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This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/H1328    most recent 00461.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Saliaris, A. P. Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Saliaris, A. P. Articles by Hare, J. M.

Chronic allopurinol administration ameliorates maladaptive alterations in Ca²⁺ cycling proteins and -adrenergic hyporesponsiveness in heart failure

The Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 5 May 2006 ; accepted in final form 16 October 2006

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). -Adrenergic hyporesponsiveness and abnormalities in Ca²⁺ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences -adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt_max), lusitropic (), and vascular (elastance; E_a) responses to -adrenergic (-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na⁺/Ca²⁺ transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P < 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca²⁺ cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and -adrenergic hyporesponsiveness.

xanthine oxidase; calcium signaling; cardiac contractility and energetics; excitation-contraction coupling; oxidative stress