Adenosine receptor antagonism in acute tacrolimus toxicity.
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.
McLaughlin
Gwenn E
GE
Department of Pediatrics, Division of Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, FL 33130, USA. gmclaugh@med.miami.edu
Alva
Maria D
MD
Egea
Marcelo
M
D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D016559:Tacrolimus / Q000633:toxicity*; D013806:Theophylline / Q000494:pharmacology
D007166:Immunosuppressive Agents; D058915:Purinergic P1 Receptor Antagonists; D013806:Theophylline; D016559:Tacrolimus