Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats.
OBJECTIVE
To assess the effect of non-selective ET(A/B) (LU 302872) and selective ET(A) (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.


METHODS
Male Wistar rats with caerulein-induced AP, lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w. of each antagonist. Edema, inflammatory infiltration, necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase, and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.


RESULTS
In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P<0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82+/-0.06 at higher dose (P<0.05) vs 0.58+/-0.06 in untreated AP. The non-selective antagonist increased slightly the vacuolization score to 2.41+/-0.07 at higher dose (P<0.01) vs 1.88+/-0.08 in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum, autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups. %FAT/TPT in untreated AP increased about four times (18.4+/-3.8 vs 4.8+/-1.3 in control group without AP, P<0.001). Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.


CONCLUSIONS
The treatment with endothelin-1 receptors (non-selective ET(A/B) and selective ET(A)) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.
Andrzejewska
Anna
A
Department of Medical Pathomorphology, Medical University of Bialystok, Waszygton Str. 13, 15-269 Białystok, Poland. anna.andrzejewska@poczta.fm
Dlugosz
Jan-W
JW
Augustynowicz
Albert
A
D000208:Acute Disease; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002108:Ceruletide; D065130:Endothelin A Receptor Antagonists; D008297:Male; D008854:Microscopy, Electron; D010179:Pancreas / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D011422:Propionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014362:Trypsinogen / Q000378:metabolism*
C405519:BSF 302146; D001559:Benzhydryl Compounds; D065130:Endothelin A Receptor Antagonists; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D002108:Ceruletide; D014362:Trypsinogen