title: Effect of acute xanthine oxidase inhibition on myocardial energetics during basal and very high cardiac workstates.
abstract: 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 ((31)P magnetic resonance spectroscopy), blood flow (radioactive microspheres), and oxygen consumption (MVO(2)) 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.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Minnesota Academic Health Center, Minneapolis, MN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lee
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.forename: Abdul
authors.initials: A
authors.lastname: Mansoor
authors.forename: Forum
authors.initials: F
authors.lastname: Kamdar
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000322:Adrenergic Agonists / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects; D001706:Biopsy; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069465:Febuxostat; D006439:Hemodynamics / Q000187:drug effects; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000322:Adrenergic Agonists; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013844:Thiazoles; D010725:Phosphocreatine; D000069465:Febuxostat; D000244:Adenosine Diphosphate; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase