RESUMEN

Endothelin evokes strong and longlasting constriction of postischemic sinusoids, leading to microcirculatory disturbances and local hypoxia, thereby causing liver damage. The aim of the study was to avoid the constrictive response of sinusoids by blocking endothelin receptors. In an in vivo ischemia-reperfusion model (21 female Wistar rats, 250-300 g) with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by cross clamping of the hepatoduodenal ligament. The endothelin receptor antagonist bosentan (10 mg/kg bw IV) was administered before ischemia. The effect of the receptor antagonist was assessed by serum levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) that were determined prior to ischemia, 2 and 6 h postoperatively. The local tissue pO2 was measured prior to inducing ischemia, 30 and 60 min after reperfusion. Application of 10 mg/kg bw endothelin receptor antagonist (ERA) intravenously did not influence the systemic blood pressure. The postischemic increase in serum ASAT and ALAT levels was diminished after receptor antagonist treatment (ASAT: p < .05). Local postischemic hepatic tissue pO2 was significantly decreased to 45% of basal values after 30 min and to 54.8% after 60 min of reperfusion (p < .05). Application of ERA results in a significant increase in local tissue pO2 to 110.9% of basal values after 30 min and to 90.7% after 60 min of reperfusion (p < .05). These data indicate that the endothelin receptor antagonist treatment results in a prevention of postischemic sinusoidal constriction avoiding hypoxia and leading to improved hepatocellular recovery.

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RESUMEN

UNLABELLED: One mechanism evoked by ischemia is endothelin mediated vasoconstriction of the hepatic vascular bed. Postischemic sinusoidal constriction leads to microcirculatory disturbances and reduced blood flow, thereby causing local hypoxia and liver damage. The aim of the study was to avoid the constrictive response of sinusoids by blocking endothelin receptors. MATERIAL AND METHODS: In an in vivo ischemia-reperfusion-model (21 Wistar rats, 250-300 g) with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by cross clamping of the hepatoduodenal ligament. The effect of the endothelin receptor antagonist bosentan (10 mg/kg bw i.v.) injected before ischemia was assessed by in vivo microscopy. Microhemodynamic studies, including the sinusoidal perfusion rate, diameters of hepatic sinusoids and postsinusoidal venules, leukocyte endothelium interactions and leukocyte velocity were performed. RESULTS: After ischemia sinusoidal diameters and diameters of postsinusoidal venules were significantly reduced to 76 +/- 7% and 86 +/- 10%, respectively, in the non-treatment group, but dilated to 109 +/- 6% and 118 +/- 8% in the group treated with endothelin receptor antagonist (p < 0.001). Increased percentage of postischemic permanent adherent leukocytes could be diminished in sinusoids and more markedly in venules by therapy (p < 0.001). Leukocyte velocity was decreased to 69 +/- 9% in the treatment group ( p < 0.001). Perfusion rate could be improved to 90 +/- 2% compared to 83 +/- 5% in the untreated group (p < 0.01). Systemic arterial blood pressure was not affected by administration of the receptor antagonist. CONCLUSION: These data indicate that the endothelin receptor antagonist treatment results in prevention of postischemic sinusoidal constriction. Perfusion rate could be improved due to dilation of sinusoids and diminished leukocyte adhesion, but leukocyte velocity was reduced by 31%.

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