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Myocardial infarction is a form of ischemia/reperfusion (I/R) injury that causes cardiac contractile dysfunction and cell death. I/R injury is mediated, in part, by decreased endothelial-derived nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS) resulting in cell death. Cytokines released from I/R tissue activate G-protein coupled receptors that in turn stimulate NADPH oxidase to produce ROS. Thus, administration of a NADPH oxidase peptide inhibitor, Nox2ds-tat (formerly known as gp91ds-tat), may be a rational approach to attenuate I/R injury. Nox2ds-tat dose-dependently inhibited (10 μM -80 μM; n=5) phorbol 12-myristate13-acetate (n=21) induced polymorphonuclear leukocyte superoxide production up to 37 ± 7% (p<0.05; Fig. 3). Similarly, Nox2ds-tat dose-dependently attenuated I/R induced cardiac contractile dysfunction as evidenced by improved post-reperfused left ventricular developed pressure (LVDP) which recovered up to 77 ± 7% (5 μM-80 μM; p<0.05; n=6-7) of initial values (pre-ischemic values) at 45 min post-reperfusion when compared to control I/R hearts (n=14) that only recovered to 46 ± 6% from initial values for LVDP in isolated perfused rat hearts subjected to global I(30 min)/R(45 min) (Table 1). I/R control hearts exhibited an infarct size of 46 ± 2.1%, whereas I/R + Nox2ds-tat hearts exhibited infarct sizes of 30 ± 4% (5 μM), 15 ± 1.4% (10 μM), 23 ± 2.0% (40 µM), and 19 ± 1.6% ( 80µM) (p<0.01 vs. control I/R hearts; Figure 4, Panel A-B). Regarding in vivo assessments, Nox2ds-tat (4.1 mg/kg, IV) significantly reduced blood H 2 O 2 (1.4 µM) and increased endothelial-derived blood NO (127 nM) at 45 min reperfusion

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