International Journal of Pancreatology

, Volume 26, Issue 3, pp 147–154 | Cite as

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

  • F. Fiedler
  • D. Ayasse
  • P. Rohmeiss
  • N. Gretz
  • C. Rehbein
  • V. Keim
Original Article

Summary

Background. Severity of pancreatitis seems to be aggravated by impairment of vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent inflammatory 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 infusion into the pancreatic duct of 1 µL/g body weight (b.w.) of either a 4% or a 5% sodium taurocholate solution. The mixed endothelin A and endothelin B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected intravenously 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 the effect of exogenous endothelin. The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepared for histological and biochemical evaluation.

Results. Irrespective of the treatment protocol (bosentan versus saline), survival 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 bosentan. 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 antagonist 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.

Key Words

Acute experimental pancreatitis endothelin endothelin-receptor antagonist bosentan 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Steer ML. How and where does acute pancreatitis begin? Arch Surg 1992;127:1350–1353.PubMedGoogle Scholar
  2. 2.
    Bassi D, Kollias N, Fernandez-del Castillo C, Foitzik T, Warshaw AL, Rattner DW. Impairment of pancreatic micro circulation correlates with the severity of acute experimental pancreatitis. J Am Coll Surg 1994;179:257–263.PubMedGoogle Scholar
  3. 3.
    Klar E, Schratt W, Foitzik T, Buhr H, Herfarth C, Messmer K. Impact of microcirculatory flow pattern changes on the development of acute edematous and necrotizing pancreatitis in rabbit pancreas. Dig Dis Sci 1994; 39:2639–2644.PubMedCrossRefGoogle Scholar
  4. 4.
    Klar E, Rattner DW, Compton C, Stanford G, Chernow B, Warshaw AL. Adverse effect of therapeutic vasoconstrictors in experimental acute pancreatitis. Ann Surg 1991;214:168–174.PubMedCrossRefGoogle Scholar
  5. 5.
    Foitzik T, Bassi DG, Schmidt J, Lewandrowski KB, Fernandez-del Castillo C, Rattner DW, Warshaw AL. Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat. Gastroenterology 1995;106:207–214.Google Scholar
  6. 6.
    Klar E, Messmer K, Warshaw AL, Herfarth C. Pancreatic ischemia in experimental acute pancreatitis: mechanism, significance, and therapy. Br J Surg 1990;77:1205–1210.PubMedCrossRefGoogle Scholar
  7. 7.
    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415.PubMedCrossRefGoogle Scholar
  8. 8.
    Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding endothelin receptor. Nature 1990;348:730–732.PubMedCrossRefGoogle Scholar
  9. 9.
    Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a nonisopeptide selective subtype of the endothelin receptor. Nature 1990;348:732–735.PubMedCrossRefGoogle Scholar
  10. 10.
    Warner TD, Allcock GH, Mickley EJ, Corder R, Vane JR. Comparative studies with the endothelin receptor antagonists BQ-123 and PD 142893 indicate at least three endothelin receptors. J Cardiovasc Pharmacol 1993;22(Suppl 8):S117-S120.PubMedCrossRefGoogle Scholar
  11. 11.
    Randall MD, Douglas SA, Hiley CR. Vascular activities of endothelin-1 and some alanyl substituted analogues in resistance beds of the rat. Br J Pharamcol 1989;98:685–699.Google Scholar
  12. 12.
    Takayanagi R, Kitazumi K, Takasaki C, Ohnaka K, Aimoto S, Tasaka K, Ohashi M, Nawata H. Presence of non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilataion. FEBS Lett 1991;282:103–106.PubMedCrossRefGoogle Scholar
  13. 13.
    De Nucci G, Thomas R, d’Orleans-Juste P. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1988;85:9797–9800.PubMedCrossRefGoogle Scholar
  14. 14.
    Hildebrand P, Mrozinski JE, Mantey SA, Patto RJ, Jensen RT. Pancreatic acini possess endothelin receptors whose internalization is regulated by PLC-activating agents. Am J Physiol 1993:264(Gastrointest Liver Physiol 27):G984-G993.PubMedGoogle Scholar
  15. 15.
    Hof RP, Hof A, Takiguchi Y. Massive regional differences in the vascular effects of endothelin. J Hypertens 1989;7:274–275.Google Scholar
  16. 16.
    Takaori K, Inoue K, Kogire M, Higashide S, Tun T, Aung T, Doi R, Fujii N, Tobe T. Effects of endothelin on microcirculation of the pancreas. Life Sci 1992;51:615–622.PubMedCrossRefGoogle Scholar
  17. 17.
    Filep JG, Sirois MG, Rousseau A, Fournier A, Sirois P. Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor. Br J Pharmacol 1991;104:797–804.PubMedGoogle Scholar
  18. 18.
    Lehoux S, Plante GE, Sirois MG, Sirois P, d’Orleans-Juste P. Phosphoramidon blocks big-endothelin-1 but not endothelin-1 enhancement of vascular permeability in the rat. Br J Pharmacol 1992;107:996–1000.PubMedGoogle Scholar
  19. 19.
    Kakugawa Y, Paraskevas S, Metrakos P, Giaid A, Qi SJ, Duguid WP, Rosenberg L. Alterations in pancreatic microcirculation and expression of endothelin-1 in a model of chronic pancreatitis. Pancreas 1996;13:89–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Liu XH, Kimura T, Ishikawa H, Yamaguchi H, Furukawa M, Nakano I, Kinjoh M, Nawata H. Effect of endothlin-1 on the development of hemorrhagic pancreatitis in rats. Scand J Gastroenterol 1995;30:276–282.PubMedCrossRefGoogle Scholar
  21. 21.
    Schmidt J, Fernandez del Castillo C, Rattner DW, Lewandrowski KB, Messmer K, Warshaw AL. Hyperoncotic ultrahigh molecular weight dextran solutions reduce trypsiongen activation, prevent acinar necrosis, and lower mortality in rodent pancreatitis. Am J Surg 1993;165:40–45.PubMedCrossRefGoogle Scholar
  22. 22.
    Aho HJ, Koskensalo SM, Nevalainen TJ. Experimental pancreatitis in the rat. Sodium taurocholate-induced acute haemorrhagic pancreatitis. Scand J Gastroenterol 1980;15:411–416.PubMedCrossRefGoogle Scholar
  23. 23.
    Buang RD. Validation in awake rats of a tail-cuff method for measuring systolic pressure. J Appl Physiol 1973;34:279–282.Google Scholar
  24. 24.
    Spormann H, Sokolowski A, Letko G. Effect of temporary ischemia upon development and histological patterns of acute pancreatitis in the rat. Pathol Res Pract 1989;184:507–513.PubMedGoogle Scholar
  25. 25.
    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–254.PubMedCrossRefGoogle Scholar
  26. 26.
    Wilcoxon S. Probability tables for individual comparisons by ranking methods. Biometrics 1947;3:119–122.CrossRefGoogle Scholar
  27. 27.
    Stojilkovic SS, Catt KJ. Expression and signal transduction pathways of endothelin receptors in neuroendocrine cells. Front Neuroendocrinol 1996;17:327–369.PubMedCrossRefGoogle Scholar
  28. 28.
    Clozel M, Breu V, Gray GA, Kalina B, Löffler BM, Burri K, Cassal JM, Hirth G, Müller M, Neidhardt W, Ramuz H. Pharmacological characterization of bosentan, a new potent orally active non-peptide endothelin receptor antagonist. J Pharmacol Exp Therap 1994;270:228–235.Google Scholar
  29. 29.
    Sogni P, Moreau R, Gomola A, Gadano A, Cailmail S, Calmus Y, Clozel M, Lebrec D. Beneficial hemodynamic effect of bosentan, a mixed ETA and ETB receptor antagonist, in portal hypertensive rats. Hepatology 1998;28:655–659.PubMedCrossRefGoogle Scholar
  30. 30.
    Oldner A, Wanecek M, Goiny M, Weitzberg E, Rudehill A, Alving K, Sollevi A. The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock. Gut 1998;42:696–702.PubMedCrossRefGoogle Scholar
  31. 31.
    Donahue P, Akimoto H, Ferguson J, Nyhus L. Vasoactive drugs in acute pancreatitis. Arch Surg 1984;119:477–480.PubMedGoogle Scholar
  32. 32.
    Kusterer K, Enghöfer M, Zendier S, Bloche C, Usadel K. Microcirculatory changes in sodium taurocholate induced pancreatitis in rats. Am J Physiol 1991;260:346–351.Google Scholar
  33. 33.
    Knoefel WT, Kollias N, Warshaw AL, Waldner H, Nishioka NS, Rattner DW. Pancreatic microcirculatory changes in experimental pancreatitis of graded severity in the rat. Surgery 1994;116:904–913.PubMedGoogle Scholar
  34. 34.
    Lewis M, Kusske A, Todd K, Toyama M, Rongione A, Reber H, Ashley S. Improvement of experimental pancreatitis by an endothelin ETA/ETB receptor antagonist. Gastroenterology 1996;110:A411.Google Scholar
  35. 35.
    De Beaux AC, Goldie AS, Ross JA, Carter DC, Fearon KCH. Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis. Br J Surg 1996;83:349–353.PubMedCrossRefGoogle Scholar
  36. 36.
    Foitzik T, Faulhaber J, Hotz HG, Kirchengast M, Buhr HJ. Endothelin receptor blockade improves fluid sequenstration, pancreatic capillary blood flow, and survival in severe experimental pancreatitis. Ann Surg 1998;228:670–675.PubMedCrossRefGoogle Scholar
  37. 37.
    Todd KE, Lewis MP, Gloor B, Lane JS, Ashley SW, Reber HA. An ETA/ETB endothelin antagonist ameliorates systemic inflammation in a murine model of acute hemorrhagic pancreatitis. Surgery 1997;122:443–449.PubMedCrossRefGoogle Scholar
  38. 38.
    Kogire M, Inoue K, Higashide SI, Takaori K, Echigo Y, Gu YJ, Sumi S, Uchida K, Imamura M. Protective effects of endothelin-1 on acute pancreatitis in rats. Dig Dis Sci 1995;40:1207–1212.PubMedCrossRefGoogle Scholar
  39. 39.
    Eibl G, Foitzik T, Hotz H, Kahrau S, Faulhaber J, Forgacs B, Kirchengast M, Buhr HJ. Effect of endothelin on pancreatic and colonic capillary permeability in mild and severe pancreatitis in the rat. Digestion 1998;59:226.Google Scholar
  40. 40.
    Foitzik T, Eibl G, Forgacs B, Faulhaber J, Hotz HG, Kirchengast M, Buhr HJ. Therapy of microcirculatory disorders in severe acute pancreatitis. Endothelin-A but not endothelin-B receptor blockade reduces capillary leakage. Pancreas 1998;17:433.Google Scholar

Copyright information

© Humana Press Inc 1999

Authors and Affiliations

  • F. Fiedler
    • 5
  • D. Ayasse
    • 5
  • P. Rohmeiss
    • 1
  • N. Gretz
    • 2
  • C. Rehbein
    • 3
  • V. Keim
    • 4
  1. 1.Medizinische Klinik V, Klinikum MannheimUniversität HeidelbergMannheimGermany
  2. 2.Zentrum für Medizinische Forschung, Klinikum MannheimUniversität HeidelbergMannheimGermany
  3. 3.Institut für Pathologie, Klinikum MannheimUniversität HeidelbergMannheimGermany
  4. 4.Medizinische Klinik und Poliklinik IIUniversität LeipzigGermany
  5. 5.Institut für Anästhesiologie und Operative Intensivmedizin, Klinikum MannheimFakultät für Klinische Medizin Mannheim der Universität Heidelberg, Theodor-Kutzer UferMannheimGermany

Personalised recommendations