Sachin Arora

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

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

Upregulation of PPARγ by Aegle marmelos ameliorates insulin resistance and β-cell dysfunction in high fat diet fed-streptozotocin induced type 2 diabetic rats.

The global epidemic of type 2 diabetes demands the rapid evaluation of new and accessible interventions. This study investigated whether Aegle marmelos fruit aqueous extract (AMF; 250, 500 and 1000 mg/kg) improves insulin resistance, dyslipidemia and β‐cell dysfunction in high fat diet fed‐streptozotocin (HFD‐STZ)‐induced diabetic rats by modulating peroxisome proliferator‐activated receptor‐γ (PPARγ) expression. The serum levels of glucose, insulin, homeostasis model assessment of insulin resistance (HOMA‐IR), homeostasis model assessment of β‐cell function (HOMA‐B), lipid profile, TNF‐α and IL‐6 were evaluated. Further, the TBARS level and SOD activity in pancreatic tissue and PPARγ protein expression in liver were assessed. In addition, histopathological and ultrastructural studies were performed to validate the effect of AMF on β‐cells. The HFD‐STZ treated rats showed a significant increase in the serum levels of glucose, insulin, HOMA‐IR, TNF‐α, IL‐6, dyslipidemia with a concomitant decrease in HOMA‐B and PPARγ expression. Treatment with AMF for 21 days in diabetic rats positively modulated the altered parameters in a dose‐dependent manner. Furthermore, AMF prevented inflammatory changes and β‐cell damage along with a reduction in mitochondrial and endoplasmic reticulum swelling. These findings suggest that the protective effect of AMF in type 2 diabetic rats is due to the preservation of β‐cell function and insulin‐sensitivity through increased PPARγ expression. Copyright

Modulation of PPAR-γ by telmisartan protects the heart against myocardial infarction in experimental diabetes

Telmisartan, an angiotensin II-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We investigated whether telmisartan improved the pathophysiology of myocardial infarction in diabetes partially through the PPAR-gamma pathway by assessing a variety of indices, e.g., hemodynamic, biochemical, histoarchitectural changes, and apoptosis. Diabetes was induced by a single dose of streptozotocin (70 mg/kg, IP). Diabetic rats received either telmisartan (10 mg/kg/day, orally), the PPAR-gamma antagonist GW9662 (1 mg/kg/day, IP), or both for 14 days with concurrent administration of isoproterenol (85 mg/kg, SC) on days 13 and 14. Compared with diabetic controls, diabetic rats with myocardial infarction exhibited altered hemodynamic profiles and reduction in the activities of creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level along with increased level of malondialdehyde in the heart. Further, diabetic animals with myocardial infarction exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with telmisartan significantly improved the redox status of the myocardium with subsequent cardiac functional recovery. However, significant effects were lowered in animals treated with telmisartan plus GW9662. Telmisartan markedly inhibited Bax expression, TUNEL-positive cells, myonecrosis, and edema. On the other hand, administration of telmisartan plus GW9662 did not elicit the same effects, nor did they increase Bcl-2 protein expression in isoproterenol-induced myocardially infarcted diabetic rats when administered concomitantly or individually. Moreover, down-regulated PPAR-gamma expression in myocardially infarcted diabetic hearts was increased by telmisartan treatment. In addition to class effects of ARBs, telmisartan reduces oxidative stress and apoptosis and improves cardiac function via the PPAR-gamma pathway.

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 800mg/kg/day, orally) or vehicle for 14 days with concurrent ISO administration (85mg/kg, subcutaneously, 2 doses at 24h 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 800mg/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.

Myocardial salvaging effect of telmisartan in experimental model of myocardial infarction

Telmisartan is a unique angiotensin II receptor blocker with an additional peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activity. The present study has been designed to investigate whether telmisartan treatment attenuates the development of acute myocardial infarction in isoproterenol-treated rats by restoring hemodynamic, biochemical, histopathological and ultrastructural changes. Isoproterenol-induced cardiotoxicity was evidenced by marked decrease in systolic, diastolic, mean arterial pressures, maximal positive rate of developed left ventricular pressure (+LVdP/dt(max), a marker of myocardial contraction), maximal negative rate of developed left ventricular pressure (-LVdP/dt(max), a marker of myocardial relaxation) and an increase in left ventricular end-diastolic pressure (LVEDP, a marker of pre-load). In addition, a significant reduction in activities of myocardial creatine kinase-MB (CK-MB) isoenzyme, lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) level along with increase in malondialdehyde (MDA) content were observed. Oral pretreatment with telmisartan (1, 5 and 10mg/kg body weight) daily for a period of 14 days, favourably modulated the studied parameters in isoproterenol-induced myocardial injury. In addition, the protective role of telmisartan on isoproterenol-induced myocardial damage was further confirmed by histopathological and ultrastructural examinations. Telmisartan at a dose of 10mg/kg produced more pronounced protective effects than the other two doses (1 and 5mg/kg body weight). Present study thus provides evidence for protective effects of telmisartan on myocardium in experimentally induced myocardial infarction.

Cardioprotective effect of lycopene against isoproterenol-induced myocardial infarction in rats

The present study was designed to evaluate the cardioprotective potential of lycopene (LCP) against isoproterenol (ISP)-induced myocardial infarction (MI), by assessing hemodynamic, biochemical and histopathological parameters. Wistar male albino rats were orally administered with LCP (0.5, 1.0 and 1.5 mg/kg) or with vehicle for 30 days, with concurrent subcutaneous injections of ISP (85 mg/kg) on days 28 and 29. ISP significantly (p < 0.05) decreased systolic, diastolic and mean arterial blood pressure (SAP, DAP and MAP, respectively) and heart rate (HR). ISP also decreased contractility (+LVdP/dt), relaxation (−LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). In addition to functional impairment, ISP also caused a significant (p < 0.05) decrease in antioxidants, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), glutathione (GSH), cardiac injury marker enzymes, creatine phosphokinase-MB (CK-MB) and lactate dehydrogenase (LDH), as well as induced lipid peroxidation, malonaldialdehyde (MDA) and histopathological alterations in heart. However, pretreatment with LCP significantly (p < 0.05) attenuated ISP-induced cardiac dysfunction as evidenced by improved SAP, DAP, MAP, HR, (±)LVdP/dt and reduced LVEDP. Pretreatment with LCP also significantly (p < 0.05) prevented the depletion of antioxidants (SOD, CAT, GSHPx and GSH), myocyte injury marker enzymes (CK-MB and LDH) and inhibited lipid peroxidation and MDA formation in the heart. Furthermore, reduced necrosis, edema and infiltration of inflammatory cells on histopathological examination also depicted the protective effect of LCP against the deleterious effect of ISP. Based on the results, it is suggested that LCP possesses significant cardioprotective potential and may serve as an adjunct in treatment and prophylaxis of MI.

Endothelin receptor antagonist BQ-123 ameliorates myocardial ischemic-reperfusion injury in rats: a hemodynamic, biochemical, histopathological and electron microscopic evidence.

We investigated the effect of BQ-123, a selective endothelin-A (ET(A)) receptor antagonist in ischemia-reperfusion (IR) induced myocardial infarction (MI) with and without endothelin-1 (ET-1) challenge. MI was produced in rats by occlusion of left anterior descending coronary artery for 40 min and reperfusion for 120 min. ET-1 was administered immediately prior to coronary occlusion whereas vehicle or BQ-123 was administered 20 min after the occlusion. IR control group exhibited marked hemodynamic changes along with significant impairment of left ventricular functions. In addition, oxidative stress was increased, as evidenced by marked reduction in the activities of antioxidants and cardiac injury markers in myocardium. Furthermore, light microscopic and ultrastructural changes revealed myocardial necrosis, edema and inflammation. Prior administration of ET-1 acts synergistically with IR injury and further aggravates the impairment of ventricular functions, increased percent infarct area and decreased antioxidant levels. However, treatment with BQ-123 (1 mg/kg, IV) with or without ET-1 caused significant improvement in cardiac functions, percent infarct area, decreased malonaldehyde level, restored myocardial enzymes activities and maintained the redox status of the myocardium as compared to IR control group. Further, histopathological and ultrastructural studies reconfirmed the protective action of BQ-123. The results of present study suggest that ET-1 acting via ET(A) receptor may exaggerate myocardial damage produced by IR injury and selective blockade of ET(A) receptor by BQ-123 might offer potential cardioprotective action.

Cardioprotective effects of benazepril, an angiotensin-converting enzyme inhibitor, in an ischaemia-reperfusion model of myocardial infarction in rats

Introduction. The present study evaluated the effects of benazepril, an angiotensin-converting enzyme inhibitor on haemodynamic, biochemical, and immunohistochemical (Bax and Bcl-2 protein) indices in ischaemia and reperfusion (IR) injury. Materials and methods. Male Wistar albino rats were divided into three groups and were orally administered saline once daily (IR-sham and IR-control) or benazepril (30 mg/kg/day; IR-benazepril) for 14 days. On the 15th day, in the IR-control and IR-benazepril groups, rats were subjected to left anterior descending coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical estimation and immunohistochemistry. Results. In the IR-control group, significant ventricular dysfunctions (p<0.05 vs. IR-sham group) were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in lactate dehydrogenase activity and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, were observed. Benazepril pretreatment significantly improved mean arterial pressure (p<0.01), reduced left ventricular end-diastolic pressure (p<0.05), and improved both inotropic and lusitropic function of the heart (+LVdP/dt and — LVdP/dt) (p<0.05; p<0.01) as compared to IR-control. Furthermore, benazepril treatment significantly decreased the level of thiobarbituric acid reactive substances and restored the activity of lactate dehydrogenase towards normal value (p<0.05 vs. IR-control). Conclusion. This study demonstrates that benazepril upregulated Bcl-2 protein and decreased Bax protein expression, thus exhibiting anti-apoptotic effects. These beneficial effects of benazepril will have an important implication in the therapeutic use of benazepril in ischaemic heart disease.

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

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