Heparin-released superoxide dismutase inhibits postischemic leukocyte adhesion 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 (SOD; 2.0-25.0 mg/kg body wt iv) were found to inhibit postischemic leukocyte adhesion and the leakage of fluid and macromolecules. Using a dorsal skinfold chamber model in hamsters, we demonstrate now that protection from reperfusion-induced leukocyte adhesion to venular endothelium after 4 h of ischemia to striated muscle can be attained by pretreatment 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 release 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 reperfusion-associated events, and hence is not susceptible to strategies directed against oxygen radicals generated during the reperfusion phase. The results of this study 1) imply that postischemic leukocyte/endothelium interaction can be attenuated by a low and clinically more relevant dose of SOD, and 2) caveat the administration of heparin in laboratory animals (i.e., to keep catheters patent) in studies of experimental ischemia/reperfusion injury or other oxygen radical-dependent pathomechanisms.
Becker
M
M
Institute for Surgical Research, University of Munich, Germany.
Menger
M D
MD
Lehr
H A
HA
D000818:Animals; D002196:Capillaries / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D006493:Heparin / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology*; D008647:Mesocricetus; D009132:Muscles / Q000098:blood supply*; D015424:Reperfusion; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D014699:Venules / Q000502:physiology*
D006493:Heparin; D013482:Superoxide Dismutase