|Year : 2012 | Volume
| Issue : 3 | Page : 333-339
Influence of pioglitazone on experimental heart failure and hyperlipidemia in rats
Arghya Biswas1, Syed Imam Rabbani2, Kshama Devi1
1 Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, India
2 Qassim University, Saudi Arabia
|Date of Submission||06-Jan-2011|
|Date of Decision||27-Sep-2011|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Syed Imam Rabbani
Objectives: To investigate the effect of pioglitazone on isoproterenol-induced heart failure and high-fructose diet-induced metabolic changes in rats.
Materials and Methods: Three doses of pioglitazone (Pio - 3, 10, 30 mg/kg, po) were tested in male Wistar rats. In the Heart Failure (HF) group, treatment was followed by Isoproterenol (ISO) injection. The markers for HF, such as enzyme estimation, relative heart weight, and antioxidant status, were evaluated. In another group, metabolic disturbances were induced by High Fructose Diet (HFD). The influence of Pio treatment on Systolic Blood Pressure (SBP), serum glucose, Triglycerides (TG), Total Cholesterol (TC), and High-Density Lipoprotein (HDL)-cholesterol (HDL-c) were determined.
Results: The results indicated that Pio at 10 mg increased significantly (P<0.05) the Lactate Dehydrogenase (LDH), Creatinine Kinase-MB (CK-MB), and antioxidant enzyme levels as compared to ISO. The high dose of Pio (30 mg) enhanced (P<0.05) Aspartate Transaminase (AST), Alanine Transaminase (ALT), Lipid Peroxidation (LPO),and relative heart weight in addition to increased LDH, CK-MB, and antioxidant enzyme activity. In the HFD group, a dose-dependent inhibitory effect was observed. Pio at 3 mg significantly reduced (P<0.05) elevated glycemia, TG, and SBP as compared to HFD rats. Further, the higher doses of Pio (10 and 30 mg) enhanced the inhibitory effect on glucose, TG, and SBP besides elevating the HDL-c levels. However, none of the tested doses of Pio significantly altered the TC level in HFD rats.
Conclusion: The observations suggest that Pio exhibits anti-diabetic and anti-hypertensive effects and also partially corrected the hyperlipidemia, but the treatment augmented the cardiac damage associated with ISO. The antioxidant property of Pio appears to have a limited role in protecting the ISO-mediated heart damage.
Keywords: Anti-hyperlipidemia, anti-hypertensive, heart failure, pioglitazone
|How to cite this article:|
Biswas A, Rabbani SI, Devi K. Influence of pioglitazone on experimental heart failure and hyperlipidemia in rats. Indian J Pharmacol 2012;44:333-9
|How to cite this URL:|
Biswas A, Rabbani SI, Devi K. Influence of pioglitazone on experimental heart failure and hyperlipidemia in rats. Indian J Pharmacol [serial online] 2012 [cited 2013 May 19];44:333-9. Available from: http://www.ijp-online.com/text.asp?2012/44/3/333/96305
| » Introduction|| |
The Thiazolidinediones (TZDs) drug class has emerged as an effective pharmacologic treatment option for improving glycemic control in patients with type-2 diabetes mellitus. These act as agonists for nuclear transcription factor Peroxisome Proliferators-Activated Receptor gamma (PPAR-γ) and primarily improve insulin sensitivity. TZDs therapy has been reported to reduce lipid levels in serum, blood pressure, inflammatory biomarkers, endothelial function, fibrinolytic status, cardiac hypertrophy, and infarct size that may benefit the diabetic patients associated with cardiovascular diseases.  However, the clinical studies revealed several adverse reactions associated with TZDs therapy. 
Troglitazone, the first clinically approved TZD for diabetes was withdrawn from market in the year 2000 due to severe hepatotoxicity.  Although pioglitazone and rosiglitazone were reported to be devoid of major hepatotoxic effects, but these agents were found to increase the body weight, edema, and low-density lipoproteins, ultimately enhancing the risk of heart failure. 
In 2007, a meta-analysis based on 42 randomized trials suggested that TZDs increased the risk of myocardial infarction and cardiovascular deaths.  It was believed that the incidences of cardiac defects were less with pioglitazone, but subsequent trials indicated no difference in the complications between pioglitzone and rosiglitazone. , A PROACTIVE (PRO spective pioglitAzone Clinical Trial In macro Vascular Events) study conducted on diabetic patients indicated 11% increased chances of congestive heart failure in pioglitazone (Pio)-treated patients as compared to placebo treated patients.  Similarly, the trials involving rosiglitazone also indicated the complications of heart failure.  These studies presumed that the chances of heart failure is more prevalent in diabetics who have a history of cardiac problems. ,, However, larger trials involving more number of patients concluded that the chances of heart failure with TZDs therapy is equal in both diabetic and non-diabetic patients.  As a consequence, Food and Drug Administration (FDA) and other drug regulatory bodies took the decision to ban TZDs from being used for diabetes therapy.  Although these drugs are not available in the market, there are uncertainties regarding the cardiovascular toxic effect of TZDs. A retrospective cohort study conducted on more than 16,000 patients reported that the mortality rates in heart failure patients treated with TZDs were 30% lower as compared with patients receiving anti-diabetic medications other than TZDs. According to this study, although TZDs may increase peripheral edema, a symptom of heart failure, these did not increase mortality and may actually decrease it. 
Considering the complex cardiovascular action of TZDs and lack of sufficient data from the chronic animal studies to support the clinical finding, the present research was planned to evaluate the influence of Pio on cardiac failure and hyperlipidemia by using isoproterenol and HFD, respectively, in rats.
| » Materials and Methods|| |
A gift sample of pioglitazone (Pio) was procured from Dr. Reddys laboratories Ltd, India. Isoproterenol was purchased from Sigma Aldrich, USA. Other chemicals and reagents used in the study were purchased from regular supplier and are of analytical grade.
Eight-week-old healthy, laboratory bred, male Wistar rats weighing 180 ± 10 gm were maintained under standard laboratory conditions-temperature 20 ± 2°C, 12-hour light/dark cycle, and provided water and pellet food ad libitum. The experiments were conducted in Committee for the purpose of control and supervision of experiments on animals, Chennai, India (CPCSEA)-approved animal house after obtaining prior approval from the Institutional Animal Ethics Committee (AACP/IAEC/M-86/2009).
The experiment was conducted in two parts viz., isoproterenol-induced heart failure and high-fructose diet-induced hyperlipidemia in rats. Each test comprised six groups of 10-12 male rats. Group 1 served as control; group 2 as negative control where Pio was tested at 30 mg/kg; group 3 as challenge (isoproterenol or high fructose diet); and group 4, 5, and 6 acted as treatment groups.
I. Isoproterenol-induced heart failure in rats
In this experiment, group 2 animals were treated with Pio 30 mg/kg for 8 weeks. Before administration, Pio was suspended in 1% carboxy methyl cellulose. Group 3 rats received two doses of isoproterenol (85 mg/kg, sc) at an interval of 24 hr to induce experimental heart failure.  The animals in groups 4, 5, and 6 were treated with Pio (3, 10, and 30 mg/kg, po daily) , for 8 weeks followed by isoproterenol (85 mg/kg) on the last two days of Pio treatment at an interval of 24 hr. At the end of the experiment period (ie, 24 hr after the last dose of the respective treatment), the overnight fasted rats were anesthetized (Diethyl ether - 2 ml/kg, open drop method), blood was collected from retro-orbital sinus, animals were sacrificed and there hearts isolated. Serum was separated from blood and the marker enzymes for heart failure such as Lactate Dehydrogenase (LDH), Creatinine Kinase (CK-MB), Aspartate Transaminase (AST) and Alanine Transaminase (ALT) were measured. From the isolated hearts, 50% were homogenized and the homogenate is used for determining the antioxidant status and remaining were subjected to histopathological studies.
Cardiac Biomarker Estimation
Following enzymes were estimated by standard procedure as described by Celik and Tuluce (2007). 
Lactate Dehydrogenase Activity
LDH (EC 22.214.171.124) catalyses the conversion of pyruvate to lactate and, in the process, converts NADH to NAD. The rate of decrease in absorbance due to oxidation of NADH to NAD is proportional to LDH activity.
The principle depends on measurement of CK (EC 126.96.36.199) activity in the presence of an antibody to CK-M monomer. This antibody completely inhibits the activity of CK-MM and half of the activity of CK-MB while not affecting the B subunit activity of CK-MB and CK-BB.
Aspartate Transaminase Activity
The principle depends on the reaction catalyzed by AST (EC 188.8.131.52) to convert L-aspartate to oxaloacetate. Further, oxaloacetate and NADH are converted to L-Malate and NAD, respectively, in the presence of malate dehydrogenase. The rate of decrease in absorbance due to conversion of NADH to NAD indicates the AST activity.
Alanine Transaminase Activity
The principle is same as AST except that ALT (EC 184.108.40.206) catalysis the conversion of L-alanine to pyruvate.
Determination of Antioxidant Profile
The heart homogenate was prepared in normal saline using the tissue homogenizer. The homogenate was centrifuged at 7,000 rpm for 20 minutes at 4°C. The supernatant was collected and used for determining the antioxidant status. Before homogenization, relative heart weight (weight of heart/animal body weight X 100) was recorded.  Standard procedures were followed so as to determine the antioxidant profile  and, in brief, they are summarized as follows:
Lipid Peroxidation (LPO)
The principle depends on the reaction between thiobarbituric acid with malondialdehyde, a secondary product of lipid peroxidation at pH 4. A reddish pink color developed was estimated at 532 nm, which indicates the extent of peroxidation. The extent of lipid peroxidation was expressed in η mol/mg protein.
Superoxide Dismutase (SOD)
The principle for measuring SOD (EC 220.127.116.11) depends on detection of the O2- generated during auto-oxidation of hydroxylamine. During the oxidation, Nitro Blue Tetrazolium (NBT) is reduced and nitrite is produced in the presence of EDTA that can be detected colorimetrically at 560 nm. The concentration of SOD is expressed as units/mg protein.
Glutathione Peroxidase (GPx - EC 18.104.22.168)
A 100-μl aliquot of the serum sample is incubated for 5 min at 37°C with stock solution (0.25 mM GSH, 0.12 mM NADPH, and 1 unit of glutathione reductase prepared in Tris buffer) in a final volume of 1.65 ml. The reaction is started by adding 50 μl of cumene hydroperoxide (1 mg/ml) to the reaction mixture, and the absorbance at 340 nm is monitored for the rate of disappearance of NADPH and the GPx value was represented as unit/mg protein (1 unit = μg of glutathione consumed/min).
Heart samples from each group were washed immediately with saline and preserved in 10% formalin solution. These samples were embedded in paraffin, cut into 5-μm sections, and stained with Hematoxylin and Eosin (H and E). The sections were then examined under light microscope for histo-architectural changes. 
II. High Fructose Diet (HFD)-induced hypertension in rats
In this, group 2 animals were treated with Pio 30 mg/kg and group 3 animals were fed HFD. The HFD was prepared according to the procedure described by Yadav et al. (2004).  During the study period, the animals were fed HFD instead of normal pellet diet. After 8 weeks of induction period, the lipid profile was determined by estimating serum triglycerides, Total Cholesterol (TC), and HDL-c levels. The SBP was recorded using non-invasive Blood Pressure (BP) recorder (Power Lab, Australia). Animals that showed significant alteration in lipid profile and higher SBP (>125 mm Hg) as compared to the control animals were selected for the study.
Three doses of Pio, eg, 3, 10, and 30 mg/kg, , were administered daily (po) for 6 weeks to the hyperlipidemic-hypertensive rats (Groups 4, 5, and 6). HFD was continued during administration of Pio. Apart from lipid profile and SBP, body weight and serum glucose level were also estimated to find the influence of the treatment on metabolism.
A. Biochemical estimation
At the end of the experimental period, blood was withdrawn from the retro-orbital sinus of the rats under light anesthesia; serum was separated by centrifuging the blood at 8,000 rpm for 10 minutes and analyzed for glucose and lipid profile. The lipid profile was determined as per standard procedures. 
The principle depends on oxidation of glucose to gluconic acid and hydrogen peroxide.  The hydrogen peroxide so generated oxidizes the chromogen system consisting of 4-amino antipyrine and phenolic compound to a red quinoneimine dye. The intensity of the color produced is proportional to the glucose concentration and is measured at 505 nm and recorded using semi auto-analyzer (Swemed diagnostic, India).
Serum TG was hydrolyzed to glycerol and free fatty acids by lipase. In the presence of ATP and glycerokinase, the glycerol is converted to glycerol-3-phosphate, which is then oxidized to yield hydrogen peroxide. Hydrogen peroxide reacts in the presence of peroxidase with N-Ethyl-N-sulfopropyl-n-anisidine and 4-aminoantipyrine to form a colored complex that is measured photometrically at 540 nm.
Total Cholesterol (TC)
Cholesterol esters are hydrolyzed by cholesterol esterase, which results in free cholesterol and fatty acids. Free cholesterol is oxidized to cholest-4-en-3-one, liberating hydrogen peroxide that couples with 4-amino antipyrine and phenol in the presence of peroxidase to form a colored compound. The intensity of the color developed is proportional to the cholesterol concentration and is measured photometrically at 500 nm.
Chylomicrons are very low-density lipoprotein and low-density lipoproteins in the serum, which are precipitated using buffered polyethylene glycol 6000. After centrifugation, HDL-c can be separated in the supernatant. The cholesterol in the HDL fraction was estimated by an enzymatic method that uses cholesterol esterase, cholesterol oxidase, peroxidase, phenol, and 4-amino antipyrine and measured at 500 nm.
Data were presented as mean±SEM. The results obtained from each group were analyzed by one-way Analysis Of Variance (ANOVA) followed by Tukey's multiple comparison tests. P<0.05 indicated statistical significance.
| » Results|| |
Effect of Pio on HF marker enzyme levels in ISO-treated rats
The influence of Pio on the serum marker enzymes for cardiac functioning is summarized in [Table 1]. Pio at 30 mg/kg significantly increased (P<0.05) the ALT level, while other enzymes such as LDH, CK-MB, and AST remained unaltered in control animals. On the other hand, the ISO-treated animals produced a significant (P<0.001) increase in the serum LDH, CK-MB, AST, and ALT levels as compared to untreated animals. Lower dose of Pio (3 mg/kg) followed by ISO did not produce significant change in enzyme activity; however, Pio at 10 mg/kg showed increase in LDH (P<0.05) and CK-MB (P<0.01) without affecting the AST and ALT levels as compared to the ISO group. When the dose of Pio was increased to 30 mg/kg, an increase (P<0.001) was noted in the LDH and CK-MB levels; besides, the treatment significantly (P<0.05) enhanced the AST and ALT levels as compared to the ISO-challenged group.
|Table 1: Effect of Pio on serum marker enzymes in isoproterenol-induced heart failure rats|
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Effect of Pio on antioxidant status and relative heart weight in ISO-treated rats
The ISO-treated animals showed a significant (P<0.001) increase in LPO and decrease in SOD and GPx level as compared to the untreated control group. Pretreatment with Pio (10 mg/kg) and, subsequently, with ISO, increased significantly (P<0.05) the SOD and GPx levels, but did not affect the LPO activity as compared to ISO. Further, when the dose of Pio was tested at 30 mg/kg, a significant increase in LPO (P<0.05), SOD (P<0.05), and GPx (P<0.01) were observed as compared to ISO-treated animals. The lower dose of Pio (3 mg/kg) did not alter the antioxidant status in the ISO group. In the control group, administration of Pio at 30 mg/kg did not change the antioxidant enzyme levels but increased (P<0.05) the LPO level as compared to that in control animals [Table 2].
|Table 2: Effect of Pio on serum antioxidant parameters in isopreterenol-induced heart failure rats|
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In case of relative heart weight, Pio at 30 mg/kg increased (P<0.05) the heart weight as compared to the control group. ISO treatment also showed a significant (P<0.01) enhancement in the relative heart weight. In the treatment group, only the higher dose of Pio (30 mg/kg) showed significant increase (P<0.05) in the weight of heart as compared to that in the ISO-treated group [Figure 1].
|Figure 1: (a) Normal heart, (b) Pio 30 mg in control animals, (c) Isoproterenoltreated animals, (d) Figure 1d: Pio 3 mg and ISO treatment, (e) Pio 10 mg and ISO treatment, (f) Pio 30 mg+ ISO treatment|
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Effect of Pio on body weight, SBP, serum glucose, and lipid levels in HFD-fed animals
Administration of Pio (30 mg/kg) for 6 weeks to control animals did not produce significant alterations in serum glucose and lipid profile. On the contrary, HFD for 8 weeks resulted in a significant (P<0.001) increase in serum glucose, TG, TC, and HDL-c levels as compared to control animals. A dose-dependent inhibitory effect on metabolic changes was observed with the administration of Pio. At lower dose, Pio (3 mg/kg) showed a significant (P<0.05) reduction in the serum glucose and TG levels, while Pio at 10 mg/kg exhibited further reduction (P<0.01) in glucose and TG level, as well as increased (P<0.05) the HDL-c level as compared to the HFD group. The increase in the dose of Pio (30 mg/kg) enhanced the anti-diabetic and anti-hyperlipidemic activities as compared to lower doses of Pio and HFD-fed rats. In addition, a dose-dependent non-significant increase in the TC level was observed when Pio was administered to HFD-fed animals [Table 3].
|Table 3: Effect of Pio on serum glucose and lipid profile in High Fructose Diet (HFD)-induced hypertensive rats|
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An increase in body weight in was observed in Pio (30 mg/kg)-treated control animals. The HFD rats also showed enhancement (P<0.001) in the body weight as compared to that in the controls. The administration of Pio (3, 10, and 30 mg/kg) to HFD animals exhibited further increase (P<0.001) in body weight as compared to untreated HFD animals [Table 4].
|Table 4: Effect of Pio on body weight and systolic blood pressure in HFDinduced hypertensive rats|
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Pio administered at 30 mg/kg did not alter SBP level in the control group. However, in HFD-fed rats, a significant (i<0.001) increase in SBP was observed as compared to normal animals. A dose-dependent anti-hypertensive effect was observed when different doses of Pio were tested. Pio at 3 mg/kg showed a significant (P<0.05) reduction in SBP. An augmentation in the anti-hypertensive action was found when higher doses of Pio were tested in HFD animals [Table 4].
Effect of Pio on histopathology of heart treated with ISO
Histopathological examination of the myocardium of normal animals showed clear integrity of myocardial cell membrane. Endocardium and pericardium were seen within normal limits and no inflammatory cell infiltration was observed [Figure 1]a. Rats treated with Pio (30 mg/kg) showed mild multifocal myocytic necrosis with mild infiltration of lymphocytes and macrophages [Figure 1]b. ISO-treated hearts exhibited severe myocardial necrosis, characterized by edema, inflammatory reaction by neutrophils and lymphocytes and myocardial degeneration [Figure 1]c. Pio (3, 10, and 30 mg/kg) pretreatment followed by ISO showed a dose-dependent enhancement in myocardial necrosis and infiltration of lymphocytes and macrophages as compared to the ISO-challenged group [Figure 1]d-f.
| » Discussion|| |
Myocardial infarction occurs when myocardial ischemia exceeds a critical threshold level resulting in irreversible myocardial cell damage or death. ISO, a synthetic catecholamine and β-adrenergic agonist, has been reported to produce several metabolic and morphologic aberrations in the heart of experimental animals similar to those seen in human myocardial ischemia.  Our results indicate that ISO increased the levels of diagnostic marker enzymes for heart failure such as LDH, CK-MB, AST, and ALT [Table 1]. Elevation in the LDH and CK-MB levels are considered as the specific marker for myocardial damage, whereas AST and ALT levels indicate several pathologies such as hepatic damage, viral infection in addition to myocardial infarction. These enzymes are released from myocardium into bloodstream due to tissue damage with myofibrillar degeneration and cellular necrosis and due to tissue specificity and catalytic activity. 
ISO is reported to exert positive inotropic and positive chronotropic effects that augment myocardial oxygen consumption. The sudden increase in energy demand produces Ca 2+ overload that results in excessive generation of oxygen free radicals.  Also, oxidation of the hydroxyl group of ISO is reported to result in the formation of quinines followed by adrenochromes. During this reaction, highly toxic oxygen-derived free radicals are generated, which are detrimental to the extracellular and intracellular enzymes and proteins. Adrenochrome and other metabolites of oxidation are reported to cause cell necrosis and contractile failure in the rat heart.  Together, these changes produce mitochondrial disruption, inactivation of tricarboxylic acid cycle enzymes and alter mitochondrial respiration producing symptoms resembling myocardial infarction and cardiac failure. ,, The increase in oxidative stress is evident in our study where ISO increased the LPO and decreased the SOD and GPx levels in rats [Table 2].
Our results indicate that Pio pretreatment at 10 and 30 mg/kg and subsequent ISO administration increased the level of marker enzymes for cardiac failure [Table 1]. The observation suggests that Pio might enhance the cardiac damage associated with ISO. The antioxidant study indicates that although Pio increases the level of antioxidant enzymes, this did not benefit in protecting the ISO-induced cardiac damage. It is difficult to describe the exact mechanism for elevated levels of marker enzymes, but the possibility of cardiac side effects of TZDs cannot be ruled out. The histopathological examination of heart in our study shows that administration of Pio enhanced the cardiac damage in ISO-treated rats and the treatment in control animals have also shown myocytic necrosis and mild-to-moderate infiltration of lymphocytes and macrophages [Figure 1]b-f. There is a likelihood of direct and/or indirect mechanism for the myocardial damage. The increase in relative heart weight after the administration of Pio to control and ISO-treated rats could be another indicator in this direction [Figure 2]. To support this, an earlier study speculated that TZDs class of agents could alter the cardiac functioning if used in the treatment of diabetes. 
|Figure 2: Effect of Pio on relative heart weight (%) in isoproterenol induced heart failure|
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HFD is an established model for producing hyperlipidemia and hypertension in experimental animals. Our observations indicate that HFD administration for 8 weeks increased the body weight, SBP, serum glucose, TG, TC levels and decreased the HDL-c level [Table 3] and [Table 4]. Fructose diet is reported to cause hypertension by various mechanisms including stimulation of sympathetic nervous system, vascular small muscle proliferation, and increased cytosolic [Ca 2+ ] i concentration.  Pio treatment showed a significant reduction in SBP [Table 4]. Studies conducted on human volunteers show that administration of Pio to hypertensive patients (with or without diabetes) decreased SBP and diastolic BP. The potential mechanisms include peripheral vasodilation, decreased sympathetic activation via improved insulin sensitivity and/or downregulation of the Rennin-Angiotensin System (RAS). 
The HFD-fed rats showed a significant increase in serum glucose levels [Table 3]. Several researchers indicated that fructose loading induces glucose intolerance due to insulin resistance. Hence, reduction in the serum glucose level after administration of Pio could be due to insulin sensitizing activity mediated through the activation of nuclear receptor PPARγ.  Earlier studies have demonstrated hypertriglyceridemia in fructose-treated rats.  Our results also indicated disturbances in the lipid profile [Table 3]. The changes have been proposed to be due to increased hepatic secretion of Very-Low-Density Lipoprotein (VLDL)-TG and decreased removal of TG-rich lipoprotein from the circulation. The increased hepatic secretion of VLDL-TG is the outcome of increase availability of substrates such as apoB for the formation of VLDL.  The Pio-treated HFD rats showed partial reversal in the disturbed lipid profile. Pio administration produced dose-dependent significant reduction in TG and increased the HDL-c levels. The treatment also showed a non-significant increase in the TC levels in HFD-fed rats [Table 3].
The influence of TZDs on the lipid profile in diabetic patients is not clearly understood. Most data show that TZDs have an overall beneficial effect since TZDs were found to increase HDL-c and lowered the atherogenic index of plasma.  However, negative effects with TZDs therapy such as increase in LDL levels have also been reported.  The activation of PPARγ by TZDs increases adipocyte differentiation and stimulates the distribution of new adipose tissue to both retroperitoneal and subcutaneous sites.  It is not clear whether the increased LDL has any association with cardiovascular complications. However, it is generally accepted that the fluid retention due to the TZD therapy is the major factor responsible for myocardial defects. ,, Further, our observation suggests that changes in TG and HDL alone may not be responsible for TZD-mediated weight gain. Other factors such as LDL formation, fluid retention, and/or enhanced insulin sensitivity might have a role, and hence their influence on the cardiac complications demands further research.
In conclusion, our study shows that administration of Pio reduced the SBP, serum glucose level, and defects in lipid profile in HFD-fed rats. However, Pio treatment enhanced the relative heart weight and markers for cardiac damage in ISO-induced heart failure. The antioxidant property of Pio plays no significant role in protecting the myocardial damage. The increase in the level of markers for cardiac damage suggests a detrimental action of this drug.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]