title: Effects of the endothelin receptor antagonist TAK-044 on hepatocyte element alterations in the ischemic-reperfused liver in Beagle dogs.
abstract: 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.
authors.affiliation: First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Imakita
authors.forename: N
authors.initials: N
authors.lastname: Yamanaka
authors.forename: N
authors.initials: N
authors.lastname: Kuroda
authors.forename: Y
authors.initials: Y
authors.lastname: Kitayama
authors.forename: S
authors.initials: S
authors.lastname: Sasaki
authors.forename: I
authors.initials: I
authors.lastname: Nakagaki
authors.forename: S
authors.initials: S
authors.lastname: Hori
authors.forename: E
authors.initials: E
authors.lastname: Okamoto
mesh_terms: 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*
chemical_list: D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; C088196:TAK 044