Effects of a new endothelin antagonist, TAK-044, on post-ischemic acute renal failure in rats

Kusumoto, K.; Kubo, K.; Kandori, H.; Kitayoshi, T.; Sato, S.; Wakimasu, M.; Watanabe, T.; Fujino, M.

Life Sciences 55(4): 301-310

1994


ISSN/ISBN: 0024-3205
PMID: 8028448
DOI: 10.1016/0024-3205(94)00732-2
Accession: 031134912

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Abstract
Protective effects of a new endothelin (ET) receptor antagonist, TAK-044, were studied in a model of acute renal failure (ARF) in rats. ARF was induced by clamping the left renal pedicle for 45 minutes with contralateral nephrectomy and subsequent reperfusion of the left kidney. Plasma creatinine concentration (Pcr) increased to 2.28 mg/dl 24 hours after reperfusion of the ischemic kidney. Intravenous administration of TAK-044 (1-10 mg/kg) prior to renal occlusion dose-dependently but partially attenuated the increase in Pcr and the morphological damages of the kidney. ET-1 and ET-3 increased perfusion pressure in isolated kidney preparations with similar potency, indicating that the renal vasoconstriction evoked by these ET isomers is mainly via ET-B receptors, and TAK-044 (10 nM) shifted the ET-1 dose-response curve to the right by a factor about 10. In a rat renal membrane fraction, ET-1 showed competitive inhibition of specific (125I)ET-1 binding with an IC-50 value of 0.34 nM and a Hill slope of 1.10. ET-3 did so with a higher IC-50 value (3.3 nM) and a lower Hill slope (0.56), suggesting that rat kidney contains both ET-A and another receptor subtype, probably ET-B. TAK-044 inhibited ET-1 binding with an IC-50 value of 6.6 nM and a Hill slope of 0.41. Plasma concentrations of immunoreactive TAK-044 were maintained over 7 nM for 8 hours following i. v. injection of 10 mg/kg TAK-044. These results suggest that endogenous ET is involved in the pathogenesis of post-ischemic ARF, at least, in part and that TAK-044 provided protective effects against ARF by blocking ET receptors, possibly both ET-A and ET-B receptors in renal vasculature and parenchymal cells.