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ABSTRACT: Background: N-acetylcysteine (NAC) has been proposed to prevent radiocontrast nephropathy in high-risk patients. Methods: The effect of single-dose and prolonged administration of NAC before application of either the ionic, high-osmolar radiocontrast agent diatrizoate sodium (DTZ) or the nonionic, low-osmolar radiocontrast agent iohexol (IOH) in a rat model combining uninephrectomy, salt depletion, and administration of indomethacin was explored. Arterial blood pressure and total, cortical, and medullary blood flow were continuously recorded in anesthetized Sprague-Dawley rats. Results: NAC had no effect on renal hemodynamics in control rats. Both DTZ and IOH induced biphasic changes in renal blood flow and cortical renal blood flux and persistently reduced medullary blood flux. Neither single-dose nor prolonged administration of NAC prevented the hemodynamic changes following administration of DTZ or IOH, respectively. Acute prophylactic administration of NAC prevented increased urinary ET excretion after injection of IOH and, to a smaller degree, of DTZ. Both an ionic, high-osmolar (DTZ) and a nonionic, low-osmolar (IOH) radiocontrast agent induce marked changes in renal hemodynamics in salt-depleted rats treated with indomethacin. Conclusions: Renal perfusion is not affected by NAC application in a model of experimental contrast nephropathy in rats. Other effects of NAC might thus account for the presumed renoprotective properties.
Kidney and Blood Pressure Research 02/2011; 34(2):125-34. · 1.46 Impact Factor
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Benito Yard,
Grietje Beck,
Peter Schnuelle,
Claude Braun,
Meike Schaub,
Mathias Bechtler, Uwe Göttmann,
Yang Xiao,
Annette Breedijk,
Silke Wandschneider,
Ralf Lösel,
Gisbert Sponer,
Martin Wehling,
Fokko J van der Woude
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ABSTRACT: The present study was conducted to dissect the underlying mechanisms by which catecholamines protect cells against preservation injury. To this end, we firstly defined the cellular and molecular differences between protected and nonprotected cells and secondly defined the mediators that were involved in cold-induced damage. Cold storage of untreated human umbilical vein endothelial cells (HUVECs) resulted in profound cellular damage as assessed by lactate dehydrogenase (LDH) release and by morphological changes, e.g. cell size alterations and loss of cytoskeletal organization. Treatment of HUVECs with catecholamines before cold storage prevented cellular damage in a dose- and time-dependent fashion. Similar results were obtained with carvedilol or its hydroxylated derivative BM91.0228. Protection was not receptor-mediated and did not require de novo protein synthesis. The onset of protection occurred relatively quickly and the duration was long lasting. Addition of superoxide dismutase (SOD) to untreated HUVECs during cold preservation also was protective. Oxidation of catecholamines completely abrogated the protective effect of these compounds on cold-induced damage. Both at 4 degrees and 37 degrees C, catecholamines reduced the amount of reactive oxygen species (ROS) produced by HUVECs. In conclusion we have demonstrated that catecholamines protect cells against preservation injury either by scavenging of ROS or by inhibition of ROS production.
American Journal of Transplantation 02/2004; 4(1):22-30. · 6.39 Impact Factor
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ABSTRACT: Initially described as the most potent vasoconstrictor peptide, endothelin (ET) has also been shown to possess extraordinary immunomodulatory and proinflammatory properties. Because of this broad spectrum of biological activities, a possible role of the ET-system in solid organ transplantation has soon become a focus of research. Several studies demonstrated a pathogenetic involvement of ET in ischemia/reperfusion injury of heart, liver, kidney, and lung grafts. ET accumulates during cold storage of organs and can be detected in the effluent preservation solution. In addition ET is very, likely to play a pivotal role in the development of chronic rejection, which represents the major cause of late allograft loss. Increased expression of components of the ET-system has been described in areas of neointimal proliferation, a hallmark of chronic graft rejection. Both selective ET-A as well as non-selective ET-A/B receptor antagonists improved histomorphological and functional sequelae of chronic rejection. However these data have largely been derived from experimental animal transplantation, and ET receptor blockers have only recently been introduced in clinical medicine. A significant number of investigational drugs are now being tested in humans, with a main focus on cardiovascular diseases, such as congestive heart failure and pulmonary hypertension. First results have markedly dampened the initial enthusiastic vision of ET receptor blockers being organoprotective super-weapons. Thus the clinical potential of ET antagonists in general, and especially in solid-organ transplantation, is still to be defined.
Current Vascular Pharmacology 11/2003; 1(3):281-99. · 2.90 Impact Factor
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ABSTRACT: Oxidative stress is markedly increased after kidney transplantation and may participate in the development and/or progression of chronic renal allograft nephropathy. In the present study we sought to assess the nephroprotective potential of antioxidative treatment in renal allograft recipients. Experiments were performed in the Fisher-Lewis rat model of chronic renal allograft nephropathy, with isografted Lewis rats serving as controls. Allografted rats were orally treated with carvedilol, an antihypertensive drug with antioxidative properties (25 mg/kg/d), its purely antioxidative derivative BM 91.0228 (5 mg/kg/d), alpha-tocopherol (100 mg/kg/d), a combination of propranolol/doxazosine (10/5 mg/kg/d), or vehicle for 24 weeks. At the end of the study, oxidative status and influence of antioxidative treatment were assessed in transplanted animals. Chronic allograft nephropathy was characterized by a marked increase of markers for oxidative stress (increased plasma and kidney levels of malondialdehyde, reduced glutathione, and tocopherol levels in renal allografts). Treatment with carvedilol, BM 91.0228, and tocopherol significantly improved antioxidative status of allograft kidney recipients. In addition, carvedilol reduced elevated blood pressure in allografted rats. However none of the drugs had a beneficial influence on functional and morphologic renal changes. Our data thus demonstrate that long-term treatment with the antioxidants carvedilol, BM 91.0228, or alpha-tocopherol does not prevent development of chronic transplant nephropathy, despite an improvement of antioxidative status.
Journal of Cardiovascular Pharmacology 10/2003; 42(3):442-50. · 2.29 Impact Factor
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ABSTRACT: We have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improved survival and reduced functional and morphological kidney damage. However, the underlying mechanisms have not yet been elucidated, as ET exhibits both hemodynamic and inflammatory properties. Therefore, in the present study we investigated acute hemodynamic effects of the selective ET-A receptor antagonist LU 302146 (LU) on chronic renal allograft rejection in rats. Experiments were performed in the Fisher-to-Lewis model of chronic renal allograft rejection. Lewis-to-Lewis isografts served as controls. After 2, 12, and 24 weeks, hemodynamic measurements were performed on anesthetized animals. Measurement of mean arterial pressure (MAP) was performed via a catheter in the femoral artery. Renal blood flow (RBF) was measured by an ultrasonic flow probe placed around the renal transplant artery. Medulla blood flow (MBF) and cortex blood flow (CBF) were determined with laser Doppler probes. Hemodynamic response upon intravenous bolus injection of LU (50 mg/kg) was investigated. The application of LU was followed by a decline in MAP that reached statistical significance only in isografts (ISOs) after 12 weeks and allografts (ALLOs) after 24 weeks. RBF slightly decreased in all groups; however, without reaching statistical significance. MBF showed a small increase in ALLO12 and ALLO24 whereas CBF slightly decreased in all groups. Acute ET-A receptor blockade does not induce important hemodynamic effects in kidneys undergoing chronic rejection. The lack of response to ET-A receptor blockade suggests that the beneficial effect of ET receptor antagonists in this model is likely to be due to improvement of renal morphology.
Transplant International 07/2003; 16(6):425-9. · 2.92 Impact Factor
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Uwe Göttmann
