Polynitroxyl-albumin (PNA) plus tempol attenuate lung capillary leak elicited by prolonged intestinal ischemia and reperfusion

Stable nitroxyl radicals (nitroxides) are potential antioxidant drugs, and we have previously reported that linking nitroxide to biological macromolec ules can improve therapeutic activity in at least two ways. First, polynitr oxylated compounds such as polynitroxyl human serum albumin (PNA) are a nov el class of high molecular weight, extracellular antioxidants. Second, comp ounds such as PNA can prolong the half-life of free (unbound, low molecular weight) nitroxides such as 3-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) in vivo. Unlike PNA, Tempol can readily access the intracellular c ompartment. Thus PNA can act alone in the extracellular compartment, or in concert with Tempol, to provide additional antioxidant protection within ce lls. In this study, we compared the abilities of PNA, Tempol, and the combi nation of PNA + Tempol to prevent lung microvascular injury secondary to pr olonged gut ischemia (I, 120 min) and reperfusion (R, 20 min) in the rat. P ulmonary capillary filtration coefficient (K-f.c) and lung neutrophil reten tion (tissue myeloperoxidase activity, MPO) were measured in normal, isolat ed rat lungs pet-fused with blood harvested from VR rats. Blood donor rats were treated with drug during ischemia. Gut YR resulted in a marked increas e in pulmonary capillary coefficient and lung MPO. PNA + Tempol, but not PN A alone or Tempol alone, at the doses used, prevented the development of lu ng leak. None of the treatments had an effect on lung neutrophil retention. Anti-inflammatory therapeutic activity appeared to correlate with blood Te mpol level: in the presence of PNA, blood Tempol levels were maintained in the 50-100 mu M range vs. essentially undetectable levels shortly after Tem pol was administered alone. In this model of lung injury secondary to prolo nged gut I/R, lung capillary leak was prevented when the membrane-permeable compound Tempol was maintained in its active, free radical state by PNA. ( C) 2000 Elsevier Science Inc.