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Improvement of postischemic hepatic microcirculation after endothelina receptor blockade—Endothelin antagonism inflfuences platelet-endothelium interactions

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Journal of Gastrointestinal Surgery

Abstract

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 endothelinA receptor antagonist (ETA-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 shamoperated (SO, n = 14), untreated ischemia (n = 14), and treatment with BSF208075 (5 mg/kg body weight IV, n = 14). The effect of the ETA-RA on I/R was assessed by in vivo microscopy 20 to 90 minutes after reperfusion; by measurement of local tissue PO2, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione S-transferase α 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 PO2 (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 (ASTandALTincrease to1330 ± 157U/Land750 ± 125U/Lrespectively; 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 ETA-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 PO2 (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 ETA-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.

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Authors and Affiliations

  1. Second Department of Surgery, University of Leipzig, Leipzig, Germany

    Dirk Uhlmann M.D., Sebastian Glasser M.D., Gabor Gaebel M.D., Barbara Armann M.D., Stefan Ludwig M.D., Johann Hauss M.D. & Helmut Witzigmann M.D.

  2. Institute of Pathology, University of Leipzig, Leipzig, Germany

    Andrea Tannapfel M.D.

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  1. Dirk Uhlmann M.D.
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  2. Sebastian Glasser M.D.
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  6. Andrea Tannapfel M.D.
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  8. Helmut Witzigmann M.D.
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Correspondence to Dirk Uhlmann M.D..

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This study was supported by a grant from the Else Kröner-Fresenius Stiftung and by a junior research fund of the Medical Faculty at the University of Leipzig.

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Uhlmann, D., Glasser, S., Gaebel, G. et al. Improvement of postischemic hepatic microcirculation after endothelina receptor blockade—Endothelin antagonism inflfuences platelet-endothelium interactions. J Gastrointest Surg 9, 187–197 (2005). https://doi.org/10.1016/j.gassur.2004.06.006

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