The effect of endothelin-1 receptor antagonists in acute experimental pancreatitis in the rats.
The relative role of endothelin-1 receptors, ET(A) and ET(B) blockade in acute pancreatitis (AP) remains controversial. The aim of the study was to compare the effect of nonselective ET(A/B) antagonist (LU 302872) and selective ET(A)antagonist (LU 302146) in severe taurocholate AP in rats. Male Wistar rats with AP were treated with increasing doses: 1, 5 or 10 mg/kg b.w. of antagonists i.p. at 0, 6, 12, 18 h after induction of AP. In 24 h survivors, free active trypsin (FAT) and total potential trypsin (TPT), chymotrypsin and lipase in 12,000 x g supernatants of the pancreases were assayed. The index of trypsinogen activation (% FAT/TPT) was elevated in untreated AP to 29.2 +/- 5.0 vs 5.4 +/- 0.9 in the control (p < 0.001). ET(A/B) antagonist at increasing doses, diminished this index to 9.8 +/- 2.7, 10.3 +/- 1.6 and 10.1 +/- 2.0 respectively (p < 0.005). ET(A) antagonist reduced % FAT/TPT ratio to 10.6 +/- 1.9 (p < 0.005), 13.4 +/- 0.5 (p < 0.001) and 10.2 +/- 2.4 (p < 0.005) at respective doses. Both antagonists to a similar degree reduced the histological scores of inflammation, hemorrhages and necrosis. The increase in chymotrypsin and lipase activities after 24 h was not significant. In conclusion, both nonselective ET(A/B) and selective ET(A) antagonists attenuated to similar degree the augmented trypsinogen activation and pancreatic injury in taurocholate acute experimental pancreatitis in rats. Endothelin-1 receptor antagonists could be beneficial in the course of acute pancreatitis by the attenuation of trypsinogen activation.
Dlugosz
Jan W
JW
Gastroenterology and Internal Diseases Department Medical University of Bialystok, Bialystok, Poland. ariosto@amb.edu.pl
Nowak
Konrad
K
Laszewicz
Wiktor
W
Andrzejewska
Anna
A
Wroblewski
Eugeniusz
E
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D002919:Chymotrypsinogen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D007274:Injections, Intraperitoneal; D008049:Lipase / Q000378:metabolism; D008297:Male; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011422:Propionates / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000633:toxicity; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism
C405519:BSF 302146; D001559:Benzhydryl Compounds; D065128:Endothelin Receptor Antagonists; C113044:LU 224332; D011422:Propionates; D011743:Pyrimidines; D013656:Taurocholic Acid; D014362:Trypsinogen; D002919:Chymotrypsinogen; D008049:Lipase; D014357:Trypsin