title: Mixed endothelin receptor antagonism with tezosentan improves intestinal microcirculation in endotoxemic shock.
abstract: BACKGROUND
  Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia.
  
  
  METHODS
  Sixteen anesthetized and mechanically ventilated pigs received an infusion of endotoxin for 300 min. After 120 min eight pigs received a bolus dose of tezosentan 1 mg/kg followed by an infusion of tezosentan of 1 mg/kg/h throughout the experiment. Eight pigs served as endotoxin controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and in the ileal and colon mucosa. PCO(2) in the ileal mucosa was measured by air tonometry and portal vein flow by an ultrasonic flow probe.
  
  
  RESULTS
  Endotoxin administration induced a state of shock with impaired splanchnic microcirculatory blood flow. Microcirculation in the mucosa of the colon and ileum and mucosal-arterial PCO(2) gap were improved by tezosentan. Portal vein flow was increased, but hepatic microcirculatory blood flow was not significantly improved. Tezosentan preserved cardiac index and decreased pulmonary capillary wedge pressure compared to controls, without causing any differences in the heart rate or mean arterial blood pressure response. Tezosentan also distinctly improved pH and arterial lactate values.
  
  
  CONCLUSIONS
  The findings of this study indicate that ET is involved in the microcirculatory dysfunction seen in the ileal and colon mucosa in early endotoxemia. Moreover, this detrimental effect was counteracted by i.v. administration of the mixed ET receptor antagonist tezosentan.
authors.affiliation: Department of Anaesthesiology & Intensive Care, Karolinska University Hospital Huddinge, Sweden. andreas.andersson@karolinska.se
authors.forename: Andreas
authors.initials: A
authors.lastname: Andersson
authors.forename: Johan
authors.initials: J
authors.lastname: Fenhammar
authors.forename: Robert
authors.initials: R
authors.lastname: Frithiof
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.forename: Alf
authors.initials: A
authors.lastname: Sollevi
authors.forename: Hans
authors.initials: H
authors.lastname: Hjelmqvist
mesh_terms: D000818:Animals; D065128:Endothelin Receptor Antagonists; D005260:Female; D007410:Intestinal Diseases / Q000209:etiology; D007422:Intestines / Q000098:blood supply*; D017078:Laser-Doppler Flowmetry; D008833:Microcirculation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage*; D012772:Shock, Septic / Q000150:complications*; D013152:Splanchnic Circulation / Q000187:drug effects; D013552:Swine; D013777:Tetrazoles / Q000008:administration & dosage*; D014652:Vascular Diseases / Q000188:drug therapy* / Q000209:etiology; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan