title: Complexity of inducible nitric oxide synthase: cellular source determines benefit versus toxicity.
abstract: BACKGROUND
  Inducible nitric oxide synthase (iNOS) has been shown to have both beneficial and detrimental effects in sepsis. We focused on a single organ, the heart, and used 2 distinct cell types that express iNOS-the cardiac myocyte and the infiltrating neutrophil-to study the distinct functional effects of iNOS derived from heterogeneous cellular sources.
  
  
  RESULTS
  In the first series of experiments, extravascular neutrophils were exposed to isolated single endotoxemic cardiac myocytes. Adhesion of wild-type neutrophils caused a rapid decrease in myocyte shortening and a concomitant increase in neutrophil-derived intracellular oxidative stress within the myocytes that was not observed with neutrophils from iNOS-deficient animals. We previously demonstrated that neutrophil-derived superoxide was essential for myocyte dysfunction; however, superoxide production was not compromised in the iNOS-deficient neutrophils. Because both superoxide and NO were essential for the neutrophil dysfunction, we probed for but could not detect any peroxynitrite assessed by detection of nitrotyrosine. There was a significant increase in length shortening in response to beta-adrenergic stimulation of wild-type myocytes. Surprisingly, myocyte iNOS activity was essential rather than detrimental for the development of beta-adrenergic receptor-mediated increases in shortening in endotoxemic iNOS-deficient myocytes.
  
  
  CONCLUSIONS
  These results demonstrate that iNOS, when expressed in isolated cardiac myocytes, can regulate the response to beta-adrenergic stimulation during sepsis. However, as the neutrophils migrate in proximity to myocytes, iNOS now becomes essential for the ability of neutrophils to damage myocytes. These findings demonstrate that cellular source strongly modulates the beneficial and detrimental effect of iNOS.
authors.affiliation: Department of Physiology and Biophysics, Cardiovascular, University of Calgary, Alberta, Canada.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Poon
authors.forename: Eko
authors.initials: E
authors.lastname: Raharjo
authors.forename: Kamala D
authors.initials: KD
authors.lastname: Patel
authors.forename: Samantha
authors.initials: S
authors.lastname: Tavener
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D019446:Endotoxemia / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D018805:Sepsis / Q000201:enzymology / Q000503:physiopathology
chemical_list: D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse