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 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 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 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 (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 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.