THE USE OF THE ENDOTHELIN RECEPTOR ANTAGONIST, TEZOSENTAN, BEFORE OR AFTER RENAL ISCHEMIA PROTECTS RENAL FUNCTION1


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Abstract

Background.Utilization of organs subjected to ischemia/reperfusion (I/R) injury could expand the donor pool. Endothelin (ET) is implicated in renal I/R injury. Therefore, our study compared the effectiveness of pre- and postischemic administration of the ET receptor antagonist, Tezosentan, in preserving renal function.Methods.In a rat model, a kidney was subjected to 45 min of ischemia along with a contralateral nephrectomy. After 24 hr of reperfusion, renal function was assessed by serum creatinine (Scr), inulin clearance (glomerular filtration rate; GFR), and histology. ET-1 peptide expression was localized using immunohistochemistry. Three groups were studied: I/R untreated (n=17), I/R pretreated (n=11), and I/R posttreated (n=13) with Tezosentan (15 mg/kg, i.v.).Results.Tezosentan significantly decreased ( P <0.05) the rise in Scr from I/R injury (2.0±0.4 mg/dl, before and 2.9±0.4 mg/dl, after treatment) compared with untreated animals (4.2±0.4 mg/dl). GFR was significantly increased ( P <0.05) from 0.13±0.03 ml/min (untreated animals) to 0.74±0.16 and 0.47±0.14 ml/min (pre- and posttreated animals). Untreated animals had significant cortical acute tubular necrosis, which was almost completely prevented by pretreatment with Tezosentan and markedly reduced by posttreatment. Increased ET-1 peptide expression was noted in the renal vasculature and in the cortical tubular epithelium of kidneys exposed to I/R.Conclusions.The purpose of this study was to optimize the function of kidneys exposed to I/R injury. Pretreatment as well as posttreatment with Tezosentan successfully decreased Scr, increased GFR, and maintained renal architecture in kidneys after ischemia. Therefore, ET receptor antagonists may be useful to preserve renal function in the transplantation setting.

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