The present study has been designed to investigate the role Clofibrate in hypercholesterolaemia-induced attenuation of cardioprotective effect of ischemic preconditioning. Experimental hypercholesterolaemia was produced by feeding high fat diet to rats for a period of 28 days. Isolated langendorff's perfused normal and hypercholesterolaemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase and creatine kinase release to assess the extent of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring TBARS and GSH. The ischemia-reperfusion has been noted to induce oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hypercholesterolaemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of increase in myocardial infarct size, LDH and CK-MB release in coronary effluent and decrease in coronary flow rate in normal and hypercholesterolaemic rat hearts. In count, the hypercholesterolaemic rat heart showed enhanced I/R-induced myocardial injury with high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, LDH, CK-MB and oxidative stress. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in hypercholesterolaemic rat hearts may be due to consequent down-regulation of PPAR-α with high oxidative stress. Treatment with Clofibrate (300mg/kg/day, i.p.), an activator of PPAR-α has not affected the cardioprotective effects of IPC in normal rat hearts, but its treatment markedly restored the cardioprotective potential of IPC in hypercholesterolaemic rat hearts.
