Endothelin A but not endothelin B receptor blockade reduces capillary permeability in severe experimental pancreatitis

• Published in: Pancreas Vol. 25; no. 2; pp. e15 - e20
• Main Authors: Eibl, Guido, Forgacs, Bence, Hotz, Hubert G, Buhr, Heinz J, Foitzik, Thomas
• Format: Journal Article
• Language: English
• Published: United States 01-08-2002
• Subjects: Acute Disease; Animals; Blood Flow Velocity - drug effects; Capillary Permeability - drug effects; Colon - blood supply; Endothelin Receptor Antagonists; Male; Pancreas - blood supply; Pancreas - pathology; Pancreatitis - physiopathology; Phenylpropionates - pharmacology; Pyrimidines - pharmacology; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B
• ISSN: 0885-3177; 1536-4828
• DOI: 10.1097/00006676-200208000-00019

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.
To find out which endothelin receptor subtype (ET-A or ET-B) mediates the changes in CapPerm.
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.
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.
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.