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A large body of experimental evidence supports the notion of free radical-generated reperfusion injury when oxygen is reintroduced to ischaemic tissue. As such, Yasmin et al. (1997) selleck compound demonstrated that myocardial ischaemia and reperfusion results in the generation of ONOO?, an effect that was prevented by inhibition of nitric oxide synthase, removal of O?2, or by the provision of low amounts of exogenous nitric oxide. This study also indicates that the formation of ONOO? at reperfusion may contribute to the development of myocardial mechanical dysfunction. Similarly, Wang et al. (2002) have shown that the infusion of ONOO? caused a rapid and significant increase of MMP�C2 activity that preceded the contractile dysfunction. The administration of glutathione prevented not only the increase in MMP�C2 activity but also the myocardial dysfunction. Thus, these studies confirm that the production of ONOO? during reperfusion activated MMP�C2 and produced myocardial dysfunction. Other authors (Prasan et al. 2002) showed that there is an increase in the pro-MMP�C2 activity after 60 min of low-flow ischaemia. However, they used low-flow ischaemia, GPX4 which induced a permanent washout of the metabolites and enzymes, including MMP�C2. Therefore, the authors could need a more prolonged period of ischaemia (60 min) to detect MMP�C2 activity in the coronary effluent. In our study, we used 30 min of global no-flow ischaemia, which allows the accumulation of metabolites and enzymes. The relationship between MMP�C2 and infarct size was shown by Giricz et al. (2006). These authors showed that ilomastat (a non-specific MMP inhibitor) decreased infarct size, similar to the effect of preconditioning. In agreement with Giricz et al. (2006), we recently showed (D��Annunzio et al. 2009) a positive and significant correlation between reperfusion MMP�C2 activity and infarct size in an isolated rabbit heart model. Furthermore, Lalu et al. (2002) showed that ischaemic preconditioning reduces ONOO? www.selleckchem.com/products/ch5424802.html formation, removing a major trigger for MMP�C2 activation and therefore decreasing MMP�C2 activity. Since the mechanisms of ischaemic postconditioning involve prevention of the burst of free radical generation, we can speculate that ischaemic postconditioning could reduce the activation of MMP�C2, inhibiting the production of ONOO? in the reperfusion. Our data partly support this hypothesis, since we showed a significant reduction in infarct size with attenuation of MMP�C2 activity in the postconditioning protocol. Furthermore, the administration of doxycycline at the beginning of reperfusion mimicked the MMP�C2 inhibition and infarct size reduction found with ischaemic postconditioning. An important finding was the lower level of cardiac protein nitration in the doxycycline-treated group.