Peroxynitrite induces contractile dysfunction and lipid peroxidation in the diaphragm

Peroxynitrite may be generated in and around muscles in several pathophysio logical conditions (e.g., sepsis) and may induce muscle dysfunction in thes e disease states. The effect of peroxynitrite on muscle force generation ha s not been directly assessed. The purpose of the present study was to asses s the effects of peroxynitrite administration on diaphragmatic force-genera ting capacity in 1) intact diaphragm muscle fiber bundles (to model the eff ects produced by exposure of muscles to extracellular peroxynitrite) and 2) single skinned diaphragm muscle fibers (to model the effects of intracellu lar peroxynitrite on contractile protein function) by examining the effects of both peroxynitrite and a peroxynitrite-generating solution, 3-morpholin osydnonimine, on force vs, pCa characteristics. In intact diaphragm prepara tions, peroxynitrite reduced diaphragm force generation and increased muscl e levels of 4-hydroxynonenal (an index of lipid peroxidation). In skinned f ibers, both peroxynitrite and 3-morpholinosydnonimine reduced maximum calci um-activated force. These data indicate that peroxynitrite is capable of pr oducing significant diaphragmatic contractile dysfunction. We speculate tha t peroxynitrite-mediated alterations may be responsible for much of the mus cle dysfunction seen in pathophysiological conditions such as sepsis.