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      Improved Recovery following Posttransplant Acute Renal Failure in Rat Renal Isografts with an Oral Endothelin-A Receptor Antagonist

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          Background: Delayed renal function after transplantation is a strong predictor of long-term graft survival. As an increased expression of endothelin (ET) has been demonstrated during ischemia/reperfusion injury, we hypothesized that ET-A receptor blockade could improve the recovery of acute renal failure in a rat model of isogeneic kidney transplantation. Methods: Kidneys of Fisher (F344, RT1<sup>1v1</sup>) rat donors flushed with cooled University of Wisconsin solution were transplanted into bilaterally nephrectomized Fisher rats. Recipient animals were treated orally either with vehicle or the selective ET-A receptor antagonist LU135252 (30 mg/kg/day p.o.) for 14 days. Unilaterally nephrectomized Fisher rats not subjected to ischemia served as controls. No immunosuppression was given. On days 2, 6 and 14, metabolic studies were performed to evaluate endogenous creatinine clearance, fractional sodium excretion, and urinary endothelin excretion. Kidneys were harvested at the end of the experiment for determination of renal ET content and immunohistochemical assessment. Results: Urinary ET excretion was increased in vehicle-treated isografts compared to uninephrectomized controls after 14 days. Treatment with LU135252 resulted in a significant improvement in creatinine clearance and fractional sodium excretion to the level of uninephrectomized rats after 14 days. Isografts treated with selective ET-A receptor blockade demonstrated a marked reduction in cell surface markers for macrophages/monocytes, T cells, MHC-II, and ICAM-1. Conclusion: Treatment with the selective ET-A receptor antagonist LU135252 accelerates recovery of renal function after isogeneic renal transplantation and attenuates cellular graft infiltration. This effect could have major implications for the treatment of patients undergoing renal transplantation, as an improved initial renal function may delay the onset of chronic allograft rejection.

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          In vivo labelling of the neuronal dopamine uptake complex in the mouse striatum by [3H]GBR 12783

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            Improvement of postischemic acute renal failure with the novel orally active endothelin-A receptor antagonist LU 135252 in the rat.

             R Birck,  T. Knoll,  C. Braun (1998)
            The endothelin (ET) system may play an important role in the pathogenesis of acute renal failure (ARF). We hypothesize that the course of ARF in an ischemia-reperfusion model will be markedly attenuated by the orally active ET(A)-receptor antagonist LU 135252 (LU) because of an improvement of renal perfusion. ARF was induced in rats by clamping both renal arteries for 60 min. The study was divided into two parts. In part 1, Rats received LU orally (100 mg/kg/day) starting 1 h after induction of ARF for 14 days. Cr(s), Cl(cr) and FE(na) were measured on days 1, 6, 9, and 14 after ARF. Cr(s) was lower in the treatment group on days 1 [1.3 +/- 0.31 mg/dl (n = 9) vs. 2.7 +/- 0.46 mg/dl (n = 10); p < 0.05] and 6 [0.5 +/- 0.1 mg/dl (n = 9) vs. 1.0 +/- 0.2 mg/dl (n = 9); p < 0.05], and Cl(cr) was higher on day 1 [0.9 +/- 0.17 ml/min (n = 9) vs. 0.2 +/- 0.1 ml/min (n = 8); p < 0.05] and 6 [1.8 +/- 0.29 ml/min (n = 9) vs. 1.0 +/- 0.21 ml/min (n = 9); p < 0.05] compared with vehicle. Additionally, FE(na) was lower in treated rats on day 1 [1 +/- 0.4% (n = 9) vs. 8 +/- 3% (n = 8); p < 0.051 compared with vehicle. In part 2, ARF was induced as described. Treated animals received 10 mg/kg LU on days 0, 1, 3, 6, 9, and 14 after ARF as an i.v. bolus injection. RBF, cortex blood flow (CBF), and medulla blood flow (MBF) were measured after application of LU on the same days: LU induced an increase in RBF (day 1: 14 +/- 5.3%, n = 6, p = 0.04; day 3: 15 +/- 2.8%, n = 8; p = 0.0008; day 6: 21 +/- 5.8%, n = 6, p = 0.02; day 9: 13 +/- 4%, n = 6; p = 0.03) and CBF (day 1: 8 +/- 2.2%, n = 7, p = 0.03; day 3: 7 +/- 2.5%, n = 7; p = 0.05; day 6: 18 +/- 4.8%, n = 6, p = 0.04; day 9: 10 +/- 2.5%, n = 6; p = 0.008) up to the first 9 days. MBF did increase on days 1 (9 +/- 3.1%, n = 6; p = 0.04) and 6 (13 +/- 3.6%, n = 6; p = 0.03). Our data confirm the hypothesis that ET plays a major role in the genesis of ARF associated with ischemia-reperfusion.
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                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2000
                31 July 2000
                : 8
                : 4-5
                : 283-290
                aFifth Department of Medicine (Nephrology/Endocrinology), University Hospital Mannheim, University of Heidelberg, Mannheim, and bKnoll AG, Ludwigshafen, Germany
                20680 Exp Nephrol 2000;8:283–290
                © 2000 S. Karger AG, Basel

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                Figures: 7, Tables: 1, References: 29, Pages: 8
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