[Impact of nitric oxide synthase 3 on myocardial dysfunction in sepsis]

Septic shock is a complex syndrome that claims over 200,000 lives per year in the United States. While majority of the late mortality of sepsis appears to be due to multi-system organ failure, early death has been attributed either to distributive shock or to a cardiogenic form of septic shock. Overproduction of nitric oxide (NO), presumably by NO synthase 2 (NOS 2), has been implicated in the pathogenesis of cardiovascular dysfunction of sepsis. However, in clinical trials, NOS inhibitors that are not isoform-specific increased mortality in septic patients due to cardiac dysfunction, suggesting salutary effects of NOS 1 and/or NOS 3. Recently, we found that cardiomyocyte-specific overexpression of NOS 3 prevents lipopolysaccharide (LPS)-induced myocardial dysfunction and mortality in mice. Myocardial mechanical efficiency was markedly impaired in wild-type and NOS 3-deficient mice but not in mice with the NOS 3 transgene after LPS challenge. Improved myocardial function by excess NO during endotoxemia was associated with decreased myocardial oxidative stress, increased myofilament sensitivity to calcium, and increased phospholamban (PLB) phosphorylation. These results suggest that increased myocardial NO levels attenuate endotoxin-induced ROS production and increase total sarcoplasmic reticulum Ca2+ load and myofilament sensitivity to Ca2+ thereby reducing myocardial dysfunction and mortality in murine models of septic shock.