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. 1998 Nov;228(5):670–675. doi: 10.1097/00000658-199811000-00006

Endothelin receptor blockade improves fluid sequestration, pancreatic capillary blood flow, and survival in severe experimental pancreatitis.

T Foitzik 1, J Faulhaber 1, H G Hotz 1, M Kirchengast 1, H J Buhr 1
PMCID: PMC1191572  PMID: 9833805

Abstract

OBJECTIVE: To evaluate the effect of a new endothelin receptor antagonist (ET-RA) on the course of severe experimental pancreatitis. BACKGROUND: Endothelin-1 has been shown to reduce regional blood flow in various organs, including the pancreas, and to aggravate cerulein-induced mild pancreatitis. METHODS: Acute necrotizing pancreatitis (ANP) was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptides (TAP) were measured to verify comparable disease severity. Starting 6 hours after the onset of ANP, animals randomly received either saline or the new ET-RA LU-135252. Monitoring included cardiorespiratory parameters, urine output, hematocrit, and TAP levels. After 24 hours, animals were relaparotomized to determine pancreatic capillary blood flow and to assess the amount of free intraabdominal fluid and acinar cell necrosis. Survival was determined in a second set of experiments on 24 animals observed for 48 hours after pancreatitis induction and treatment with either normal saline or ET-RA. RESULTS: Comparable TAP increases confirmed equally severe ANP in both groups before treatment. Treatment with ET-RA significantly reduced the mortality rate, from 50% in untreated animals to 8%. Improved survival was associated with significantly decreased hematocrit, improved urinary output, decreased ascites, and increased pancreatic capillary blood flow. There were no significant differences in plasma TAP and acinar cell injury in the surviving animals of the two treatment groups. CONCLUSION: Therapy with the new ET-RA reduces the early mortality rate in experimental ANP, probably by reducing fluid sequestration and improving microcirculation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai H., Hori S., Aramori I., Ohkubo H., Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990 Dec 20;348(6303):730–732. doi: 10.1038/348730a0. [DOI] [PubMed] [Google Scholar]
  2. Foitzik T., Bassi D. G., Schmidt J., Lewandrowski K. B., Fernandez-del Castillo C., Rattner D. W., Warshaw A. L. Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat. Gastroenterology. 1994 Jan;106(1):207–214. doi: 10.1016/s0016-5085(94)95457-7. [DOI] [PubMed] [Google Scholar]
  3. Foitzik T., Fernández-del Castillo C., Ferraro M. J., Mithöfer K., Rattner D. W., Warshaw A. L. Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. Ann Surg. 1995 Aug;222(2):179–185. doi: 10.1097/00000658-199508000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gullo A., Berlot G. Ingredients of organ dysfunction or failure. World J Surg. 1996 May;20(4):430–436. doi: 10.1007/s002689900068. [DOI] [PubMed] [Google Scholar]
  5. Hotz H. G., Schmidt J., Ryschich E. W., Foitzik T., Buhr H. J., Warshaw A. L., Herfarth C., Klar E. Isovolemic hemodilution with dextran prevents contrast medium induced impairment of pancreatic microcirculation in necrotizing pancreatitis of the rat. Am J Surg. 1995 Jan;169(1):161–166. doi: 10.1016/s0002-9610(99)80126-3. [DOI] [PubMed] [Google Scholar]
  6. Hurley P. R., Cook A., Jehanli A., Austen B. M., Hermon-Taylor J. Development of radioimmunoassays for free tetra-L-aspartyl-L-lysine trypsinogen activation peptides (TAP). J Immunol Methods. 1988 Jul 22;111(2):195–203. doi: 10.1016/0022-1759(88)90127-5. [DOI] [PubMed] [Google Scholar]
  7. Kirkpatrick C. J., Bittinger F., Klein C. L., Hauptmann S., Klosterhalfen B. The role of the microcirculation in multiple organ dysfunction syndrome (MODS): a review and perspective. Virchows Arch. 1996 Feb;427(5):461–476. doi: 10.1007/BF00199506. [DOI] [PubMed] [Google Scholar]
  8. Klar E., Foitzik T., Buhr H., Messmer K., Herfarth C. Isovolemic hemodilution with dextran 60 as treatment of pancreatic ischemia in acute pancreatitis. Clinical practicability of an experimental concept. Ann Surg. 1993 Apr;217(4):369–374. doi: 10.1097/00000658-199304000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kogire M., Inoue K., Higashide S., Takaori K., Echigo Y., Gu Y. J., Sumi S., Uchida K., Imamura M. Protective effects of endothelin-1 on acute pancreatitis in rats. Dig Dis Sci. 1995 Jun;40(6):1207–1212. doi: 10.1007/BF02065525. [DOI] [PubMed] [Google Scholar]
  10. Liu X. H., Kimura T., Ishikawa H., Yamaguchi H., Furukawa M., Nakano I., Kinjoh M., Nawata H. Effect of endothelin-1 on the development of hemorrhagic pancreatitis in rats. Scand J Gastroenterol. 1995 Mar;30(3):276–282. doi: 10.3109/00365529509093277. [DOI] [PubMed] [Google Scholar]
  11. Luiten E. J., Hop W. C., Lange J. F., Bruining H. A. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg. 1995 Jul;222(1):57–65. doi: 10.1097/00000658-199507000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mandavilli U., Schmidt J., Rattner D. W., Watson W. T., Warshaw A. L. Continuous complete collection of uncontaminated urine in conscious rodents. Lab Anim Sci. 1991 Jun;41(3):258–261. [PubMed] [Google Scholar]
  13. Mann D. V., Hershman M. J., Hittinger R., Glazer G. Multicentre audit of death from acute pancreatitis. Br J Surg. 1994 Jun;81(6):890–893. doi: 10.1002/bjs.1800810632. [DOI] [PubMed] [Google Scholar]
  14. McMillen M. A., Sumpio B. E. Endothelins: polyfunctional cytokines. J Am Coll Surg. 1995 May;180(5):621–637. [PubMed] [Google Scholar]
  15. Mithöfer K., Fernández-del Castillo C., Ferraro M. J., Lewandrowski K., Rattner D. W., Warshaw A. L. Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis. Gastroenterology. 1996 Jan;110(1):232–240. doi: 10.1053/gast.1996.v110.pm8536862. [DOI] [PubMed] [Google Scholar]
  16. Mithöfer K., Schmidt J., Gebhard M. M., Buhr H. J., Herfarth C., Klar E. Measurement of blood flow in pancreatic exchange capillaries with FITC-labeled erythrocytes. Microvasc Res. 1995 Jan;49(1):33–48. doi: 10.1006/mvre.1995.1004. [DOI] [PubMed] [Google Scholar]
  17. Pederzoli P., Bassi C., Vesentini S., Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet. 1993 May;176(5):480–483. [PubMed] [Google Scholar]
  18. Raschack M., Unger L., Riechers H., Klinge D. Receptor selectivity of endothelin antagonists and prevention of vasoconstriction and endothelin-induced sudden death. J Cardiovasc Pharmacol. 1995;26 (Suppl 3):S397–S399. [PubMed] [Google Scholar]
  19. Riechers H., Albrecht H. P., Amberg W., Baumann E., Bernard H., Böhm H. J., Klinge D., Kling A., Müller S., Raschack M. Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem. 1996 May 24;39(11):2123–2128. doi: 10.1021/jm960274q. [DOI] [PubMed] [Google Scholar]
  20. Sakurai T., Yanagisawa M., Takuwa Y., Miyazaki H., Kimura S., Goto K., Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990 Dec 20;348(6303):732–735. doi: 10.1038/348732a0. [DOI] [PubMed] [Google Scholar]
  21. Schmidt J., Ferńandez-del Castillo C., Rattner D. W., Lewandrowski K. B., Messmer K., Warshaw A. L. Hyperoncotic ultrahigh molecular weight dextran solutions reduce trypsinogen activation, prevent acinar necrosis, and lower mortality in rodent pancreatitis. Am J Surg. 1993 Jan;165(1):40–45. doi: 10.1016/s0002-9610(05)80402-7. [DOI] [PubMed] [Google Scholar]
  22. Schmidt J., Rattner D. W., Lewandrowski K., Compton C. C., Mandavilli U., Knoefel W. T., Warshaw A. L. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992 Jan;215(1):44–56. doi: 10.1097/00000658-199201000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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(8):615–622. doi: 10.1016/0024-3205(92)90231-d. [DOI] [PubMed] [Google Scholar]
  24. Weidenbach H., Lerch M. M., Gress T. M., Pfaff D., Turi S., Adler G. Vasoactive mediators and the progression from oedematous to necrotising experimental acute pancreatitis. Gut. 1995 Sep;37(3):434–440. doi: 10.1136/gut.37.3.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  26. Yotsumoto F., Manabe T., Ohshio G., Imanishi K., Ando K., Kyogoku T., Hirano T., Tobe T. Role of pancreatic blood flow and vasoactive substances in the development of canine acute pancreatitis. J Surg Res. 1993 Nov;55(5):531–536. doi: 10.1006/jsre.1993.1179. [DOI] [PubMed] [Google Scholar]
  27. d'Uscio L. V., Moreau P., Shaw S., Takase H., Barton M., Lüscher T. F. Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension. Hypertension. 1997 Jan;29(1 Pt 2):435–441. doi: 10.1161/01.hyp.29.1.435. [DOI] [PubMed] [Google Scholar]
  28. de Beaux A. C., Goldie A. S., Ross J. A., Carter D. C., Fearon K. C. Serum concentrations of inflammatory mediators related to organ failure in patients with acute pancreatitis. Br J Surg. 1996 Mar;83(3):349–353. doi: 10.1002/bjs.1800830317. [DOI] [PubMed] [Google Scholar]

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