The effect of ranolazine, a novel anti-ischemic drug that stimulates the activity of pyruvate dehydrogenase, on hydrogen peroxide (H₂O₂)-induced mechanical and metabolic derangements was studied in isolated rat heart and compared with that of dichloroacetate (DCA), an activator of pyruvate dehydrogenase. The heart was perfused aerobically by the Langendorff’s technique at a constant flow and driven electrically. H₂O₂ (600 μM) decreased the left ventricular developed pressure and increased the left ventricular end-diastolic pressure (i.e., mechanical dysfunction), decreased the tissue level of adenosine triphosphate (i.e., metabolic derangement), and increased the tissue level of malondialdehyde (MDA) (i.e., lipid peroxidation). These mechanical and metabolic derangements induced by H₂O₂ were significantly attenuated by ranolazine (10 or 20 μM). On the other hand, DCA (1 mM) was ineffective in attenuating the H₂O₂-induced mechanical and metabolic derangements. Ranolazine, however, did not modify the tissue MDA level, which was increased by H₂O₂. In the normal (H₂O₂-untreated) heart, ranolazine did not alter the mechanical function and energy metabolism. These results demonstrate that ranolazine attenuates mechanical and metabolic derangements induced by H₂O₂. It is suggested that the protective action of ranolazine against the H₂O₂-induced derangements is due to neither the energy-sparing, DCA-like, nor anti-oxidant effects.