title: Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart.
abstract: Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.
authors.affiliation: Department of Medicine, Cardiology Division and Institute of Molecular Cardiobiology, Johns Hopkins Medical Institutions, Baltimore, Md, USA.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Saavedra
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Marcus E
authors.initials: ME
authors.lastname: St John
authors.forename: Michel W
authors.initials: MW
authors.lastname: Skaf
authors.forename: Garrick C
authors.initials: GC
authors.lastname: Stewart
authors.forename: Jin-Sheng
authors.initials: JS
authors.lastname: Xie
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.forename: Joshua
authors.initials: J
authors.lastname: Zeichner
authors.forename: Daniel
authors.initials: D
authors.lastname: Mudrick
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000493:Allopurinol / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D002304:Cardiac Pacing, Artificial; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000008:administration & dosage; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D019323:omega-N-Methylarginine; D000493:Allopurinol; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D001205:Ascorbic Acid