Endothelin A receptor blockade reduces hepatic ischemia/reperfusion injury after warm ischemia in a pig model.
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 (p(ti)O(2)) 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 p(ti)O(2) 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.
Uhlmann
Dirk
D
Department of Abdominal Transplantation, University of Leipzig, Leipzig, Germany. uhld@medizin.uni-leipzig.de
Armann
Barbara
B
Gaebel
Gabor
G
Ludwig
Stefan
S
Hess
Jochen
J
Pietsch
Uta Carolin
UC
Escher
Evelyn
E
Fiedler
Martin
M
Tannapfel
Andrea
A
Hauss
Johann
J
Witzigmann
Helmut
H
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005969:Glutamate Dehydrogenase / Q000097:blood; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008833:Microcirculation; D010100:Oxygen / Q000032:analysis; D011897:Random Allocation; D044022:Receptor, Endothelin A; D012039:Regional Blood Flow; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D010100:Oxygen