic investigation ex-vivo. SD rats were pretreated with different doses (5, 10, 15, and 20mg/kg, i.p.) of GA for 21 days, followed by subcutaneous administration of ISO (85mg/kg) on the 20th and 21st days. At the end of the experiment, electrocardiograph (ECG), blood pressure, myocardial injury marker enzymes, infarct size, lipid profile, and histological changes in myocardium were carried out. The possible underlying mechanisms were explored ex-vivo. GA prevented the ISO-induced changes in ECG parameters in rats in a dose-dependent manner. GA also reversed the fall in blood pressure associated with ISO treatment. GA diminished the elevated cardiac biomarkers and limited the infarcted area size (8%) indicated by decrease in heart weight to body weight ratio. GA ameliorated the inflammation, edema, and necrosis and reduced collagen fiber deposition associated with ISO-induced MI. The results suggest that GA is an effective cardioprotective agent in rats by reversing ischemic changes in ECG and correcting histopathological and biochemical changes.

Cardio-Protective Effect of the Leaf Extract of Andrographis paniculata in Isoproterenol-Induced Myocardial Infarction

Background: Nowadays, myocardial infarction has been regarded as one of the chronic diseases with increasing mortality rate worldwide. The use of medicinal plants in the treatment of this chronic disease is gaining wide acceptance globally.
 Materials and Methods: This study was carried out to evaluate the cardio-protective effect of the leaf extract of A. paniculata in isoproterenol-induced myocardial infarction. Fresh green leaves of A paniculata were collected from the Faculty of Agriculture farmland, Nnamdi Azikiwe University, Awka, Nigeria. The plant was identified and authenticated at the Department of Botany, Nnamdi Azikiwe University and a voucher specimen was deposited at the herbarium accordingly. The shredded, air-dried sample was then pulverized and weighed. Solvent-solvent (ethanol and water) (7:3) was used for extraction via maceration for 72 hr. The filtrate was evaporated to dryness to obtain the ethanol extract which was used for further bioassay study. The bioactive constituents of the plant extract were quantitatively analyzed by Gas chromatography mass spectrometry (GC-MS). The animals were administered with the extract of A. paniculata orally for seven days at a divided dose of 100 mg/kg, 200 mg/kg and 400 mg/kg body weights. On the eight day, myocardial infarction was induced through subcutaneous administration of isoproterenol at a dose of 150 mg/kg/day diluted in 2 ml of saline on two consecutive days. Subsequently, the blood pressures were monitored and blood collected for bioassay studies.
 Results: The results of the study showed that the leaf extract of A. paniculata was rich in 2,5-Octadecadiynoic acid, methyl ester (28.21%); 1,2,3,5-Cyclohexanetetrol,(1à,2á,3à,5á)- (15.10 %) and 10-12-Pentacosadiynoic acid (13.05%). The findings also showed a significant decrease (p>0.05) in the Mean arterial blood pressure, heart rate, aspartate transaminase, alanine transaminase, creatinine kinase and lactate dehydrogenase activities of the treatment group compared with the untreated control group while the antioxidant (superoxide dismutase, catalase and glutathione) activities were significantly increased in the treatment group, compared with the untreated control group.
 Conclusion: The findings of this work have shown that leaf of A. paniculata was rich in bioactive compounds which could be synthesized to produce plant based products to combat cardiovascular diseases especially myocardial infarction.

Cardioprotective Effect of Polymyxin-B and Dantrolene Combination on Isoproterenol-Induced Hypertrophic Cardiomyopathy in Rats, via Attenuation of Calmodulin-Dependent Protein Kinase II.

Hypertrophic cardiomyopathy is a major cause of mortality worldwide. In this study, we hypothesized that the combination of Dantrolene and Polymyxin-B will provide cardioprotective action against isoproterenol-induced hypertrophic cardiomyopathy via attenuation of Calmodulin-dependent protein kinase II (CaMKII). Hypertrophic cardiomyopathy was induced in rats by subcutaneous administration of isoproterenol (5 mg/kg) for 14 days. Simultaneously, animals were treated with Polymyxin-B per se, Dantrolene per se, and Dantrolene and Polymyxin-B combination for 14 days. Hemodynamic parameters, biochemical parameters, and histological analysis were performed. Administration of isoproterenol for 14 days resulted in severe myocardial damage, characterized by cardiac hypertrophy and increase serum CK-MB, CK-Nac, LDH, AST, and ALT levels. It also caused alteration in electrocardiogram and blood pressure. A significant increase in CaMKII was observed in heart homogenate. Treatment with the Polymyxin-B and Dantrolene combination significantly ameliorated cardiac hypertrophy, biochemical parameters, ECG parameters, and heart histopathology. Further, significant attenuation in CaMKII levels was observed. The effect of the combination was more than per se treatment. Results of the current study showed that the combination of Polymyxin-B and Dantrolene prevented the development of isoproterenol-induced hypertrophic cardiomyopathy in rats via attenuation of the CaMKII.

PHARMACODYNAMIC INTERACTION OF TINOSPORA CORDIFOLIA WITH ATENOLOL AND PROPRANOLOL IN ISOPROTERENOL INDUCED CARDIAC NECROSIS IN RATS

Objective: The present study was carried out to evaluate the combined cardioprotective effect of standardized extract of Tinospora cordifolia extract (TCE) with atenolol (AT) and propranolol (PP) in isoproterenol (ISO) induced cardiac necrosis in rats. 
 Methods: Myocardial infarction (MI) or cardiac necrosis was induced by subcutaneous administration of ISO for two days consecutively at an interval of 24 h. Rats were pre-administered with test drugs for 21 d followed by ISO was administration on 20 and 21st day. 24 h after final ISO administration, mean arterial blood pressure (MAB), Heart rate (HR), electrocardiogram (ECG), heart bio-marker enzyme, and histopathological study of cardiac tissue were evaluated from control and experimental groups and analyzed statistically by one-way ANOVA followed by Tukeys’s test. 
 Results: Rats administered with ISO showed significant (p<0.001) changes in ECG, HR, MAB, heart bio-marker enzyme, antioxidant parameters, and histopathology of the heart. The activities of biomarkers have reduced in serum and there is a significant (p<0.001) increase in antioxidants in the heart tissue of animals treated with drug combination. Similarly, ECG, MAB, and HR were restored to normalcy in drug-treated animals. 
 Conclusion: It may be concluded that the herb-drug combinations i. e TCE (500 mg/kg)+AT (10 mg/kg) and TCE (500 mg/kg)+PP (10 mg/kg) has shown increased cardioprotective activity than they were used alone.

Musa balbisiana Fruit Rich in Polyphenols Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats via Inhibition of Inflammation and Oxidative Stress.

Musa balbisiana Colla (Family: Musaceae), commonly known as banana and native to India and other parts of Asia, is very rich in nutritional value and has strong antioxidant potential. In the present study, we have developed Musa balbisiana (MB) fruit pulp powder and evaluated its cardioprotective effect in cardiac hypertrophy, which is often associated with inflammation and oxidative stress. An ultra-high-pressure liquid chromatography-mass spectrometer (UPLC-MS/MS) has been used for the detection and systematic characterization of the phenolic compounds present in Musa balbisiana fruit pulp. The cardioprotective effect of MB was evaluated in a rat model of isoproterenol- (ISO-) induced cardiac hypertrophy by subcutaneous administration of isoproterenol (5 mg/kg−1/day−1), delivered through an alzet minipump for 14 days. Oral administration of MB fruit pulp powder (200 mg/kg/day) significantly (p < 0.001) decreased heart weight/tail length ratio and cardiac hypertrophy markers like ANP, BNP, β-MHC, and collagen-1 gene expression. MB also attenuated ISO-induced cardiac inflammation and oxidative stress. The in vivo data were further confirmed in vitro in H9c2 cells where the antihypertrophic and anti-inflammatory effect of the aqueous extract of MB was observed in the presence of ISO and lipopolysaccharide (LPS), respectively. This study strongly suggests that supplementation of dried Musa balbisiana fruit powder can be useful for the prevention of cardiac hypertrophy via the inhibition of inflammation and oxidative stress.

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.

MicroRNA-135a inhibits cardiac fibrosis induced by isoproterenol via TRPM7 channel

BackgroundCardiac fibrosis is a crucial factor of heart failure. It has been reported that several microRNAs (miRNAs, miRs) were involved in cardiac fibrosis, however, the role and possible regulatory mechanism of microRNA-135a (miR-135a) in cardiac fibrosis have not been investigated. Here, we explored the regulation mechanism of miR-135a on cardiac fibrosis. Methods and ResultsIn vitro, cardiac fibroblasts (CFs) from neonatal rats were treated by isoproterenol (ISO) at the final concentration of 10 μM for 24 h and miR-135a expression was decreased obviously. A miR-135a mimic inhibited CFs proliferation and differentiation by down-regulating transient receptor potential melastatin 7 (TRPM7) expression and current, whose effects were reversed by either the addition of miR-135a mimic or silencing TRPM7. In vivo, adult SD rat cardiac fibrosis was induced by subcutaneous administration of ISO (5 mg/kg/day) for 10 days. The expression of Collagen I, α-smooth muscle actin (α-SMA) and TRPM7 were up-regulated while miR-135a was down-regulated. In summary, our results illustrated that TRPM7 channel played an essential role in regulating fibrosis and that miR-135a protected against ISO-induced cardiac fibrosis via TRPM7 channel. ConclusionMiR-135a inhibits cardiac fibrosis via miR-135a- TRPM7-collagen production pathway.

Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear Factor-Like 2 activation

Introduction: Icariin, a major component of Epimedium species and a mild phosphodiesterase 5 (PDE-5) inhibitor, was evaluated for the prevention of myocardial oxidative stress in isoproterenol (ISO)-challenged Wistar rats. Objective: This study aimed to evaluate the cardioprotective action of icariin in ISO-intoxicated rats. Materials and Methods: Rats were daily treated with icariin (1, 5, and 10 mg/kg, p.o.) and sildenafil (0.7 mg/kg, i.p.) for 15 days. Oxidative stress was induced by subcutaneous administration of ISO (85 mg/kg s.c) in two consecutive doses at an interval of 24 h on 14th and 15th day of the study. After induction, rats were anesthetized for recording the electrocardiogram (ECG) and then sacrificed to perform immunohistochemistry and biochemical assays of heart tissue. Results: ISO treatment resulted in a marked increase in lipid peroxidation, serum markers (lactate dehydrogenase [LDH], creatine kinase-MB [CK-MB], and C-reactive protein [CRP]), and infarct size and a significant decrease in the level of reduced glutathione (GSH) and endogenous antioxidant enzymes in the myocardium. Lowering of arterial blood pressure and alteration in ECG showed significant alteration in cardiac hemodynamics. Hematoxylin and eosin staining of the cardiac tissue showed considerable myocardial damage. Pretreatment with icariin (5 and 10 mg/kg, p.o.) and sildenafil (0.7 mg/kg, i.p) significantly decreased the elevated lipid peroxidation, LDH, CK-MB, and CRP. Moreover, the results also showed an increase in endogenous antioxidants and protein expression of nuclear factor-like 2 (Nrf-2) when compared to the ISO-treated group. Conclusion: The results indicated that icariin significantly ameliorates the ISO-induced oxidative stress and restores membrane integrity and cellular damage. Thus, we can conclude that the activation of Nrf-2 signaling and PDE-5 inhibition by icariin is possibly responsible for the cardioprotection. Abbreviations used: Nrf-2: Nuclear factor-like 2, PDE-5: Phosphodiesterase-5, ISO: Isoproterenol, TCM: Traditional Chinese Medicine, ECG: Electrocardiogram, LDH: Lactate dehydrogenase, CK-MB: Creatine kinase-MB, CRP: C-reactive protein, GSH: Endogenous glutathione, TBARS: Thiobarbituric acid reactive substances, GPx: Glutathione peroxidase, GR: Glutathione reductase, GST: Glutathione-S-transferase, SOD: Superoxide dismutase, CAT: Catalase, H and E: Hemotoxylin and eosin, MAPK: Mitogen-activated protein kinase, CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals guidelines, DMSO: Dimethyl sulfoxide, MM-GBSA: Molecular mechanics-generalized born surface area, BPM: Beats per minute.

In vivo ameliorative effect of cerium oxide nanoparticles in isoproterenol-induced cardiac toxicity

BackgroundCerium oxide nanoparticles have gained much more attention especially in the field of nanomedicine. This work represents cerium oxide nanoparticles as a new prophylactic model for heart failure progression. ObjectiveTo investigate the potential protective effect of cerium oxide nanoparticles on Isoproterenol (ISO)-induced cardiac toxicity in rats. MethodsCerium oxide nanoparticles (5±1nm) were synthesized by reverse micelle method and characterized using High Resolution Transmission Electron Microscopy, X-Ray Diffraction and particle size analyzer. The experiments were performed on 96 male Wistar rats. The rats were randomly allocated into eight groups. Namely; two Negative and positive control groups, captopril administered group, Nano-ceria (low dose) group, Nano-ceria (high dose) group, Captopril- Isoproterenol group, Nano-ceria (low dose)-Isoproterenol group and Nano-ceria (high dose)-Isoproterenol group. Cardio toxic rat model was induced by subcutaneous administration of Isoproterenol (ISO) (30mg/kg) for two consecutive days in adult male rats. Two doses (0.5 and 5μg/kg/week) of cerium oxide nanoparticles were applied for five weeks and 50mg/kg/day of Captopril was used as a reference drug. Cardiac marker enzymes, Cortisol and Aldosterone hormones were assessed in serum. Oxidant-antioxidant parameters and histopathological examination in heart tissues were also determined. ResultsThese dose of nano-ceria, showed a promising ameliorative and prophylactic effect against cardiac toxicity compared to Captopril reference drug. Serum cardiac markers were decreased by noticeable percentage, CK-MB (50% and 57%), LDH (47% and 57.7%), AST (38% and 36.5%) and ALT (33.5% and 30.6%) for both doses respectively, while increased tissues level of the antioxidant enzymes, catalase (48% − 26%) and superoxide dismutase (64%, 143%). ConclusionThese consistent biochemical and histopathological results suggest that, nano-ceria could be used as effective antioxidant in prophylactic protocols for management of cardiac disorders associated with oxidative stress.

Nigella sativa protects against isoproterenol-induced myocardial infarction by alleviating oxidative stress, biochemical alterations and histological damage

ObjectiveTo evaluate the cardioprotective effect of Nigella sativa L. (N. sativa) in isoproterenol-induced myocardial infarction (MI). MethodsGroups were treated with different doses of ethanol extract of N. sativa (EENS) and N. sativa oil alone and along with enalapril for 28 days. MI was induced by subcutaneous administration of isoproterenol (85 mg/kg) in two consecutive doses. Levels of cardiac biomarkers and antioxidant enzymes such as creatine kinase–N-acetyl-l-cysteine, lactate dehydrogenase, aspartate aminotransferase, malondialdehyde, superoxide dismutase, reduced glutathione and catalase were evaluated along with gross histopathological examination. ResultsIsoproterenol (85 mg/kg) induced MI by causing the significant (P < 0.01) reduction in the activity of cardiac biomarkers (creatine kinase–N-acetyl-l-cysteine, lactate dehydrogenase, aspartate aminotransferase) and antioxidant markers (superoxide dismutase, catalase, glutathione) along with significant (P < 0.01) increase in the level of malondialdehyde. Furthermore, histopathological evaluation also confirmed the isoproterenol-induced MI. Pretreatment with EENS (800 mg/kg) and combination of EENS (800 mg/kg) with enalapril (1 mg/kg) significantly (P < 0.01) prevented the development of these alteration and restored activity of cardiac biomarkers as well as antioxidant markers almost near to normal levels. Histopathological evaluation of cardiac tissue further confirmed the restoration of biochemical activity. ConclusionsExperimental findings thus indicate that EENS (800 mg/kg) demonstrated cardioprotective effect against isoproterenol-induced MI by restoring cardiac biomarkers and antioxidant status.

Synthetic catecholamine triggers β1-adrenergic receptor activation and stimulates cardiotoxicity via oxidative stress mediated apoptotic cell death in rats: Abrogating action of thymol

Nowadays, there are considerable interests in the studies which are more connected with the impact of natural antioxidants against the free radical mediated damage in biological systems. Cardiotoxicity is one of the lethal manifestations of cardiovascular diseases (CVDs) which have been associated with the incidence of apoptotic cell death due to oxidative stress. We evaluated the impact of thymol, a dietary monoterpene phenol on isoproterenol (ISO), a synthetic catecholamine and a β1-adrenergic receptor agonist in rats. Thymol (7.5 mg/kg body weight) was pre and co-treated into male albino Wistar rats daily for a period of 7 days. Induction of cardiotoxicity was done by the subcutaneous administration of ISO (100 mg/kg body weight) into rats on 6th and 7th day. Cardiotoxicity in rats was confirmed by the increased levels/activity of serum troponin-T and creatine kinase in the serum alongwith decreased activity of creatine kinase in the heart. ISO induced cardiotoxic rats also showed a significant increase in the concentrations of lipid peroxidation products and a significant decrease in the activities/levels of antioxidants in the myocardium whereas Reverse Transcription Polymerase Chain Reaction study revealed an increased expression of caspase-8, caspase-9 and Fas genes along with a decreased expression of Bcl-xL gene in the myocardium. Thymol pre and co-treated ISO induced cardiotoxic rats showed considerable protective effects on all the biochemical parameters studied. Histopathological and in vitro findings are found in line with our biochemical findings. Thus, the present study revealed that thymol counters ISO induced cardiotoxicity by inhibiting oxidative stress and apoptotic cell death in rats by virtue of its potent antioxidant property.

Activation of β1-adrenoceptor triggers oxidative stress mediated myocardial membrane destabilization in isoproterenol induced myocardial infarcted rats: 7-hydroxycoumarin and its counter action

Activation of β1-adrenoceptor stimulates myocardial membrane destabilization in isoproterenol induced rats. Male albino Wistar rats were pre and co-treated with 7-hydroxycoumarin (16mg/kg body weight) daily for 8 days. Myocardial infarction was induced into rats by the subcutaneous administration of isoproterenol (100mg/kg body weight) at an interval of 24h daily for a period of two days (7th and 8th day). The levels/activities of serum cardiac troponin-T, lactate dehydrogenase and the concentrations of heart lipid peroxidation products were significantly increased and the antioxidant status was significantly decreased in isoproterenol induced rats. Furthermore, the activity of sodium/potassium-dependent adenosine triphosphatase was significantly decreased and the activities of calcium and magnesium-dependent adenosine triphosphatases were significantly increased in the heart of isoproterenol induced myocardial infarcted rats. Isoproterenol induced rats also revealed increased concentrations of sodium and calcium and decreased concentrations of potassium in the heart. 7-hydroxycoumarin pre- and co-treatment showed considerable impact on all biochemical parameters assessed. Also, 7-HC greatly reduced the infarct size of the myocardium. The in vitro study confirmed its potent free radical scavenging activity. Thus, the present study revealed that 7-HC attenuates myocardial membrane destabilization by reinstating the activities/levels of adenosine triphosphatases and minerals in isoproterenol induced rats by inhibiting oxidative stress. These effects are attributed to the membrane stabilizing and free radical scavenging properties of 7-hydroxycoumarin.

Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: Biochemical and ultrastructural evidence

Objectives: The present study was designed to evaluate the cardioprotective potential of edaravone on oxidative stress, anti-apoptotic, anti-inflammatory and ultrastructure findings in isoproterenol (ISO) induced myocardial infarction (MI) in rats.Methods: Rats were pretreated with edaravone (1, 3, 10 mg/kg body weight-1 day-1) intraperitoneally. MI was induced by subcutaneous administration of ISO (85 mg/kg body weight-1) at two doses with 24h interval.Results: ISO treated rats showed significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and decreased levels of reduced glutathione, glutathione perdoxidase, glutathione reductase and glutathione-S- transferase in the cardiac tissues. Moreover, significant increase in the levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), C - reactive protein and caspase-3 activity was observed in ISO treated group. Pretreatment of ISO intoxicated rats with edaravone showed significant decrease in the level of TBARS, increased activities of antioxidant enzymes and significantly decreased levels of LDH and CK-MB. Moreover, results also showed decreased C-reactive protein level, caspase-3 activity and maintained ultrastructure of the myocardial cells.Discussion: Our study suggests that edaravone possess strong cardioprotective potential. Edaravone may have exhibited cardioprotective effects by restoring antioxidant defense mechanism, maintaining integrity of myocardial cell membrane, reducing apoptosis and inflammation against ISO induced MI and associated oxidative stress.

Cardioprotective role of H3R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats

The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.

The potential benefits of a garlic and hydrochlorothiazide combination as antihypertensive and cardioprotective in rats

The purpose of the present study was to investigate the protective effects of combined therapy of garlic homogenate and hydrochlorothiazide (HCTZ) in animals with hypertension and myocardial damage. Three weeks of high fructose (10% w/v) in fluid to albino rats resulted in hypertension. They were subsequently administered garlic (125, 250 and 500 mg/kg, 3 weeks in separate groups) and HCTZ (10 mg/kg, 6th week) once daily in their respective groups. At the end of 6 weeks, myocardial damage was induced by subcutaneous administration of isoproterenol (175 mg/kg) for 2 consecutive days. The results showed that garlic and HCTZ increase the lactate dehydrogenase, creatinine phosphokinase, superoxide dismutase and catalase activities in heart homogenate when used concurrently or separately. Further, restoration of normal values in fluid/food intake, body weight, systolic blood pressure, cholesterol, triglycerides, glucose and histopathological scores were observed in all treated groups. Furthermore, histological disturbances and hypertension were significantly ameliorated in treated animals. Moreover, moderate dose of garlic was more effective than low dose, while a high dose of garlic was least effective in correcting electrocardiographic changes. Thus it is concluded that garlic in moderate dose (250 mg/kg) with added HCTZ possesses synergistic cardioprotective and antihypertensive properties against fructose- and isoproterenol-induced toxicities.

Cardioprotective Activity of Methanolic Extract of Aegle Marmelos Leaf Extract against Isoproterenol Induced Myocardial Damage in Rats

The present study was undertaken to evaluate the cardioprotective effect of methanolic extract of Aegle marmoles leaves (AMLE) against isoproterenol (ISO) induced myocardial damage in rats. Rats of either sex were administered AMLE (100 and 500 mg/kg) for three weeks and propranolol (PRO, 10 mg/kg) for one week in their respective groups orally. Subsequently myocardium injury was induced by subcutaneous administration of isoproterenol (150 mg/kg) for two consecutive days. The influence of prophylactic treatment was analysed by quantification of biomarkers and antioxidants. The CK-MB activities were fallen in serum and raised in heart tissue of animals treated with low and high doses of AMLE as well as PRO compared to ISO control. However, low dose of AMLE did not demonstrate any significant change in serum and tissue LDH activity when compared to ISO control. Further, high and low doses of AMLE caused significant elevation in SOD and CAT activities compared to ISO control. Furthermore, TBARS level declined in heart tissues of animals treated with PRO and high doses of AMLE, whereas, low dose of AMLE was not equally potent. Hence it is concluded that the low dose of AMLE was less effective than the high dose of AMLE and PRO.

Effect of Aqueous Extract of Nutmeg on Hyperglycaemia, Hyperlipidaemia and Cardiac Histology Associated with Isoproterenol-induced Myocardial Infarction in Rats

Purpose: The present study was designed to evaluate the hypoglycaemic and hypolipidaemic activities of the aqueous extract of nutmeg (i.e., the kernel of Myristica fragrans) in rat models against myocardial infarction (MI) induced by isoproterenol (ISO).Methods: Rats were pretreated with nutmeg extract (NM) at an oral dose of 100 mg/kg/day for a period of 30 days, followed by the induction of MI by subcutaneous administration of ISO (85 mg/kg) for two consecutive days. The heart tissue was excised immediately, washed with chilled isotonic saline and used in histopathological studies. Blood was also collected from the animals and the plasma separated was subjected to biochemical analysis.Results: In ISO-administered group, a significant (p < 0.05) increase in the levels of blood glucose, plasma lipids and lipoprotein lipase activity was observed along with hyalinization of muscle fibres, compared NM-pretreated ISO-administered rats. In rats treated with NM, biochemical parameters were near normal. Histological studies revealed reduced damage of heart tissue in ISO-administered rats that were pretreated with NM.Conclusion: NM possesses protected rats against hyperglycaemia, hyperlipidaemia and cardiac tissue damage following MI. Therefore, NM should be further investigated as a prophylactic against the risk of MI.

Effect of DuP 753, a nonpeptide angiotensin II receptor antagonist, on the drinking responses to acutely administered dipsogenic agents in rats.

The present studies examine the effect of the nonpeptide angiotensin II (AII) type 1 receptor antagonist, DuP 753, on water intake in rats treated with dipsogenic stimuli, which are thought to induce drinking via release of renin and subsequent formation of AII. Subcutaneous administration of DuP 753 in doses that are known to inhibit drinking induced by AII failed to inhibit the water intake of rats following subcutaneous administration of the beta-adrenoceptor agonist isoproterenol. The peptide antagonist1 Sar, 8Ileu-AII, which blocks both AII type 1 and AII type 2 receptors, also failed to inhibit isoproterenol-induced drinking, suggesting that neither subtype is involved in this drinking response. Additional studies verified previous reports that acute subcutaneous administration of both the beta-adrenoceptor antagonist propranolol and the angiotensin I-converting enzyme inhibitor captopril could block the drinking response to subcutaneous administration of isoproterenol. Subcutaneous administration of DuP 753 also failed to inhibit the drinking responses to subcutaneous administration of serotonin, 5-hydroxytryptophan, hypertonic saline, and polyethylene glycol. However, central intraventricular administration of DuP 753 inhibited the drinking response to subcutaneous administration of isoproterenol. The results are discussed in terms of the importance of AII in mediating isoproterenol-, serotonin-, and 5-hydroxytryptophan-induced water intake and suggest a need to readdress this mechanism.

Effects of lipoxygenase and cyclooxygenase inhibitors on the induction of ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate and isoproterenol in mouse tissues in vivo.

I.p. administration of 12-O-tetradecanoylphorbol-13-acetate (TPA) (400 micrograms/kg) caused a remarkable increase in ornithine decarboxylase (ODC) activity in CD-1 mouse liver (8.3-fold), spleen (17.8-fold), kidney (4-fold), lung (7.7-fold) and brain (2.7-fold). TPA induced an increase in ODC activity in liver, spleen and kidney in a dose-dependent manner (100-800 micrograms/kg). The putrescine contents of these tissues were also increased by TPA injection. BW755C, an inhibitor of cyclooxygenase and lipoxygenase, prevented the TPA-induced increase in ODC activity in liver, spleen and kidney in a dose-dependent manner. AA861-a selective lipoxygenase inhibitor, also showed the inhibition of TPA-induced increase in ODC activity in these tissues. Significant inhibition was observed either by BW755C or AA861 at the dose of 30 mg/kg. On the other hand, indomethacin, a selective cyclooxygenase inhibitor, enhanced the TPA-induced increase in ODC activity in these tissues dose-dependently. Significantly enhancement was observed at 3 mg/kg for liver and spleen and 1 mg/kg for kidney. The subcutaneous administration of isoproterenol (1 mg/kg) caused an increase in ODC activity in both liver (11-fold) and spleen (3.4-fold). Both AA861 and BW755C failed to inhibit the isoproterenol-induced increase in ODC activity in these tissues. These results indicate that product(s) of lipoxygenase pathway play an important role in ODC induction caused by TPA in liver, spleen and kidney, while the lipoxygenase pathway does not play an essential role in the isoproterenol-induced increase in ODC activity.

Mediation of isoproterenol-induced thirst in rats by β2-adrenergic receptors

Isoproterenol-induced thirst in rats has been attributed to the activation of beta-adrenergic receptors. Since these receptors can be further differentiated pharmacologically into beta1 and beta2 types, experiments were performed using several beta-adrenergic agonists and antagonists to determine the receptor type initiating the isoproterenol-induced thirst. The beta1- and beta2-adrenergic antagonist, d,l-propranolol (1 mg/kg, ip), blocked the increase in water intake usually accompanying acute subcutaneous administration of isoproterenol (25 microgram/kg) to female rats. Since l-propranolol is known to stabilize membranes and to possess anesthetic-like properties, d-propranolol was also used. This isomer has little beta-adrenergic-blocking activity but possesses anesthetic-like activity. Administration of d-propranolol (1 mg/kg, ip) failed to affect the drinking response to acute administration of isoproterenol (25 microgram/kg). Practolol (125 mg/kg), a beta1-adrenergic antagonist with little anesthetic properties, also had no effect on water intake of isoproterenol-treated rats. Butoxamine, a selective beta2-adrenergic antagonist, attenuated the drinking response to isoproterenol. Salbutamol (150 microgram/kg), a beta2-adrenergic agonist, mimicked the effect of isoproterenol on water intake. These results are consistent with the suggestion that beta2-adrenergic receptors mediate the isoproterenol-induced thirst in rats.