Effect of Endothelin Receptor Antagonist (TAK-044) on Autotransplanted Perfused Kidneys in Dogs

Abstract

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. Materials and 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. Conclusion: 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.

Endothelin Receptor Antagonists - An Overview

“…It was concluded from a study in a lamb model that ET A antagonist, PD180988, is a selective inhibitor of hypoxic pulmonary constriction and is amenable to use in infants [127]. TAK-044 was found to be effective in reducing damage in autotransplanted perfused kidneys in dogs, indicating that it could also be useful in reducing damage to the kidney due to necrosis after renal transplantation in humans [128]. It is hoped that the results from the clinical trials of some of these drug candidates would suitably position ET-antagonists as useful therapeutic agents for human cardiovascular diseases.…”