Myocardial cell death is an important contributor to the development of the diabetic cardiomyopathy. It has been proposed that diabetes-mediated upregulation of the renin-angiotensin system leads to oxidative stress, the trigger for cardiomyocyte death and contractile dysfunction. However, the adverse effect of angiotensin II on the diabetic heart may extend beyond the development of the cardiomyopathy. Angiotensin II also alters specific modulators of ischemic injury, such as protein kinase C and calcium transport. Therefore, the present study examined the effect of angiotensin II on hyperglycemic preconditioning, a glucose-mediated condition associated with the elevation of protein kinase C activity and alterations in calcium transport that render the cell resistant to hypoxia. Exposure of the glucose treated cell to angiotensin II during the pre-hypoxic period blocked glucose-mediated cardioprotection. The reversal of hyperglycemic preconditioning was associated with enhanced accumulation of Ca²⁺ during hypoxia, an effect prevented by inhibition of the Na⁺ / H⁺ exchanger and the Ttype Ca²⁺ channel. The inhibitors of hypoxia-mediated Ca²⁺ accumulation also blocked the reversal of hyperglycemic preconditioning by angiotensin II. Thus, angiotensin II and glucose treatment exert opposite actions on the Na⁺ / H⁺ exchanger and the T-type Ca²⁺channel. Since those transporters are involved in hypoxia-mediated apoptosis, they are logical candidates for the beneficial effects of high glucose and the adverse effects of angiotensin II on the hypoxic cardiomyocyte.