Effects of XO inhibitors in chronic heart failure
Model | Disease or Trigger | Mode of XO Inhibition | Effects of XO Inhibition | Reference |
|---|---|---|---|---|
| Mouse | Coronary ligation-induced HF | Allopurinol | Allopurinol doubled the survival and improved contractility and response to isoproterenol both in vivo and in isolated muscle; allopurinol also reduced the elevated XO activity in mice with heart failure | Stull et al. (2004) |
| Mouse | Coronary ligation-induced HF | Allopurinol | Allopurinol improved left ventricular contractile function, decreased ROS generation, attenuated LV cavity dilation, and reduced myocardial hypertrophy and fibrosis | Engberding et al. (2004) |
| Mouse | Transgenic model of cardiomyopathy | Allopurinol | Chronic treatment prevented myofibrillar protein oxidation and preserved cardiac function | Duncan et al. (2005) |
| Mouse | Acute heart failure | Allopurinol, oxypurinol | XO inhibitors improved ventricular function | Naumova et al. (2005) |
| Rat | Monocrotaline-induced right ventricular hypertrophy and failure model and HF-induced by coronary ligation | N.A. | Increase in myocardial XO levels | de Jong et al. (2000) |
| Rat | Coronary ligation-induced HF | Oxypurinol | Oxypurinol improved cardiac contractility and mechanoenergetic coupling in HF without affecting resting tension and intracellular Ca2+ transients | Kögler et al. (2003) |
| Rat | Coronary ligation-induced HF | Allopurinol | Both acute (5-day) and chronic (10-week) treatment with allopurinol improved LV hemodynamics; chronic treatment also prevented LV remodeling | Mellin et al. (2005) |
| Rat | Spontaneously hypertensive heart failure rat | Oxypurinol | 4-week treatment restored cardiac structure and function | Minhas et al. (2006) |
| Dog | Pacing-induced HF | Allopurinol | Allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced HF; increased myocardial XO activity or levels and subsequent increases in oxidative stress in the failing hearts | Ekelund et al. (1999); Saavedra et al. (2002) |
| Dog | Pacing-induced HR | Allopurinol | Allopurinol had no effects on LV contractile function or adrenergic responsiveness in normal conscious animals; in pacing-induced CHF, allopurinol improved LV systolic function at rest and during adrenergic stimulation and exercise | Ukai et al. (2001) |
| Dog | Pacing-induced HF | Allopurinol | Allopurinol ameliorated increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular-vascular coupling | Amado et al. (2005) |
| Human (56 patients) | CHF | N.A. | In patients with CHF, elevated circulating uric acid levels correlate with inflammatory markers (e.g., TNF-α and ICAM-1) | Leyva et al. (1998) |
| Human (9 patients) | Idiopathic dilated cardiomyopathy | Allopurinol | Intracoronary administration of allopurinol resulted in an acute improvement in myocardial efficiency by diminishing oxygen consumption in the presence of standard supportive therapy | Cappola et al. (2001) |
| Human (19 patients) | CHF | Allopurinol | Allopurinol improved endothelial function | Doehner et al. (2002); Farquharson et al. (2002) |
| Human (1760 patients) | CHF | Allopurinol | High-dose treatment with allopurinol was found to beneficially affect survival, whereas low-dose allopurinol treatment actually appeared to increase mortality | Struthers et al. (2002) |
| Human (50 patients) | CHF | Allopurinol | 3-month allopurinol treatment had no effect on excerise capacity but reduced B-type natriuretic peptide, a surrogate marker for prognosis in CHF | Gavin and Struthers (2005) |
| Human (405 patients multicenter) | CHF | Oxypurinol | Failed to show significant benefits | Cardiome Pharma Corp. (Vancouver, BC, Canada) |
HF, heart failure; N.A., not applicable; TNF-α, tumor necrosis factor-α; ICAM-1, intercellular adhesion molecule-1.