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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Mellin
Virginie
V
INSERM U644, IFRMP no. 23, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Isabelle
Marc
M
Oudot
Alexandra
A
Vergely-Vandriesse
Catherine
C
Monteil
Christelle
C
Di Meglio
Benoit
B
Henry
Jean Paul
JP
Dautreaux
Brigitte
B
Rochette
Luc
L
Thuillez
Christian
C
Mulder
Paul
P
D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005609:Free Radicals / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy*; D008026:Ligation; D015227:Lipid Peroxidation; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D017382:Reactive Oxygen Species; D000493:Allopurinol; D014969:Xanthine Oxidase; D010100:Oxygen