European Heart Journal Advance Access published online on May 4, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi305
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1 INSERM U644 (IFRMP no. 23), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, Rouen, France
* To whom correspondence should be addressed. 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.
Received July 29, 2004
Revised March 22, 2005
Accepted March 31, 2005
Preclinical research
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
2 Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Dijon, France
3
INSERM U644 (IFRMP no. 23), Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, Rouen, France
Paul Mulder, E-mail: paul.mulder{at}univ-rouen.fr
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