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Endothelin a receptor blockade reduces hepatic ischemia/reperfusion injury after warm ischemia in a pig model

  • Published:
Journal of Gastrointestinal Surgery

Abstract

It is well established that endothelin-1 (ET-1) is a very potent mediator of vasoconstriction that leads to microcirculatory disturbances. The aim of the study was to evaluate the effect of a selective endothelin A receptor antagonist on severe ischemia/reperfusion injury in a pig model. Fourteen pigs were subjected to 120 minutes of complete vascular exclusion of the liver with a passive bypass. The animals were randomized into two groups: a control group, which was given isotonic saline solution, and a therapy group, which received the selective endothelin A receptor antagonist BSF 208075 at the beginning of reperfusion. On postoperative days 4 and 7, animals were relaparotomized to obtain tissue specimens. Blood monitoring included aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), alkaline phosphatase, and ET-1. Partial oxygen tension (ptiO2) was measured by a Clarke-type electrode and blood flow by laser Doppler. A semiquantitative scoring index was used for assessment of histologic injury and for immunohistochemical analysis of ET-1. Treatment with the endothelin A receptor antagonist significantly reduced the severity of the ischemia/reperfusion injury, as evidenced by lower levels of AST, ALT, and GLDH. The dramatic increase in plasma ET-1 in the therapy group is clear evidence of effective receptor blockade. Analysis of PtiO2 and blood flow revealed a significant improvement in capillary perfusion and blood flow in the treated group and was associated with relevant reduction of tissue injury. In summary, in the control group we observed serious microcirculatory disturbances and severe histologic damage in the liver after reperfusion. Treatment with a selective endothelin A receptor antagonist attenuated the ischemia/reperfusion injury in a porcine model of severe ischemia/reperfusion, as demonstrated by improved microcirculation, a reduction in histologic damage, and an decrease in liver enzymes.

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Authors and Affiliations

  1. Departments of Abdominal Transplantation and Vascular Surgery, University of Leipzig, Leipzig, Germany

    Dirk Uhlmann M.D., Barbara Armann, Stefan Ludwig M.D., Jochen Hess, Evelyn Escher, Johann Hauss M.D. & Helmut Witzigmann M.D.

  2. Anesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany

    Uta-Carolin Pietsch M.D.

  3. Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany

    Martin Fiedler M.D.

  4. Pathology, University of Leipzig, Leipzig, Germany

    Andrea Tannapfel M.D.

Authors
  1. Dirk Uhlmann M.D.
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  2. Barbara Armann
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  3. Gabor Gaebel
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  4. Stefan Ludwig M.D.
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  5. Jochen Hess
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  6. Uta-Carolin Pietsch M.D.
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  7. Evelyn Escher
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  8. Martin Fiedler M.D.
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  9. Andrea Tannapfel M.D.
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  10. Johann Hauss M.D.
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  11. Helmut Witzigmann M.D.
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Corresponding author

Correspondence to Dirk Uhlmann M.D..

Additional information

Supported by a grant from the Else Kröner-Fresenius Stiftung and by a junior research fund of the Medical Faculty at the University of Leipzig.

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Uhlmann, D., Armann, B., Gaebel, G. et al. Endothelin a receptor blockade reduces hepatic ischemia/reperfusion injury after warm ischemia in a pig model. J Gastrointest Surg 7, 331–339 (2003). https://doi.org/10.1016/S1091-255X(02)00417-1

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  • DOI: https://doi.org/10.1016/S1091-255X(02)00417-1

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