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* Institut National de la Santé et de la Recherche Médicale (INSERM) U408 and IFR 02, Faculté X. Bichat, Paris, France;
Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Argentina; and
§ Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina
1Correspondence: INSERM U408, Faculté X. Bichat, BP416, 75870 Paris Cedex 18, France. E-mail: jbb2{at}bichat.inserm.fr
It has been shown that nitric oxide (NO), synthesized by the inducible NO synthase (iNOS) expressed in the diaphragm during endotoxemia, participates in the development of muscular contractile failure. The aim of the present study was to investigate whether this deleterious action of NO was related to its effects on cellular oxidative pathways. Rats were inoculated with E. coli lipopolysaccharide (LPS) or sterile saline solution (controls) and studied at 3 and 6 h after inoculation. iNOS protein and activity could be detected in the rat diaphragm as early as 3 h after LPS, with a sustained steady-state concentration of 0.5 µM NO in the muscle associated with increased detection of hydrogen peroxide (H2O2). In vitro, the same NO concentration produced a marked increase in H2O2 production by isolated control diaphragm mitochondria, thus reflecting a higher intramitochondrial concentration of nondiffusible superoxide anion (O2-·). In a similar way, whole diaphragmatic muscle and diaphragm mitochondria from endotoxemic rats showed a progressive increase in H2O2 production associated with uncoupling and decreased phosphorylating capacity. Simultaneous with the maximal impairment in respiration (6 h after LPS), nitration of mitochondrial proteins (a peroxynitrite footprint) was detected and diaphragmatic force was reduced. Functional mitochondrial abnormalities, nitration of mitochondrial proteins, and the decrease in force were significantly attenuated by administration of the NOS inhibitor L-NMMA. These results show that increased and sustained NO levels lead to a consecutive formation of O2-· that reacts with NO to form peroxynitrite, which in turn impairs mitochondrial function, which probably contributes to the impairment of muscle contractility.—Boczkowski, J., Lisdero, C. L., Lanone, S., Samb, A., Carreras, M. C., Boveris, A., Aubier, M., Poderoso, J. J. Endogenous peroxynitrite mediates mitochondrial dysfunction in rat diaphragm during endotoxemia.
Key Words: sepsis • respiratory insufficiency • respiratory muscles • mitochondria • nitric oxide • oxidative stress • nitrotyrosine
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