HEPARIN-RELEASED SUPEROXIDE-DISMUTASE INHIBITS POSTISCHEMIC LEUKOCYTEADHESION TO VENULAR ENDOTHELIUM

Superoxide radicals formed during reperfusion of ischemic tissues have been identified as a key mediator in the microvascular manifestations of postischemic tissue damage. This understanding is based on studies in laboratory animals in which high doses of superoxide dismutase (SO D; 2.0-25.0 mg/kg body wt iv) were found to inhibit postischemic leuko cyte adhesion and the leakage of fluid and macromolecules. Using a dor sal skinfold chamber model in hamsters, we demonstrate now that protec tion from reperfusion-induced leukocyte adhesion to venular endotheliu m after 4 h of ischemia to striated muscle can be attained by pretreat ment of the animals with a significantly lower dose of exogenous CuZn- SOD (0.25 mg/kg body wt) or with heparin (2,000 IU/kg body wt), which induces a comparable increase in SOD plasma activity through the relea se of endogenous extracellular SOD from endothelial cell binding sites . This protective effect was maintained until 24 h after reperfusion. In contrast, CuZn-SOD or heparin failed to attenuate the postischemic shutdown of nutritional capillary perfusion, a phenomenon that is due to ischemia-induced endothelial cell swelling, rather than due to repe rfusion-associated events, and hence is not susceptible to strategies directed against oxygen radicals generated during the reperfusion phas e. The results of this study 1) imply that postischemic leukocyte/endo thelium interaction can be attenuated by a low and clinically more rel evant dose of SOD, and 2) caveat the administration of heparin in labo ratory animals (i.e., to keep catheters patent) in studies of experime ntal ischemia/reperfusion injury or other oxygen radical-dependent pat homechanisms.