EFFECTS OF A NEW ENDOTHELIN ANTAGONIST, TAK-044, ON POSTISCHEMIC ACUTE-RENAL-FAILURE IN RATS

Protective effects of a new endothelin (ET) receptor antagonist, TAK-0 44, 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 con tralateral nephrectomy and subsequent reperfusion of the left kidney. Plasma creatinine concentration (Per) increased to 2.28mg/dl 24 hours after reperfusion of the ischemic kidney. Intravenous administration o f TAK-044 (1-10mg/kg) prior to renal occlusion dose-dependently but pa rtially attenuated the increase in Per and the morphological damages o f the kidney. ET-1 and ET-3 increased perfusion pressure in isolated k idney preparations with similar potency, indicating that the renal vas oconstriction evoked by these ET isomers is mainly via ET(B) receptors , and TAK-044 (10nM) shifted the ET-1 dose-response curve to the right by a factor about 10. In a rat renal membrane fraction, ET-1 showed c ompetitive inhibition of specific [I-125]ET-1 binding with an IC50 val ue of 0.34nM and a Hill slope of 1.10. ET-3 did so with a higher IC50 value (3.3nM) and a lower Hill slope (0.56), suggesting that rat kidne y contains both ET(A) and another receptor subtype, probably ET(B). TA K-044 inhibited ET-I binding with an IC50 Value of 6.6nM and a Hill sl ope of 0.41. Plasma concentrations of immunoreactive TAK-044 were main tained over 7nM for 8 hours following i.v. injection of 10mg/kg TAK-04 4. These results suggest that endogenous ET is involved in the pathoge nesis of post-ischemic ARF, at least, in part and that TAK-044 provide d protective effects against ARF by blocking ET receptors, possibly bo th ET(A) and ET(B) receptors in renal vasculature and parenchymal cell s.