Stress-induced, acute hyperglycemia co-presenting with myocardial infarctions is associated with poor prognosis. Hyperglycemia-induced oxidative stress result in DNA damage and subsequent activation of poly-ADP-ribose polymerase (PARP) as a restorative mechanism. However, PARP attenuates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity, thereby diverting upstream glycolytic metabolites into damaging non-oxidative glucose pathways (NOGP). For example, hyperglycemia-induced stimulation of four NOGP, i.e. the polyol pathway, hexosamine biosynthetic pathway (HBP), advanced glycation end products (AGE), and PKC activation elicit cardiovascular complications. We therefore hypothesized that NOGP inhibition blunts hyperglycemia-induced oxidative stress and cardiac contractile dysfunction following ischemia-reperfusion. We employed several experimental systems: 1) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 90 min, followed by 30 min global ischemia and 60 min reperfusion ± respective NOGP inhibitors added during the first 20 min of reperfusion. The following inhibitors were individually employed: AGE pathway (100 μM aminoguanidine); PKC (5 μM chelerythrine chloride); HBP (40 μM 6-diazo-5-oxo-L-norleucine); and polyol pathway (1 μM zopolrestat); 2) Infarct size determination as in #1) but with 30 min regional ischemia and 120 min reperfusion ± similar treatments. Our data shows that acute administration of each inhibitor attenuated superoxide levels and concomitantly increased superoxide dismutase activity. In parallel, we found that it decreased PARP and enhanced GAPDH activities while diminishing myocardial apoptosis. Each inhibitor employed blunted activation of the other three pathways here examined. Hearts treated with NOGP inhibitors also displayed improved functional recovery and smaller infarct sizes following ischemia-reperfusion. Interestingly, NOGP inhibitors resulted in the same degree of change (for all above-mentioned parameters evaluated) when compared to each other. The current study demonstrates that acute NOGP inhibition initiated after ischemia offers significant potential as therapeutic agent(s) for myocardial infarction under acute hyperglycemia. Moreover, our findings establish for the first time that there is a convergence of downstream NOGP effects in our model, i.e. increased myocardial oxidative stress, further pathway activation, apoptosis, and impaired contractile function. Thus a vicious metabolic cycle is established whereby hyperglycemia-induced NOGP further fuels its own activation by generating even more oxidative stress, thereby exacerbating damaging effects on the heart under these conditions.