Reduction of Ischemia/Reperfusion Injury after Complete Vascular Exclusion of the Liver by a Selective ET-A Receptor Antagonist in a Pig Model
Abstracts
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Introduction: The ischemia/reperfusion injury occurring during liver resections as a result of the vascular exclusion plays a major role in mortality and morbidity. It recently has been reported, that endothelin-1 (ET-1) is a very strong mediator of vasoconstriction that leads to microcirculatory disturbances. Aim: Our goal was a reduction of the ischemia/reperfusion (I/R) injury through a selective ET-A receptor antagonist (ET-A-RA) in a pig model as a preclinical test. Methods: In 14 German landrace pigs a complete vascular exclusion of the liver with a passive bypass was performed. The animals were randomised. In the therapy group the selective ET-A-RA BSF208075 (Knoll, Germany) was administered at the beginning of reperfusion in a dosage of 5 mg/kg i.v., control animals received a saline infusion. To analyse the severity of the I/R injury the following parameters were measured: partial oxygen pressure of the tissue (ptiO2, Licox, GMS), blood gas in the tissue (pO2para, pCO2para, pHpara, Paratrend, Agilent); laser-doppler-flow (DRT4, Moor Instruments); semiquantitive analysis of histological changes, ET-immunohistochemistry; ASAT, ALAT, GLDH and a-GST. The animals were observed for a 5 day period. Results: Following data show the microcirculatory disturbance in the control group 1 h after reperfusion: ptiO2 34.7 ± 5.4 mmHg (preop.: 42.8 ± 8.4 mmHg), pO2para 43.4 ± 3.0 mmHg (preop.: 61.0 ± 12.9 mmHg), Laser-Doppler-area: 166.4 ± 25.4 (preop.: 220.6 ± 26.6). The therapy group showed in all 3 parameters significantly better data as observed in the controls (ptiO2: 50.8 ± 13.3 mmHg, pO2para: 65.0 ± 11.8 mmHg, laser-doppler-area: 225.5 ± 31.3; p<0.05). In the histological analysis 2 h after reperfusion the therapy animals showed a significant reduction of tissue damage regarding edema, haemorrhages, and quality of the sinusoids (p<0.05). ASAT had a significantly lower increase in the therapy group (15.7 ± 5.1 µmol/l vs. controls: 27.5 ± 6.3 µmol/l, p<0.05). The differences in the observed ALAT-data were not significant between the groups. GLDH (0.4 ± 0.2 µmol/l vs. controls: 1.1 ± 0.2 µmol/l, p<0.05) and a-GST were only significantly lower at one time point (18 h after reperfusion) of the observation period. Conclusion: In the control group we observed strong microcirculatory disturbances and a severe histological damage in the liver. The therapy with a selective ET-A-RA after vascular exclusion leads to a reduction of the I/R injury in the porcine model. |
