Endothelin-A receptor blockade improves postischemic hepatic microhemodynamics.
The aim of this study was to investigate a possible protective role of a selective endothelin-A receptor antagonist on hepatic microcirculation after ischemia/reperfusion. In a rat model, warm ischemia of the left liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Shamoperated and untreated ischemic groups and a group treated with BSF 208075 were investigated. The effect of the endothelin-A receptor antagonist on ischemia/reperfusion was assessed by in-vivo microscopy and measurement of aspartate aminotransferase and alanine aminotransferase levels. In the untreated group, sinusoidal constriction to 70% of basal diameters was observed, leading to a significant decrease in perfusion rate. In addition, we found an increased percentage of stagnant leukocytes and platelets in sinusoids and in postsinusoidal venules (P < 0.05). A significant increase in liver enzymes was detected 6 hours after reperfusion (P < 0.05). In the treatment group, sinusoidal diameters were maintained at 108%, and perfusion rate was significantly increased (P < 0.05). Hepatocellular damage was decreased and leukocyte and platelet-endothelium interactions were reduced (P < 0.05). Our results provide evidence that the new therapeutic approach using an endothelin-A receptor antagonist is effective in reducing hepatic ischemia/reperfusion injury. It could be shown for the first time that endothelin receptor blockade also influences platelet-endothelium interactions.
Uhlmann
Dirk
D
Second Department of Surgery, University of Leipzig, Germany. uhld@medizin.uni-leipzig.de
Glasser
Sebastian
S
Lauer
Heike
H
Ludwig
Stefan
S
Gaebel
Gabor
G
Serr
Frederick
F
Hauss
Johann
J
Witzigmann
Helmut
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D036904:Leukocyte Rolling / Q000187:drug effects; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008102:Liver Circulation / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D010666:Phenylpropionates / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
D002317:Cardiovascular Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011724:Pyridazines; D044022:Receptor, Endothelin A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C467894:ambrisentan