Effects of the endothelin receptor antagonist TAK-044 on hepatocyte element alterations in the ischemic-reperfused liver in Beagle dogs.
OBJECTIVE
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.
Imakita
M
M
First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Yamanaka
N
N
Kuroda
N
N
Kitayama
Y
Y
Sasaki
S
S
Nakagaki
I
I
Hori
S
S
Okamoto
E
E
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004577:Electron Probe Microanalysis; D065128:Endothelin Receptor Antagonists; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy*
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C088196:TAK 044