| Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. | |
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MedLine Citation:
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PMID: 11861418 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Walter F Saavedra; Nazareno Paolocci; Marcus E St John; Michel W Skaf; Garrick C Stewart; Jin-Sheng Xie; Robert W Harrison; Joshua Zeichner; Daniel Mudrick; Eduardo Marbán; David A Kass; Joshua M Hare |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Circulation research Volume: 90 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2002 Feb |
Date Detail:
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Created Date: 2002-02-25 Completed Date: 2002-02-27 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 297-304 Citation Subset: IM |
Affiliation:
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Department of Medicine, Cardiology Division and Institute of Molecular Cardiobiology, Johns Hopkins Medical Institutions, Baltimore, Md, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Allopurinol
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administration & dosage Animals Antioxidants / administration & dosage Ascorbic Acid / administration & dosage Cardiac Pacing, Artificial Cardiomyopathy, Dilated / drug therapy, etiology*, physiopathology* Dogs Energy Metabolism / drug effects Fluorescent Antibody Technique Free Radical Scavengers / administration & dosage Hemodynamics / drug effects Infusions, Intravenous Myocardial Contraction / drug effects Myocardium / enzymology, pathology Nitric Oxide Synthase / antagonists & inhibitors, metabolism* Signal Transduction* / drug effects Xanthine Oxidase / antagonists & inhibitors, metabolism* omega-N-Methylarginine / administration & dosage |
| Grant Support | |
ID/Acronym/Agency:
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K08 HL-03238/HL/NHLBI NIH HHS; P50 HL52307/HL/NHLBI NIH HHS; R01 HL-65455/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Free Radical Scavengers; 17035-90-4/omega-N-Methylarginine; 315-30-0/Allopurinol; 50-81-7/Ascorbic Acid; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.17.3.2/Xanthine Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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