Effects of the endothelin receptor antagonist TAK-044 on hepatocyte element alterations in the ischemic-reperfused liver in Beagle dogs.

摘要

BACKGROUND/AIMS: This study was designed to investigate elemental alterations of subcellular organelles (cytoplasm, nucleus, mitochondria) after ischemia of the liver, and the effects of the pre-ischemic administration of an endothelin ETA/ETB receptor antagonist (TAK-044) on subcellular elements. METHODS: We determined serial changes in subcellular elements by X-ray microanalysis using liver biopsy specimens, and we compared the liver functions of a control and a TAK-044-treated group 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. RESULTS: In the control, the Ca concentration in the cytoplasm showed a slight increase after ischemia and a marked increase immediately after reperfusion. It returned to approximately pre-ischemic levels at 6 h after reperfusion. In contrast, in the TAK-044 group, the increase was significantly suppressed. The changes in Na and Cl, which increased in parallel with Ca, were also suppressed in the TAK-044 group. The alterations in K were opposite to those Ca. These changes were also suppressed to a significant degree in the TAK-044 group. Elemental alterations in the nucleus and mitochondria were similar to those in the cytoplasm in both the control and TAK-044 groups. The changes in the liver functions and the electron microscopic findings supported the differences in serial changes in subcellular elements between the two groups. CONCLUSIONS: TAK-044 exhibited a hepatoprotective effect on ischemia-reperfusion injury from the aspect of subcellular elemental dynamics and liver functional and morphologic changes.