Endothelin receptor antagonists are not beneficial in the therapy of acute experimental pancreatitis.
OBJECTIVE
Due to increased capillary permeability and the early appearance of vasoactive and toxic agents, patients suffering from necrotizing pancreatitis frequently develop a systemic inflammatory response syndrome (SIRS). Endothelin, a potent vasoconstrictor, is thought to play a major role in these changes via the regulation of microcirculation. An improved outcome of acute experimental necrotizing pancreatitis by blocking the endothelin receptors ETA and ETB, either selectively (only ETA) or unselectively (ETA and ETB), has been suggested. The aim of this study was to investigate further the beneficial effects of new, highly potent endothelin-receptor (ET-R) antagonists in acute experimental pancreatitis.


METHODS
The influence of the selective ET-RA antagonist BSF208075 (1 mg/kg) on mortality was studied in three severity groups of acute necrotizing pancreatitis (retrograde injection of 4%, 5% and 6% of sodium taurocholate into the main pancreatic duct). The effects of the selective ET-RA antagonists LU135252 (LU13) and BSF208075 (BSF20) and of the unselective endothelin receptor (ET-R(A/B)) antagonist BSF420627 (BSF42) were additionally analyzed in 4% taurocholate-induced necrotizing pancreatitis. Furthermore, the significance of variable doses of the endothelin receptor antagonist LU13 (1 mg/kg, 3 mg/kg and 100 mg/kg) was determined in a 4% sodium taurocholate model and in a cerulein pancreatitis model.


RESULTS
Prophylactic ET-R antagonism increased the mortality rate in the 4% sodium taurocholate-induced pancreatitis. No reduction in pancreatic damage after induction of taurocholate pancreatitis was found by ET-R blockage. Application of ET-R antagonists had no beneficial influence in ascites development. However, administration of LU13 (100 mg/kg) resulted in a non-significant increase in pancreatic oedema, whereas peritoneal necrosis was not affected.


CONCLUSIONS
The selective and unselective ET-R antagonists BSF20, BSF42 and LU13 failed to improve survival and pancreatic damage during acute experimental pancreatitis. Therefore, previously reported beneficial effects of ET-R antagonists in experimental acute pancreatitis have to be critically evaluated before conclusions for further clinical development are made.
Martignoni
M E
ME
Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Ceyhan
G O
GO
Ayuni
E
E
Kondo
Y
Y
Zimmermann
A
A
Büchler
M W
MW
Friess
H
H
D000818:Animals; D002108:Ceruletide; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D008297:Male; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy*; D010666:Phenylpropionates / Q000008:administration & dosage / Q000627:therapeutic use*; D011724:Pyridazines; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid; D017211:Treatment Failure
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D011743:Pyrimidines; C107831:darusentan; D013656:Taurocholic Acid; D002108:Ceruletide; C467894:ambrisentan