title: Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs.
abstract: BACKGROUND
  Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors.
  
  
  RESULTS
  A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference.
  
  
  CONCLUSIONS
  These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury.
authors.affiliation: Department of Anaesthesiology & Intensive Care, Karolinska University Hospital Huddinge, Huddinge, Stockholm, Sweden. johan.fenhammar@karolinska.se
authors.forename: Johan
authors.initials: J
authors.lastname: Fenhammar
authors.forename: Andreas
authors.initials: A
authors.lastname: Andersson
authors.forename: Jakob
authors.initials: J
authors.lastname: Forestier
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
authors.forename: Robert
authors.initials: R
authors.lastname: Frithiof
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists; D019446:Endotoxemia / Q000097:blood* / Q000503:physiopathology; D004731:Endotoxins / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007677:Kidney Function Tests; D010100:Oxygen / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D012079:Renal Circulation; D013552:Swine / Q000097:blood*
chemical_list: D065130:Endothelin A Receptor Antagonists; D004731:Endotoxins; D044022:Receptor, Endothelin A; D010100:Oxygen