Myocardial ischemia is associated with reduced myocardial adenosine triphosphate (ATP) and increased free adenosine diphosphate (ADP) similar to the normal heart at very high cardiac workstates (HCW). We examined whether acute xanthine oxidase inhibition (XOI) in vivo can decrease myocardial free ADP in normal hearts functioning at basal cardiac workstates (BCW) or very HCW (catecholamine-induced). Myocardial high-energy phosphate (31P magnetic resonance spectroscopy), blood flow (radioactive microspheres), and oxygen consumption (MVO2) were measured in an open-chest canine model before and after infusion of vehicle or an XO inhibitor (allopurinol or febuxostat; n=10 in each group) during BCW and infusion of dobutamine + dopamine to induce a very HCW. During BCW, both allopurinol and febuxostat resulted in higher phosphocreatine (PCr)/ATP, corresponding to lower ADP levels. During vehicle infusion, HCW caused a decrease of PCr/ATP and an increase in myocardial free ADP. Although XOI did not prevent an increase in free ADP during catecholamine infusion, the values in the allopurinol or febuxostat groups (0.141±0.012 and 0.136±0.011 μmol/g dry wt, respectively) remained significantly less than in the vehicle group (0.180±0.017; P<0.05). Thus, at a given rate of ATP synthesis, XOI decreased the free ADP level needed to drive ATP synthesis, suggesting a more energy-efficient status. As contractile dysfunction in ischemia is characterized by increase of myocardial free ADP and energy deficiency, the data suggest that XOI might be a potential therapy for improving energy efficiency during myocardial ischemia.
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Acknowledgments The authors gratefully acknowledge Drs. Lin Zhao and Jerry Wessale, Takeda Global Research & Development Center, Inc., Deerfield, IL, for their scientific contributions to the study. This work was supported by an American Heart Association Predoctoral Fellowship Award (0415468Z to J. Lee), National Institutes of Health Medical Scientist Training Program Grant (GM008244 to University of Minnesota Combined MD–PhD Program), and US Public Health Service Grants NIH RO1 HL50470 and HL67828 UO1HL 100407. This work was supported in part by a research grant awarded by TAP Pharmaceutical Products, Inc. (now a part of Takeda Global Research & Development Center, Inc., Deerfield, IL, USA)
- Magnetic resonance spectroscopy
- Myocardial high-energy phosphates
- Reactive oxygen species