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 × 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.