Arsenic toxicity is posing great risk to the world population. Arsenic has been reported to cause various organ damage including blood vessels and heart. Ischemic heart disease is the leading cause of death worldwide. It has been reported that arsenic is associated with the generation of oxidative stress and cardiac impairment but its role in ischemic preconditioning has not been studied yet. It has been long hypothesized that arsenic & cadmium may contribute to the pathogenesis of CVD via the mitochondrial permeability transition due to upregulation of the caveolin protein The present study has been designed to investigate the beneficial role of an antithyroid drug, propylthiouracil in arsenic and cadmium induced-attenuation of ischemic preconditioning (IPC) and ischemic postconditioning (I post). Isolated normal arsenic and cadmium treated rat hearts were subjected to global ishchemia for 30 min, followed by reperfusion for 120 min. 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. The oxidative stress in the heart was assessed by measuring thiobarbituric acid reactive substances (TBARS), superoxide anion generation and reduced form of glutathione (GSH) in normal arsenic and cadmium treated rat hearts. The arsenic and cadmium treated rat hearts showed enhanced I/R -induced myocardial injury and a high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC and I-Post (5 min each) 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, levels of LDH, CK-MB and oxidative stress. On the other hand, IPC and I-Post mediated myocardial protection against I/R were abolished in arsenic and cadmium treated rat hearts. Propylthiouracil an antithyroid drug in a dose of (5mg/kg/day p.o.) for 21 days did not affect the cardioprotective effects of IPC in normal rat hearts but its treatment markedly restored the cardioprotective potential of IPC in arsenic treated rat hearts.