Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia

ALVAREZ, SILVIA; BOVERIS, ALBERTO

FREE RADICAL BIOLOGY AND MEDICINE

Elsevier

Año: 2004 vol. 37 p. 1472 - 1478

0891-5849

Heart and diaphragm mitochondria produced 0.69 and 0.77 nmol NO/min. mg protein; rates that account for 67 and 24% of maximal cellular NO production, respectively. Endotoxemia and septic shock occur with an exacerbated inflammatory response that damages tissue mitochondria. Skeletal muscle appears as one of the main target organs in septic shock, showing an increased nitric oxide (NO) production and an early oxidative stress. The kinetic properties of mitochondrial nitric oxide synthase (mtNOS) of heart and diaphragm were determined. For diaphragm, the KM values for O2 and L-arg were 4.6 and 37 mM, and for heart were 3.3 and 36 mM. The optimal pH for mtNOS activity was 6.5 for diaphragm and 7.0 for heart.  A marked increase in mtNOS activity was observed in endotoxemic rats, 90% in diaphragm and 30% in heart. Diaphragm and heart mitochondrial O2·- and H2O2 production were 2-3 increased during endotoxemia and Mn-SOD activity showed a 2-fold increase in treated animals, whereas catalase activity was unchanged. One of the current hypotheses for the molecular mechanisms underlying the complex condition of septic shock is that the enhanced NO production by mtNOS leads to excessive peroxynitrite production and protein nitration in the mitochondrial matrix, causing mitochondrial dysfunction and contractile failure.