Pretreatment with allopurinol in cardiac hypoxic-ischemic reperfusion injury in newborn lambs exerts its beneficial effect through afterload reduction

The aim of this study was to determine whether allopurinol (ALLO) reduces reperfusion injury inflicted upon the heart resulting from excess production of free oxygen radicals after hypoxia and ischemia (HI) in newborn animals. We, therefore, produced severe HI in 13 newborn lambs by low O2-ventilation and blood volume reduction. One hour before HI seven lambs received ALLO (20 mg/kg i.v.), six received a placebo (CONT). Cardiac function and hemodynamic parameters were assessed by sequential measurement of left ventricular (LV) contractility through the end-systolic pressure-volume relation (ESPVR) using the conductance catheter method. Stroke volume (SV), cardiac output (CO), and aortic pressure (P(ao)) were measured and ejection fraction and total peripheral resistance (TPR) were calculated before HI, upon resuscitation (UR), and at 60 and 120 min post-HI. To estimate the effect of ALLO on redox status and anti-oxidative capacity, we measured concentrations of uric acid, sulfhydryl (SH), malondialdehyde (MDA), ascorbic acid (AA), and dehydroxylated ascorbic acid (DHAA) in plasma obtained from the coronary sinus and calculated the AA/DHAA ratio. Compared to CONT lambs, TPR in ALLO treated lambs decreased significantly, accompanied by a rise in CO and SV. ALLO did not affect myocardial contractility, because the ESPVR showed no significant differences between groups. AA/DHAA and SH showed a significant decrease in ALLO animals vs pre-HI, but not in CONT animals. Uric acid was significantly decreased in ALLO as compared to pre-HI and CONT animals. MDA was significantly increased in CONT animals at 15 min post-HI as compared to pre-HI, whereas in ALLO animals MDA showed a significant increase at 120 min post-HI vs CONT. We conclude that pretreatment with ALLO has a beneficial effect on the pump function by afterload reduction but not by changes in contractility. Furthermore, ALLO inhibited uric acid formation with a consequent decrease in antioxidative capacity.