Endothelin(A) receptor blockade reduces ischemia/reperfusion injury in pig pancreas transplantation.
OBJECTIVE
The effect of prophylactic administration of a selective endothelin(A) receptor antagonist (ET(A)-RA) on ischemia/reperfusion injury in an experimental model of graft pancreatitis after pancreas transplantation was evaluated.


BACKGROUND
It is well established that endothelin-1 (ET-1), a powerful vasoconstrictor, plays an important role in the development of pancreatitis. Recent studies have shown a beneficial effect of endothelin receptor antagonists in the therapy for experimental pancreatitis.


METHODS
Relevant ischemia/reperfusion injury was induced in pig pancreas transplants after 6 hours hypothermic preservation in University of Wisconsin solution. The recipients were randomized into 2 groups: control pigs received isotonic saline and the treated group received the selective ET(A)-RA BSF 208075 at the beginning of reperfusion. On postoperative days 2 and 5, animals were relaparotomized to obtain tissue specimens. Blood monitoring included lipase, amylase, C-reactive protein, trypsinogen-activation peptide, thiobarbituric acid-reacting substances, 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 score index was used for assessment of histologic injury and for immunohistochemical analysis of ET-1 and ET(A) receptor expression. Tissue mRNA levels of prepro ET-1, ET(A) receptor, pro-interleukin (IL)-6, and pro-IL-1beta were quantified using TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Prophylactic treatment with ET(A)-RA significantly reduced the severity of graft pancreatitis evidenced by C-reactive protein. The finding of transient capillary perfusion at the beginning of reperfusion supports the application of the ET(A)-RA during this period. The dramatic increase of plasma ET-1 in the therapy group is a clear evidence of effective receptor blockade. Mean trypsinogen-activation peptide levels from the portal venous effluent, but not mean systemic plasma TAP values were significantly lower in the treated group. Analysis of p(ti)O(2) and blood flow revealed a significant improvement of capillary perfusion and blood flow in the treated group and was associated with relevant reduction of tissue injury. Intrapancreatic ET-1 and IL-6 mRNA expression and ET-1 protein levels were significantly lower in the therapy group as compared with the control group. In contrast, ET(A) mRNA showed a marked up-regulation by ET(A) receptor blockade.


CONCLUSIONS
Application of a ET(A)-RA reduces ischemia/reperfusion induced graft pancreatitis in a pig transplantation model by improving microcirculation and reducing tissue injury.
Witzigmann
Helmut
H
Department of Abdominal, Transplantation and Vascular Surgery, University of Leipzig, Leipzig, Germany. with@medizin.uni-leipzig.de
Ludwig
Stefan
S
Armann
Barbara
B
Gäbel
Gäbor
G
Teupser
Daniel
D
Kratzsch
Jürgen
J
Pietsch
Uta Carolin
UC
Tannapfel
Andrea
A
Geissler
Felix
F
Hauss
Johann
J
Uhlmann
Dirk
D
D000681:Amylases / Q000097:blood; D000818:Animals; D001783:Blood Flow Velocity; D002097:C-Reactive Protein / Q000032:analysis; D003196:Computer Graphics; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood; D008049:Lipase / Q000097:blood; D010100:Oxygen / Q000032:analysis; D016035:Pancreas Transplantation; D019283:Pancreatitis, Acute Necrotizing / Q000517:prevention & control; D011897:Random Allocation; D044022:Receptor, Endothelin A; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D044022:Receptor, Endothelin A; D002097:C-Reactive Protein; D008049:Lipase; D000681:Amylases; D010100:Oxygen