Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy.
Oxidative stress is a hallmark of systemic illnesses, including heart failure. Nevertheless, the overall importance of radical production in the heart remains conjectural; is it merely a marker of illness, or can intervention alter the progression of disease? This question was addressed by blocking xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in animal models of heart failure. In a randomized prospective trial design, we administered the XO inhibitor allopurinol orally to mice that had undergone massive myocardial infarction (MI). Cardiac XO activity was elevated in untreated mice after MI; allopurinol suppressed the XO activity to levels comparable to those in sham-operated mice. Eighty-one percent of untreated mice died of advanced heart failure over 2 to 4 weeks of follow-up. Survival doubled in the allopurinol-treated mice, whereas cardiac contractile function (both in vivo and in isolated muscle) was markedly improved. Response to isoproterenol was restored to near-normal levels in the allopurinol group but was attenuated in untreated mice. Oxidative modifications to proteins were prevented in the allopurinol-treated mice. Our findings indicate that targeted blockade of just one source of oxidants, XO, impacts dramatically on the progression of postischemic cardiomyopathy in mice and prevents oxidative protein modifications.
Stull
Linda B
LB
Institute of Molecular Cardiobiology, Johns Hopkins University School of Medicine, Baltimore, Md, USA.
Leppo
Michelle K
MK
Szweda
Luke
L
Gao
Wei Dong
WD
Marbán
Eduardo
E
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000493:Allopurinol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D007545:Isoproterenol / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D011446:Prospective Studies; D011897:Random Allocation; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D000318:Adrenergic beta-Agonists; D000975:Antioxidants; D000493:Allopurinol; D014969:Xanthine Oxidase; D007545:Isoproterenol