title: Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload.
abstract: Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF ± allopurinol (100 mg·kg(-1)·day(-1), n ≥7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension (P < 0.001), a twofold increase in LV end-diastolic pressure/wall stress (P < 0.05), and a twofold increase in lung weight (P < 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF + allopurinol rats, all of which occurred in the absence of changes in the maximum O2 consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca(2+) sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure.
authors.affiliation: University of Alabama at Birmingham (UABComprehensive Cardiovascular Center, UAB Birmingham, Alabama;
authors.forename: James D
authors.initials: JD
authors.lastname: Gladden
authors.forename: Blake R
authors.initials: BR
authors.lastname: Zelickson
authors.forename: Jason L
authors.initials: JL
authors.lastname: Guichard
authors.forename: Mustafa I
authors.initials: MI
authors.lastname: Ahmed
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Yancey
authors.forename: Scott
authors.initials: S
authors.lastname: Ballinger
authors.forename: Mayilvahanan
authors.initials: M
authors.lastname: Shanmugam
authors.forename: Gopal J
authors.initials: GJ
authors.lastname: Babu
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects*; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase; D003402:Creatine Kinase
keywords: heart failure; mitochondria; volume overload; xanthine oxidase