title: Endothelin A but not endothelin B receptor blockade reduces capillary permeability in severe experimental pancreatitis.
abstract: BACKGROUND
  Microcirculatory disorders, in particular increased capillary permeability (CapPerm), contribute to the multiple organ dysfunction syndrome in severe acute pancreatitis (AP). Endothelin receptor antagonists (ET-RA) have been shown to stabilize capillary leakage and improve organ function in AP.
  
  
  OBJECTIVE
  To find out which endothelin receptor subtype (ET-A or ET-B) mediates the changes in CapPerm.
  
  
  METHODS
  Severe AP was induced in rats by intraductal bile salt infusion and i.v. cerulein. Animals were randomized to receive (1) saline; (2) selective ET-A-RA (LU-135252; 30 mg/kg); (3) selective ET-B-RA (A-192621); (4) nonselective ET-RA (LU-135252; 120 mg/kg); or (5) combined ET-A/B-RA (30 mg/kg LU-135252 + A-192621). Capillary blood flow (CBF) and CapPerm in the pancreas and colon and leukocyte rolling in mesenteric venules were determined.
  
  
  RESULTS
  Selective ET-A-RA increased CBF and decreased CapPerm in the pancreas and colon by 90-147% and reduced leukocyte rolling in AP but had no effect in healthy controls. Selective ET-B-RA increased pancreatic CBF (2.3 +/- 0.03 versus 2.1 +/- 0.04 nL/min) and enhanced CapPerm in the pancreas and colon by 24-35% in healthy controls but had no effect in AP. Blockade of both receptors produced effects similar to but less pronounced than those of selective ET-A-RA.
  
  
  CONCLUSIONS
  Blockade of ET-A and ET-B receptors has different effects on CapPerm in healthy animals and those with AP. This may explain the inconclusive results reported with nonselective ET-RA. In severe AP, blockade of ET-A but not ET-B receptors reduces CapPerm.
authors.affiliation: Department of Surgery, Benjamin Franklin Medical Center, Freie Universität, Berlin, Germany. Geibl@mednet.ucla.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Eibl
authors.forename: Bence
authors.initials: B
authors.lastname: Forgacs
authors.forename: Hubert G
authors.initials: HG
authors.lastname: Hotz
authors.forename: Heinz J
authors.initials: HJ
authors.lastname: Buhr
authors.forename: Thomas
authors.initials: T
authors.lastname: Foitzik
mesh_terms: D000208:Acute Disease; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D003106:Colon / Q000098:blood supply; D065128:Endothelin Receptor Antagonists; D008297:Male; D010179:Pancreas / Q000098:blood supply / Q000473:pathology; D010195:Pancreatitis / Q000503:physiopathology*; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
chemical_list: C120508:A 192621; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C107831:darusentan