Endothelin A but not endothelin B receptor blockade reduces capillary permeability in severe experimental pancreatitis.
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.
Eibl
Guido
G
Department of Surgery, Benjamin Franklin Medical Center, Freie Universität, Berlin, Germany. Geibl@mednet.ucla.edu
Forgacs
Bence
B
Hotz
Hubert G
HG
Buhr
Heinz J
HJ
Foitzik
Thomas
T
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
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C107831:darusentan