Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia‐reperfusion injury and preconditioning

There appears to be a controversy in the study of myocardial ischaemia‐reperfusion injury and preconditioning whether nitric oxide (NO) plays a protective or detrimental role. A number of findings and the interpretation of the results to date do not support such a controversy. An understanding of the latest developments in NO, superoxide (O 2 − ·) and peroxynitrite (ONOO − ) biology, as well as the various ischaemic animal models utilized is necessary to resolve the apparent controversy. NO is an important cardioprotective molecule via its vasodilator, antioxidant, antiplatelet, and antineutrophil actions and it is essential for normal heart function. However, NO is detrimental if it combines with O 2 − · to form ONOO − which rapidly decomposes to highly reactive oxidant species. There is a critical balance between cellular concentrations of NO, O 2 − ·, and superoxide dismutase which physiologically favour NO production but in pathological conditions such as ischaemia and reperfusion result in ONOO − formation. In contrast, exposure of the heart to brief episode(s) of ischaemia markedly enhances its ability to withstand a subsequent ischaemic injury. The triggering of this endogenous cardioprotective mechanism known as preconditioning requires both NO and O 2 − · synthesis. However, preconditioning in turn attenuates the overproduction of NO, O 2 − · and ONOO − during a subsequent episode of ischaemia and reperfusion, thereby protecting the heart. Here we review the roles of NO, O 2 − ·, and ONOO − in both ischaemia‐reperfusion injury and preconditioning. British Journal of Pharmacology (2003) 138 , 532–543. doi: 10.1038/sj.bjp.0705080