Evaluation of Cardioprotective Effects of Colesevelam Hcl on Isoproterenol Induced Myocardial Infarction in Rats

Abstract

Myocardial cell protection and prevention of cell ischemia have been therapeutic targets for a long time. Colesevelam HCl is the newer bile acid sequesterant drug having antihyperlipiadamic, antidiabitic effects. Colesevelam HCl cause reduction in the cholesterol levels by bile acid depleting action. Long term administration of Colesevelam HCl shows the beneficial effects related to cardiovascular events particularly in myocardial infarction and stroke. Literature survey revealed no reports on cardioprotective effects of Colesevelam HCl. In the present study, an attempt has been made to assess the cardioprotective effects of Colesevelam HCl using well established animal model of isoproterenol induced myocardial infarction in male wistar rat. Objectives To evaluate the cardioprotective activity of Colesevelam HCl on isoproterenol (ISO) induced myocardial ischemia in male wistar rats. Methodology The present study was carried out using 36 male wistar rats, divided into 6 groups, 6 animals in each group: Control, disease control group, three treatment groups (dietary administration of Colesevelam HCl: 0.3% w/w, 0.7% w/w, 1.5% w/w), standard group (10 mg/kg Rosuvastatin orally), the drugs were administered daily for 28 days. At the end of the treatment period, myocardial damage was induced by ISO administration (85 mg/kg single dose s.c. for two days) in all the groups except control group. Blood was collected by retro-orbital plexus for biochemical estimation. The isolated heart was used for enzyme estimation and histological examination. The incidence of myocardial damage and its protection was assessed by measuring cardiac biomarker levels such as ALT, AST, ALP, CRP and CK-MB, oxidative stress parameters such as GSH, SOD and CAT, MDA levels and lipid profile. Electrocardiograph parameters were monitored and recorded.Results Our study suggested that there was no significant change in either body weight or food intake in all the animals. We observed significant increase in the levels of AST, ALT, ALP in disease control group which was ameliorated in all the treatment groups as well as in standard treated group. The rise in CRP and CK- MB levels were significantly reduced in all the three treatment group and standard treatment. There was a rise in activities of GSH, SOD, Catalase and fall in MDA content in all the treatment groups as compared diseased control group. We observed significant increase in serum TC, TG, LDL, VLDL as well as decrease in serum HDL in diseased control group. Dietary administration of Colesevelam HCl significantly decreased serum TC, TG, LDL, VLDL as well as increase in serum HDL. Isoproterenol-induced (85 mg/kg, s.c.) rats showed a significant rise in ST segment, decrease in P wave amplitude, decrease in time for QRS complex, increase in QT interval time, along with increase in heart rate which were restored by Colesevelam HCl in all three treatment groups as well as in standard treatment group. Histopathological examination showed severe necrosis, vacuolization, mineralization and cellular infiltration in the isoproterenol induced group. The protective role of Colesevelam HCl on isoproterenol-induced myocardial damage was confirmed by restoring the histopathological changes in all the three treatments groups as well as in standard group. Thus it prevented almost all the parameters of isoproterenol-induced heart failure and myocardial injury. Conclusion The results of the present study indicated that prior administration of Colesevelam HCl is effective in minimizing all the deleterious effects induced by isoproterenol, thereby justifying its use as a potent cardioprotective agent.