Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure.
Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). beta-Adrenergic hyporesponsiveness and abnormalities in Ca(2+) cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences beta-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt(max)), lusitropic (tau), and vascular (elastance; E(a)) responses to beta-adrenergic (beta-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(+)/Ca(2+) 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 Ca(2+) 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 beta-adrenergic hyporesponsiveness.
Saliaris
Anastasios P
AP
Johns Hopkins Medical Institutions, Broadway Research Bldg, Baltimore MD 21205, USA.
Amado
Luciano C
LC
Minhas
Khalid M
KM
Schuleri
Karl H
KH
Lehrke
Stephanie
S
St John
Marcus
M
Fitton
Torin
T
Barreiro
Chris
C
Berry
Cristine
C
Zheng
Meizi
M
Kozielski
Kristen
K
Eneboe
Virginia
V
Brawn
Jeff
J
Hare
Joshua M
JM
D000493:Allopurinol / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D002118:Calcium; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy*; D009200:Myocardial Contraction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D014969:Xanthine Oxidase / Q000378:metabolism
D002135:Calcium-Binding Proteins; D000493:Allopurinol; D014969:Xanthine Oxidase; D002118:Calcium