Improvement of postischemic hepatic microcirculation after endothelinA receptor blockade--endothelin antagonism influences platelet-endothelium interactions.
Endothelin (ET) contributes to disturbances of hepatic microcirculation after ischemia/reperfusion (I/R) by causing vasoconstriction and enhancing leukocyte- and platelet-endothelium interactions. The aim of this study was to investigate a possible protective role of a selective endothelin(A) receptor antagonist (ET(A)-RA) in this setting. In a rat model, warm ischemia of the left lateral liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Groups of rats consisted of sham-operated (SO, n=14), untreated ischemia (n=14), and treatment with BSF208075 (5 mg/kg body weight IV, n=14). The effect of the ET(A)-RA on I/R was assessed by in vivo microscopy 20 to 90 minutes after reperfusion; by measurement of local tissue Po(2), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione S-transferase alpha levels, and by histologic investigation. In the untreated group, sinusoidal constriction to 69.4+/-6.7% of diameters of SO rats was observed, leading to a significant decrease in perfusion rate (74.3+/-2.1% of SO) and liver tissue Po(2) (43.5+/-3.2% of SO) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes (142.9+/-11.9%) and platelets (450.1+/-62.3%) in sinusoids and in postsinusoidal venules (P < 0.05). Hepatocellular damage (AST and ALT increase to 1330+/-157 U/L and 750+/-125 U/L respectively; previously, 27.1+/-3.5 U/L and 28.5+/-3.6 U/L) was detected 6 hours after reperfusion (P < 0.05). Administration of the ET(A)-RA before reperfusion significantly reduced I/R injury. Sinusoidal diameters were maintained (108.5+/-6.6%), and perfusion rate (93.1+/-1.8%) and tissue Po(2) (95.3+/-5.7%) were significantly increased (P < 0.05). According to reduced leukocyte-endothelium interactions after therapy, both platelet rolling and adhesion were significantly reduced (P < 0.05). The number of stagnant platelets in sinusoids was 199.5+/-12.3% of 50 (P < 0.05). After treatment, hepatocellular damage was decreased (AST and ALT levels after 6 hours of reperfusion: 513+/-106 U/L and 309+/-84 U/L, respectively; P < 0.05), and histologic changes were reduced in the long term. Our results provide evidence that the new therapeutic approach with an ET(A)-RA is effective in reducing hepatic I/R injury. In addition to reduced leukocyte-endothelium interactions, the number of stagnant and rolling platelets in sinusoids and venules was significantly reduced. The reduction in microcirculatory damages is responsible for better organ outcome.
Uhlmann
Dirk
D
Second Department of Surgery, University of Leipzig, 04103 Leipzig, Germany. Uhld@medizin.uni-leipzig.de
Glasser
Sebastian
S
Gaebel
Gabor
G
Armann
Barbara
B
Ludwig
Stefan
S
Tannapfel
Andrea
A
Hauss
Johann
J
Witzigmann
Helmut
H
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood*; D001792:Blood Platelets / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D065130:Endothelin A Receptor Antagonists; D005260:Female; D017078:Laser-Doppler Flowmetry; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008102:Liver Circulation; D008833:Microcirculation / Q000187:drug effects*; D010666:Phenylpropionates / Q000494:pharmacology*; D010973:Platelet Adhesiveness; D011724:Pyridazines; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology*
D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011724:Pyridazines; D001219:Aspartate Aminotransferases; C467894:ambrisentan