title: Carbon monoxide, but not endothelin-1, plays a major role for the hepatic microcirculation in a murine model of early systemic inflammation.
abstract: OBJECTIVE
  Endothelin-1 and carbon monoxide play a major role in the regulation of liver microcirculation in numerous disease states. During sepsis and endotoxemia, elevated formation of endothelin-1 results in reduced sinusoidal blood flow. However, the role of carbon monoxide and endothelin-1 and its receptors endothelin receptor A and endothelin receptor B in the deranged liver microcirculation during early systemic inflammation remains unclear.
  
  
  METHODS
  Prospective, randomized, controlled experiment.
  
  
  METHODS
  University animal laboratory.
  
  
  METHODS
  Male C57/BL6 mice, weighing 23-27 g.
  
  
  METHODS
  To induce a systemic inflammation, mice were treated with 1 hr of bilateral hind limb ischemia followed by 3 hrs or 6 hrs of reperfusion. Animals were randomly exposed to the nonselective endothelin receptor antagonist Ro-61-6612 (Tezosentan) and/or a continuous endothelin-1 infusion. Different animals were randomized to methylene chloride gavage or carbon monoxide inhalation during the reperfusion period.
  
  
  RESULTS
  After ischemia/reperfusion, endothelin-1 plasma concentrations, endothelin-1 messenger RNA expression, and endothelin receptor A and B messenger RNA expression revealed no significant changes when compared with sham animals. After 6 hrs of ischemia/reperfusion, hepatic microcirculatory variables (sinusoidal density, sinusoidal diameter, and red blood cell velocity) deteriorated. Tezosentan after 6 hrs of ischemia/reperfusion did not improve the liver microcirculation, whereas the continuous infusion of endothelin-1 after 6 hrs of ischemia/reperfusion further impaired sinusoidal blood flow. Tezosentan treatment did not produce any alterations in hepatocellular injury or hepatic redox status when compared with the untreated animals receiving 6 hrs of ischemia/reperfusion. Animals receiving 6 hrs of ischemia/reperfusion and exposed to methylene chloride gavage or inhaled carbon monoxide during limb reperfusion showed significantly improved microcirculatory variables, hepatic redox status, and attenuated hepatocellular injury.
  
  
  CONCLUSIONS
  These data suggest that endothelin-1 and the endothelin receptors A and B are not responsible for the observed hepatic microcirculatory and cellular dysfunction during early systemic inflammation, but exposure to exogenous carbon monoxide protected the hepatic microcirculation and improved the impaired hepatic cellular integrity and the hepatocellular redox status.
authors.affiliation: Klinik und Poliklinik für Anästhesiologie, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brock
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.forename: Winfried
authors.initials: W
authors.lastname: Göttsch
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.forename: Otto
authors.initials: O
authors.lastname: Eichelbrönner
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D002248:Carbon Monoxide