Effect of endothelin receptor antagonist (TAK-044) on autotransplanted perfused kidneys in dogs.
BACKGROUND
Endothelin-1 (ET-1) is involved in some diseases, including renal disease. Recently, the role of ET-1 in postrenal transplantation has been demonstrated in experimental and clinical studies. A new endothelin receptor antagonist, TAK-044, blocks both, ETA and ETB receptors, and was useful in treating acute renal failure in rats. In this study, we evaluated the effect of TAK-044 on autotransplanted kidneys with 18 h of perfusion.


METHODS
TAK-044 was injected subcutaneously at 15 mg/kg/day for 2 weeks in one group of dogs, and blood analysis and renal function, were evaluated. A control group was given saline in the same manner as that used for the TAK-044 group. Histopathological examination and immunohistochemistry for ET-1 were performed in the two groups.


RESULTS
In the control group, 5 of the 7 dogs died of renal failure within 2 weeks after autotransplantation of the kidney. In the TAK-044 group, 5 of the 7 dogs survived and 2 died of renal failure within the same period. Although the histological changes in the tubules in both groups were severe due to the 18 h of perfusion, TAK-044 ameliorated these changes. Immunohistochemical staining for ET-1 was seen in tubules in the control group.


CONCLUSIONS
These findings suggest that TAK-044 effectively reduces damage in autotransplanted perfused kidneys in dogs, and may be useful in limiting damage to the kidney by acute tubular necrosis after renal transplantation in humans.
Yoshida
K
K
Division of Hemodialysis Unit, Nara Medical University, Nara, Japan. Kappo@nmu-gw.naramed-u.ac.jp
Kagebayashi
Y
Y
Kitauchi
T
T
Kimura
S
S
Yoneda
T
T
Ozono
S
S
Hirao
Y
Y
Watanabe
T
T
D000818:Animals; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010477:Perfusion; D014182:Transplantation, Autologous
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C088196:TAK 044