Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats

Gwenn E McLaughlin, Lutifat A. Kashimawo, Bernard W Steele, John W. Kuluz

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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. Design: Prospective, randomized, placebo-controlled experimental study. Setting: University-based basic science research laboratory. Subjects: Adult male Sprague-Dawley rats. Interventions: 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. Measurements and Main 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 51Cr-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.

Original languageEnglish
Pages (from-to)358-362
Number of pages5
JournalPediatric Critical Care Medicine
Volume4
Issue number3
DOIs
StatePublished - Dec 1 2003

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Tacrolimus
Theophylline
Vasoconstriction
Kidney
Renal Circulation
Glomerular Filtration Rate
Urine
Purinergic P1 Receptor Antagonists
Phosphodiesterase Inhibitors
Isoflurane
Nitrous Oxide
Microspheres
Artificial Respiration
Edetic Acid
Sprague Dawley Rats
Analysis of Variance
Anesthesia
Placebos

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Critical Care and Intensive Care Medicine

Cite this

Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats. / McLaughlin, Gwenn E; Kashimawo, Lutifat A.; Steele, Bernard W; Kuluz, John W.

In: Pediatric Critical Care Medicine, Vol. 4, No. 3, 01.12.2003, p. 358-362.

Research output: Contribution to journalArticle

McLaughlin, Gwenn E ; Kashimawo, Lutifat A. ; Steele, Bernard W ; Kuluz, John W. / Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats. In: Pediatric Critical Care Medicine. 2003 ; Vol. 4, No. 3. pp. 358-362.
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