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

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). β-Adrenergic hyporesponsiveness and abnormalities in Ca²⁺ cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences β-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt_max), lusitropic (τ), and vascular (elastance; E_a) responses to β-adrenergic (β-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 Ca ²⁺-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 β-adrenergic hyporesponsiveness.