title: Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts.
abstract: OBJECTIVE
  This study tested the hypothesis that acute administration of the xanthine oxidase (XO) inhibitor allopurinol improves cardiac high-energy phosphate concentrations in human heart failure (HF) and increases the rate of adenosine triphosphate (ATP) synthesis through creatine kinase (CK), the primary myocardial energy reserve.
  
  
  BACKGROUND
  Studies of patients and animal models implicate impaired myocardial high-energy phosphate availability in HF. The XO reaction is a critical terminal step in ATP and purine degradation and an important source of reactive oxygen species. Thus, XO inhibition is a potentially attractive means to improve energy metabolism in the failing human heart.
  
  
  METHODS
  We randomized 16 patients with nonischemic cardiomyopathy in a double-blind fashion to allopurinol (300 mg intravenously) or placebo infusion, 4-to-1, the latter for purposes of blinding only. The myocardial concentrations of ATP and creatine phosphate (PCr) and the rate of ATP synthesis through CK (CK flux) were determined by (31)P magnetic resonance spectroscopy.
  
  
  RESULTS
  Allopurinol infusion increased mean cardiac PCr/ATP and PCr concentration by ∼11% (p < 0.02), and mean CK flux by 39% (2.07 ± 1.27 μmol/g/s to 2.87 ± 1.82 μmol/g/s, p < 0.007). Calculated cytosolic adenosine diphosphate concentration decreased, whereas the free energy of ATP hydrolysis (ΔG(∼ATP)) increased with allopurinol. The increased CK flux was disproportionate to substrate changes, indicating increased CK enzyme activity.
  
  
  CONCLUSIONS
  Intravenous administration of the XO inhibitor allopurinol acutely improves the relative and absolute concentrations of myocardial high-energy phosphates and ATP flux through CK in the failing human heart, offering direct evidence that myofibrillar CK energy delivery can be pharmaceutically augmented in the failing human heart. (Intravenous Allopurinol in Heart Failure; NCT00181155).
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Hirsch
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bottomley
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.forename: Robert G
authors.initials: RG
authors.lastname: Weiss
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000493:Allopurinol / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014969:Xanthine Oxidase / Q000009:adverse effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase