Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats.
OBJECTIVE
To determine whether theophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, reverses the acute declines in renal blood flow and glomerular filtration rate induced by high-dose tacrolimus in rats.


METHODS
Prospective, randomized, placebo-controlled experimental study.


METHODS
University-based basic science research laboratory.


METHODS
Adult male Sprague-Dawley rats.


METHODS
After mechanical ventilation and instrumentation under isoflurane and nitrous oxide anesthesia, animals received either tacrolimus 0.5 mg/kg intravenously or vehicle and 1 hr later either theophylline 4 mg/kg intravenously or vehicle.


RESULTS
By using radiolabeled microspheres, renal blood flow was measured in three groups: control (n = 5), tacrolimus plus vehicle (n = 6), and tacrolimus plus theophylline (n = 6) at four time points-baseline and 60, 75, and 90 mins after tacrolimus or vehicle (the latter two time points being 15 and 30 mins after theophylline or vehicle, respectively). Whole blood tacrolimus and serum theophylline concentrations were measured. In a separate group of animals, by using (51)Cr-EDTA, glomerular filtration rate was measured in two groups: tacrolimus plus vehicle (n = 5) and tacrolimus plus theophylline (n = 5) at baseline and over two consecutive 20-min time periods beginning 61 mins posttacrolimus. Urine flow rate also was measured. Following tacrolimus, both renal blood flow and glomerular filtration rate declined in parallel by approximately 33% and 50% from baseline after 75 and 90 mins, respectively (p <.05 by two-way repeated-measures analysis of variance). Theophylline completely reversed these tacrolimus-induced decreases in renal blood flow and glomerular filtration rate. Urine flow rate also increased in response to theophylline.


CONCLUSIONS
Low-dose theophylline reverses tacrolimus-induced declines in renal blood flow and glomerular filtration rate observed in an acute model of tacrolimus toxicity. Theophylline's effect in chronic toxicity remains to be determined.
McLaughlin
Gwenn E
GE
Department of Pediatrics, University of Miami School of Medicine, Miami, FL 33101, USA. gmclaugh@med.miami.edu
Kashimawo
Lutifat A
LA
Steele
Bernard W
BW
Kuluz
John W
JW
D000704:Analysis of Variance; D000818:Animals; D003627:Data Interpretation, Statistical; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010919:Placebos; D011446:Prospective Studies; D058915:Purinergic P1 Receptor Antagonists; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D016559:Tacrolimus / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D013806:Theophylline / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D007166:Immunosuppressive Agents; D010726:Phosphodiesterase Inhibitors; D010919:Placebos; D058915:Purinergic P1 Receptor Antagonists; D013806:Theophylline; D016559:Tacrolimus