European Heart Journal Advance Access originally published online on May 4, 2005
European Heart Journal 2005 26(15):1544-1550; doi:10.1093/eurheartj/ehi305
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Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure
1INSERM U644 (IFRMP no. 23), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, Rouen, France
2Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Dijon, France
Received 29 July 2004; revised 22 March 2005; accepted 31 March 2005; online publish-ahead-of-print 4 May 2005.
* Corresponding author. Tel: +33 2 3514 8359; fax: +33 2 3514 8365. E-mail address: paul.mulder{at}univ-rouen.fr
See page 1458 for the editorial comment on this article (doi:10.1093/eurheartj/ehi321)
Aims Oxidative stress, i.e. imbalance between reactive oxygen species (ROS) and antioxidant defences, contributes to the progression of chronic heart failure (CHF). Acute inhibition of xanthine oxidase (XO), which produces ROS, improves mechanical efficiency of the failing heart, but whether long-term XO inhibition exerts beneficial effects in CHF is unknown.
Methods and results In rats with established CHF induced by left coronary ligation, we assessed the effects of a 5-day and a 10-week treatment with the XO inhibitor allopurinol (50 mg kg–1 day–1) on haemodynamics and left ventricular (LV) function and structure. Both acute and chronic allopurinol treatment increase cardiac output without modification of arterial pressure, but only chronic allopurinol treatment reduces LV end-diastolic pressure and LV relaxation constant. Chronic allopurinol treatment decreases both LV systolic and diastolic diameters, but acute allopurinol treatment only decreases LV systolic diameter. Moreover, chronic allopurinol decreases LV weight and collagen density. Despite XO inhibition after acute and chronic allopurinol treatment, as both treatments reduce uric acid plasma levels, only acute allopurinol treatment reduces LV ROS determined using electron spin resonance spectroscopy. However, the CHF-enhanced myocardial thiobarbituric acid reactive substances levels were never modified.
Conclusion In experimental CHF, long-term allopurinol treatment, initiated in a pathological state of overt CHF, improves LV haemodynamics and function and prevents LV remodelling. These long-term effects are, at least partially, caused by a transient reduction of myocardial ROS shortly after initiation of allopurinol treatment, but whether other mechanism(s), independent of myocardial redox ‘status’, such as reduced inflammation, are implicated remains to be confirmed.
Key Words: Heart failure • Allopurinol • Reactive oxygen species
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