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; Ea) responses to -adrenergic (-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg p.o. daily) or placebo during a 4-week induction of pacing HF. With HF induction, the decrease 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 SERCA2a, phospholamban (PLB), phosphorylated PLB (P-PLB), and sodium calcium (Ca²⁺) transporter (NCX) gene expression and protein. While 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/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.