Mitochondrial dynamics are altered in favor of mitochondrial fission during MI/R. Mitochondrial fission is associated with shortening of mitochondria, decreased ATP production, and increased reactive oxygen species during MI/R, and is thought to promote cardiomyocyte loss. Therefore, inhibition of mitochondrial fission may be a new strategy to salvage injured cardiac myocytes and limit infarct size. To test this hypothesis, the cardioprotective effects of a novel mitochondrial fission inhibitor, P110 (MW=2427 g/mol), a cell permeable peptide, that selectively inhibits the interaction between dynamin related protein 1 and fission protein 1, were determined in isolated perfused rat hearts subjected to I (30 min)/R (45 min). P110 (1 µM) given for 10 min before ischemia and for 20 min post‐reperfusion, significantly restored left ventricular developed pressure (LVDP) and the peak of the first derivative of left ventricular pressure (dP/dtmax) to 77 ± 9% and 58 ± 7% of baseline values at 45 min post‐reperfusion, respectively, as compared to control I/R hearts (both p<0.01, n=6). The LVDP and dP/dtmax of control I/R hearts (n=8) only recovered to 34 ± 8% and 29 ± 4% of baseline values at 45 min post‐reperfusion, respectively. P110 also significantly reduced infarct size to 20 ± 3% compared to 41 ± 4% in control I/R hearts (p<0.01). The preliminary results suggest that inhibition of mitochondrial fission during MI/R improves post‐reperfused cardiac contractile function and reduces infarct size.

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Oxidative stress is a major cause of I/R injury. NADPH oxidase is an important source of oxidative stress during I/R, and it consists of NOX1‐5 and DOUX1‐2 isoforms. The role of NOX1 in myocardial I/R injury is unclear. In this study, a specific NOX1 inhibitor, ML171 (MW=241.31 g/mol, IC50 for NOX1=0.25 μM), was tested in isolated perfused rat hearts following I (30 min)/R (45 min). We found that left ventricular developed pressure (LVDP) and the peak of the first derivative of left ventricular pressure (dP/dtmax) only recovered to 42 ± 4% and 30 ± 3% of baseline values, respectively, at 45 min post‐reperfusion in control I/R hearts (n=8). By contrast, ML171 (1 μM, n=5) given at reperfusion for 5 min significantly restored LVDP and dP/dtmax to 90 ± 6% and 67 ± 7% of baseline values, respectively (both p<0.01). ML171 also significantly reduced infarct size to 18 ± 3% compared to 41 ± 2% in control I/R hearts (p<0.01). Furthermore, a selective mitochondrial ATP‐dependent K+ channel (mitoKatp) inhibitor, 5‐ hydroxydecanoate (100 μM, n=4); and a heme oxygenase‐1 inhibitor, SnPP (20 μM, n=3), significantly abolished the cardioprotective effects of ML171 (all p<0.05). We also confirmed that ML171 (0.1‐1 μM, n=4) did not inhibit phorbol 12‐myristate 13‐acetate (30 nM) induced superoxide release from isolated rat neutrophils. These results suggest that NOX1 inhibition improves post‐reperfused contractile function and reduces infarct size, possibly by opening mitoKatp channels and activating heme oxygenase‐1.