PEG-SOD and myocardial protection: Studies in the blood- and crystalloid-perfused rabbit and rat hearts

Abstract

Background. Polyethylene glycol, covalently linked to superoxide dismutase (PEG-SOD) has a long plasma half-life (>30 hours) and has been proposed as an effective agent for reducing free radical-mediated injury during ischemia and reperfusion. Methods and Results. Using an isolated rabbit heart perfused with arterial blood from a support rabbit, we have demonstrated that pretreatment with PEG-SOD (30,000 units/kg, intravenous bolus, 12-24 hours before 60 minutes of normothermic global ischemia), combined with addition of PEG-SOD to the blood perfusion circuit (30,000 units/kg to the support rabbit) and inclusion of PEG-SOD (150 μg/ml) in a cardioplegic solution, enhanced the postischemic recovery of left ventricular developed pressure (LVDP) from 51±6 to 74±9 mm Hg (p<0.05; n=9 per group). In further studies we showed that, whereas maximum protection was obtained when PEG-SOD was given as a combined pretreatment and additive to both the cardioplegic and the reperfusate solutions (postischemic LVDP recovery increased from 44±4% in the control group to 70±3% in the PEG-SOD group), the administration of PEG-SOD during pretreatment plus cardioplegia or during reperfusion alone also resulted in a significant improvement in postischemic function (62±7% and 60±3%, respectively). However, the use of PEG-SOD as a cardioplegic additive alone failed to afford protection (47±4% recovery of LVDP). In dose-response studies (with 0, 3,000, 6,000, 12,000, 30,000, or 60,000 units/kg; n=8 per group), maximum recovery of LVDP was obtained with the administration of 12,000 units/kg of PEG-SOD. Studies of the plasma activity of PEG-SOD confirmed its long half-life and showed that the treatment with PEG-SOD either 1 hour or 12-24 hours before the study resulted in similar levels of plasma activity. In an attempt to assess any involvement of blood-borne elements in the protection afforded by PEG-SOD, studies were also carried out in the crystalloid-perfused rabbit heart, and no protection was observed. Similarly, no protection was observed at any one of a variety of doses in the crystalloid-perfused rat heart. Conclusions. PEG-SOD can afford protection in the blood-perfused rabbit heart; this protection is dose dependent and probably involves some action of PEG-SOD on blood-borne elements, possibly leukocytes.