The endothelin antagonist bosentan does not improve survival in severe experimental pancreatitis in rats

Background. Severity of pancreatitis seems to be aggravated by impairment o f vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent i nflammatory response. Because vasoactive substances, including endothelin, seem to contribute to early mortality in acute pancreatitis, we tested the hypothesis that the inhibition of endothelin action could alter the outcome after severe experimental pancreatitis. Methods. In two groups of rats, pancreatitis was induced by intraductal inf usion into the pancreatic duct of I mu L/g body weight (b.w.) of either a 4 % or a 5% sodium taurocholate solution. The mixed endothelin A and endothel in B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected i ntravenously in 12-h intervals for 3 d starting 1 h after induction of bile acid pancreatitis. This dose of bosentan is known to completely inhibit th e effect of exogenous endothelin, The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepare d for histological and biochemical evaluation. Results. Irrespective of the treatment protocol (bosentan versus saline), s urvival was not different in animals challenged with either 4% or 5% sodium taurocholate. The corresponding survival rates were 62% with bosentan and 77% without bosentan in the 4% sodium taurocholate group. In the 5% sodium taurocholate group!, the survival rates were 20% with and 27% without bosen tan. Morphological and biochemical alterations were identical in control as well as in endothelin-antagonist-treated rats. Conclusion. Therapy with the mixed endothelin A and endothelin B receptor a ntagonist bosentan does not influence the outcome after severe experimental pancreatitis. Therefore, blockade of endothelin A and B receptor subtypes may not be of major importance as a therapeutic principle in this model of experimental pancreatitis.