Dynamic changes in nitric oxide and mitochondrial oxidative stress with site-dependent differential tissue response during anoxic preconditioning in rat heart

Abstract

J. Dynamic changes in nitric oxide and mitochondrial oxidative stress with site-dependent differential tissue response during anoxic preconditioning in rat heart. Am J Physiol Heart Circ Physiol 293: H1457-H1465, 2007. First published June 1, 2007; doi:10.1152/ajpheart.01282.2006.-In this study, dynamic changes in nitric oxide (NO) and mitochondrial superoxide (O 2 •Ϫ ) were examined during anoxic preconditioning (AP) in rat heart model. AP and anoxia-reoxygenation (A/R) were performed on isolated hearts and single cardiomyocytes. The cellular insult in the form of infarct size and DNA damage were localized and correlated with NO synthases (endothelial and inducible) expression levels. The results showed that endocardium was the most affected region in AP groups, whereas the larger area of infarct was confined to mid-and epicardium in the A/R group. Interestingly, a high-level expression of immunofluorescent NO synthases was restricted to viable areas in the AP. In contrast to the gradual increase in O 2•Ϫ level that occurred in the AP group, a sudden massive increase in its level was demonstrated at the onset of reoxygenation in the A/R group. The observed increase in NO production during reoxygenation in the AP group was attenuated by inducible NO synthase inhibitor. The study revealed, on a real-time basis, the role played by preconditioning for modulating NO and O 2•Ϫ levels on behalf of cell survival. The results afford a better understanding of cardiac-adapting mechanism during AP and the role of inducible NO synthase in this important phenomenon. mitochondrial superoxide; endocardium; inducible nitric oxide synthase HEART FAILURE DUE TO ischemic-reperfusion injury is one of the most serious problems in heart disease. Ischemic preconditioning, in which short-term ischemia and reperfusion are followed by long-term ischemia, can protect the heart against ischemia and reperfusion-induced cardiac injuries (25). Although preconditioning by a nitric oxide (NO) donor can mimic the anoxic preconditioning (AP) phenomenon to protect the heart from anoxia-reoxygenation (A/R) injuries, the evidence that a change in NO concentration contributes to either pro-or antiapoptotic effects remains equivocal (13). NO stimulates soluble guanylate cyclase, leading to an activation of both the sarcolemmal and mitochondrial ATP-sensitive K ϩ (K ATP ) channels, thus reducing ischemia and reperfusion-induced heart damage (10, 18). However, this is a double-edged sword, since NO interacts with the reactive oxygen species (ROS) superoxide (O 2•Ϫ ) to form peroxynitrite (ONOO Ϫ ), which is a reactive nitrogen species (RNS) that causes oxidative DNA damage (4,16, 27). An early state of reoxygenation produces a massive increase in ROS levels, and the resulting apoptosis and/or necrosis impair cardiac function through arrhythmia or heart failure (26).Recent studies have demonstrated that differences in O 2•Ϫ dismutase distribution, action potential duration, and myosinactin dynamics lead to regional differences in ischemia and reperfus...

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Intermittent hypoxia modulates nitric oxide-dependent vasodilation and capillary perfusion during ischemia-reperfusion-induced damage

“…Recently, Ding et al (18) showed that IH upregulated the baseline level of iNOS mRNA and protein expression, leading to an increase in NO production in the isolated heart. Cuong et al (16) studied changes in NO and mitochondrial superoxide during anoxic preconditioning in isolated hearts and single cardiomyocytes. They concluded that the increase in NO production during reoxygenation in the preconditioned animals was attenuated by the iNOS inhibitor.…”

Intermittent hypoxia has organ-specific effects on oxidative stress

“…The hypothesis that IH causes oxidative stress stems from observations that ischemia-reperfusion (I/R) or anoxia-reoxygenation injury gave rise to reactive oxygen species (ROS) (3,5,20,32,48,75,99). Applicability of this concept to OSA has been shown in several studies, as exemplified by increased exhaled isoprostanes (9,10), blood reactive oxygen metabolites (18), serum malondialdehyde (MDA) (6,52), neutrophil superoxide production (80), and susceptibility of serum LDL to oxidation (80) in OSA.…”