title: Preservation of cardiac contractility after long-term therapy with oxypurinol in post-ischemic heart failure in mice.
abstract: Previously, we showed that oral allopurinol increased survival in mice with post-ischemic cardiomyopathy and attributed this outcome to an improvement of excitation-contraction coupling that boosted contractility. In this study, we tested the sustainability of this enhanced contraction associated with decreased oxidative damage over an extended time. Mice were divided into three groups: sham-operated control, myocardial infarction-heart failure (MI-HF), and oxypurinol-treated heart failure (Oxy-HF). After 9-11 months, echocardiography showed that mice treated with oxypurinol (1mM in drinking water) had significantly higher left ventricle fractional contraction and fractional wall thickening during systole than did mice in the MI-HF group (left ventricle fractional contraction: 28.4+/-2.2% vs. 19.9+/-2.3%, P<0.05; left ventricle fractional wall thickening: 45.0+/-4.0% vs. 23.5+/-2.0%, P<0.05). Left ventricular diastolic dimension, however, remained enlarged (0.50+/-0.04 vs. 0.54+/-0.05 cm, not significant). Twitch force was significantly higher at any given external Ca(2+) concentration in the Oxy-HF group than in the MI-HF group (P<0.01); amplitudes of intracellular Ca(2+) transients were also higher in the Oxy-HF group but were not statistically different from those of the MI-HF group. Force-frequency relation was improved in the Oxy-HF group. Muscle in the Oxy-HF group exhibited increases in myofilament Ca(2+) responsiveness, as evidenced by significantly higher maximal Ca(2+)-activated force (77.8+/-12.7 vs. 36.4+/-4.4 mN/mm(2), P<0.01). Finally, lipid peroxidation and myofilament oxidation were suppressed in the Oxy-HF group. These results indicate that the beneficial effects of antioxidation can be sustained by long-term treatment with oxypurinol after ischemic heart failure, with significantly improved cardiac contractility.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tan
authors.forename: Tieying
authors.initials: T
authors.lastname: Dai
authors.forename: Xin
authors.initials: X
authors.lastname: Zhong
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Leppo
authors.forename: Wei Dong
authors.initials: WD
authors.lastname: Gao
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000150:complications*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010117:Oxypurinol / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D014969:Xanthine Oxidase; D010117:Oxypurinol; D002118:Calcium