ENDOTOXIN-INDUCED SKELETAL-MUSCLE CONTRACTILE DYSFUNCTION - CONTRIBUTION OF NITRIC-OXIDE SYNTHASES

The aims of this study were to assess the role of nitric oxide (NO) an d the contribution of different NO synthase (NOS) isoforms in skeletal muscle contractile dysfunction in septic shock. Four groups of consci ous rats were examined. Group 1 served as control; groups 2, 3, and 4 were injected with Escherichia coli endotoxin [lipopolysaccharide (LPS ), 20 mg/kg ip] and killed after 6, 12, and 24 h, respectively. Protei n expression was assessed by immunoblotting and immunostaining. LPS in jection elicited a transient expression of the inducible NOS isoform, which peaked 12 h after LPS injection and disappeared within 24 h. Thi s expression coincided with a significant increase in nitrotyrosine fo rmation (peroxynitrite footprint). Muscle expression of the endothelia l and neuronal NOS isoforms, by comparison, rose significantly and rem ained higher than control levels 24 h after LPS injection. In vitro me asurement of muscle contractility 24 h after LPS injection showed that incubation with NOS inhibitor (S-methyliosothiourea) restored the dec line in submaximal force generation, whereas maximal muscle force rema ined unaffected. We conclude that NO plays a significant role in muscl e contractile dysfunction in septic animals and that increased NO prod uction is due to induction of the inducible NOS isoform and upregulati on of constitutive NOS isoforms.