Changes of vasoregulatory gene expression following hepatic ischemia/reperfusion and treatment with endothelin-A receptor blockade.
The objective of this study was to investigate the effect of a specific endothelin-A receptor antagonist on mRNA expression of genes encoding vasoactive mediators and proinflammatory cytokines following complete vascular exclusion of the porcine liver. Fourteen adult German Landrace pigs were subjected to 120 minutes of warm hepatic ischemia by total vascular exclusion. The animals were divided into two groups: the control group received saline solution and the therapy group was given the selective endothelin-A receptor antagonist BSF 208075. Liver tissue samples were collected 1 hour after reperfusion and mRNA expression for preproendothelin-1, prointerleukin-1beta, prointerleukin- 6, pro-tumor necrosis factor-alpha and endothelial nitric oxide synthase was analyzed quantitatively using the TaqMan system. Additionally, immunohistochemical analysis using a semiquantitative score for endothelin-1 and endothelin-A receptor was performed. One hour after reperfusion, quantitative reverse transcriptase-polymerase chain reaction revealed significantly lower expression of preproendothelin-1, pro-tumor necrosis factor-alpha, and prointerleukin-6 in the therapy group compared to controls. Immunohistochemical analysis demonstrated significantly reduced endothelin-1 immunostaining after therapy. Treatment with the selective endothelin-A receptor antagonist exerts a protective effect on the microcirculation after liver ischemia and reperfusion. We were able to show that the endothelin-A receptor antagonist not only has effects on the expression of vasoactive genes, it also decreases gene expression of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6.
Uhlmann
Dirk
D
Second Department of Surgery, University of Leipzig, Leipzig, Germany. uhld@medizin.uni-leipzig.de
Gaebel
Gabor
G
Teupser
Daniel
D
Armann
Barbara
B
Tannapfel
Andrea
A
Ludwig
Stefan
S
Pietsch
Uta-Carolin
UC
Fiedler
Georg Martin
GM
Hauss
Johann
J
Witzigmann
Helmut
H
D042501:Angiogenic Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010666:Phenylpropionates / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D052096:Warm Ischemia
D042501:Angiogenic Proteins; D002317:Cardiovascular Agents; D016207:Cytokines; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D010666:Phenylpropionates; D011724:Pyridazines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; C467894:ambrisentan