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NDT Advance Access published online on March 7, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl082
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 4, 2005
Accepted February 7, 2006

Orginal Article

Adenosine receptor antagonism in acute tacrolimus toxicity

Gwenn E. McLaughlin 1 *, Maria D. Alva 1, and Marcelo Egea 1

1 Department of Pediatrics, Divisions of Critical Care Medicine University of Miami, Miami, FL, USA

* To whom correspondence should be addressed.
Gwenn E. McLaughlin, E-mail: gmclaugh{at}med.miami.edu



  Abstract

Background. Calcineurin inhibitors induce renal vasoconstriction and oliguria during acute toxicity. We previously demonstrated that the non-specific adenosine receptor antagonist theophylline improved glomerular filtration rate (GFR) and renal blood flow in the setting of acute tacrolimus (TAC) toxicity. This study was undertaken to determine which of the known adenosine receptor subtypes is responsible for the observed effect of theophylline.

Methods. The GFR was measured by clearance of 51Cr-EDTA in anaesthetized, instrumented Sprague-Dawley rats at three time points: at baseline, 60 min after intravenous administration of TAC (0.05 mg/kg) or vehicle (V) and at 100 min after TAC or V. Either DMSO (n = 5) or one of the three available specific adenosine receptor subtype antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 2 mg/kg, n = 5), a selective A1 receptor antagonist, 8-(3-chlorostyryl) caffeine (CSC, 2 mg/kg, n = 4), a selective A2a receptor antagonist and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-dihydropyridine-3,5 dicarboxylate (MRS1191, 1 mg/kg, n = 5), a selective A3 receptor antagonist, was administered intra-peritoneally prior to the final GFR measurement. Repeated measures analysis of variance was used to detect differences between groups (P<0.05).

Results. Measured GFR declined by 30% from baseline 60 min after TAC. In DMSO treated animals, GFR decreased 51% from baseline at 100 min after TAC, but increased 45% from baseline at 100 min after TAC + MRS1191.

Conclusions. Only administration of the A3 adenosine antagonist increased GFR following TAC, suggesting that this receptor mediates the effect of theophylline on GFR.

Keywords: glomerular filtration rate; adenosine antagonist; tacrolimus; prograf; calcineurin inhibitor; adenosine; receptors; purinergic.
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