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

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

Péter Ferdinandy et al. Br J Pharmacol. 2003 Feb.

Abstract

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.

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Figures

Figure 1
Figure 1

Cellular mechanisms of nitric oxide (NO), superoxide (O2−·), and peroxynitrite (ONOO−) actions. 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 O2−· to form ONOO− which rapidly decomposes to highly reactive oxidant species leading to tissue injury. There is a critical balance between cellular concentrations of NO, O2−·, and superoxide dismutase (SOD) which physiologically favor NO production but in pathological conditions such as ischaemia and reperfusion result in ONOO− formation. ONOO− is detoxified if it combines with reduced glutathione (GSH) or other thiols to form S-nitrosoglutathione (GSNO) or other nitrosothials, an NO donor molecule. MMP – matrix metalloproteinase; NOS – NO synthase; PARP – poly-ADP ribose synthase; XOR – xanthine oxidoreductase.

Figure 2
Figure 2

Increased synthesis of nitric oxide (NO) and superoxide (O2−·) leads to a pronounced formation of the toxic metabolite peroxynitrite (ONOO−) upon reperfusion thereby leading to myocardial injury (A). Preceding short periods of ischaemia/reperfusion during preconditioning, however, results in a moderate formation of reactive oxygen species which triggers a cardioprotective mechanism leading to subsequent inhibition of ONOO− formation (B). A similar mechanism is suspected during late preconditioning, however, expression of iNOS and antioxidant enzymes such as superoxide dismutase (SOD) also occurs. Changes in cardiac NO, O2−·, and ONOO− and the exact role of increased iNOS are questions of debate (C). Bars denote periods of ischaemia, arrows indicate formation of reactive oxygen species upon reperfusion or expression of enzymes, font size shows relative amount of NO, O2−·, and ONOO− formation.

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References

    1. ALTUG S., DEMIRYUREK A.T., AK D., TUNGEL M., KANZIK I. Contribution of peroxynitrite to the beneficial effects of preconditioning on ischaemia-induced arrhythmias in rat isolated hearts. Eur. J. Pharmacol. 2001;415:239–246. - PubMed
    1. ALTUG S., DEMIRYUREK A.T., KANE K.A., KANZIK I. Evidence for the involvement of peroxynitrite in ischaemic preconditioning in rat isolated hearts. Br. J. Pharmacol. 2000;130:125–131. - PMC - PubMed
    1. ARSTALL M.A., SAWYER D.B., FUKAZAWA R., KELLY R.A. Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation. Circ. Res. 1999;85:829–840. - PubMed
    1. BAXTER G.F. The neutrophil as a mediator of myocardial ischaemia-reperfusion injury: time to move on. Basic Res. Cardiol. 2002;97:268–275. - PubMed
    1. BAXTER G.F., FERDINANDY P. Delayed preconditioning of myocardium: current perspectives. Basic Res. Cardiol. 2001;96:329–344. - PubMed

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