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Peroxynitrite induces contractile dysfunction and lipid peroxidation in the diaphragm
G Supinski1, D Stofan, L A Callahan
1Pulmonary Division, Department of Medicine, Case Western Reserve University, Cleveland 44106; and Metrohealth Medical Center, Cleveland, Ohio 44109, USA.
Journal of Applied Physiology (Bethesda, Md. : 1985)
|August 13, 1999
Summary
Peroxynitrite significantly impairs diaphragm muscle force generation. This reactive nitrogen species causes contractile dysfunction, potentially explaining muscle weakness in sepsis and other critical illnesses.
Area of Science:
- Physiology
- Biochemistry
- Pathophysiology
Background:
- Peroxynitrite is implicated in muscle dysfunction during pathophysiological states like sepsis.
- The direct impact of peroxynitrite on muscle force generation remains under-assessed.
Purpose of the Study:
- To investigate the effects of peroxynitrite on diaphragmatic force-generating capacity.
- To differentiate the impact of extracellular versus intracellular peroxynitrite exposure on muscle function.
Main Methods:
- Assessed force vs. pCa in intact diaphragm muscle fiber bundles and single skinned fibers.
- Administered peroxynitrite and 3-morpholinosydnonimine (a peroxynitrite generator).
- Measured 4-hydroxynonenal as an indicator of lipid peroxidation.
Main Results:
- Peroxynitrite reduced force generation in intact diaphragm preparations.
- Increased levels of 4-hydroxynonenal were observed in intact muscle exposed to peroxynitrite.
- Both peroxynitrite and 3-morpholinosydnonimine decreased maximum calcium-activated force in skinned fibers.
Conclusions:
- Peroxynitrite significantly impairs diaphragmatic contractile function.
- These findings suggest peroxynitrite contributes to muscle dysfunction in sepsis and similar conditions.
- Both extracellular and intracellular peroxynitrite impact muscle contractility.