a-192621 and Pancreatitis

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.

Topics: Acute Disease; Animals; Blood Flow Velocity; Capillary Permeability; Colon; Endothelin Receptor Antagonists; Male; Pancreas; Pancreatitis; Phenylpropionates; Pyrimidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B