EFFECTS OF THE ENDOTHELIN RECEPTOR ANTAGONIST TAK-044 ON HEPATOCYTE ELEMENT ALTERATIONS IN THE ISCHEMIC-REPERFUSED LIVER IN BEAGLE DOGS

Background / Aims: This study was designed to investigate elemental al terations of subcellular organelles (cytoplasm, nucleus, mitochondria) after ischemia of the liver, and the effects of the pre-ischemic admi nistration of an endothelin ETA/ETB receptor antagonist (TAK-044) on s ubcellular elements. Methods: We determined serial changes in subcellu lar elements by X-ray microanalysis using liver biopsy specimens, and we compared the liver functions of a control and a TAK-044-treated gro up of Beagle dogs, before and after 70% partial ischemia (60 min). TAK -044 was given intravenously at a dose of 3 mg/kg before ischemia. Res ults: In the control, the Ca concentration in the cytoplasm showed a s light increase after ischemia rind a marked increase immediately after reperfusion. It returned to approximately pre-ischemic levels of 6 h after reperfusion. In contrast, in the TAK-044 group, the increase was significantly suppressed. The changes in Na and Cl, which increased i n parallel with Ca, were also suppressed in the TAK-044 group. The alt erations in K were opposite to those Ca. These changes were also suppr essed to a significant degree in the TAK-044 group, Elemental alterati ons in the nucleus and mitochondria Ia were similar to those in the cy toplasm in both the control and TAK-044 groups. The changes in the liv er functions and the electron microscopic findings supported the diffe rences in serial changes in subcellular elements between the two group s. Conclusions: TAK-044 exhibited a hepatoprotective effect on ischemi a-reperfusion injury front the aspect of subcellular elemental dynamic s and liver functional and morphologic changes.