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O₂ affinity of cross-linked hemoglobins modifies O₂ metabolism in proximal tubules

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada

Submitted 3 March 2003 ; accepted in final form 22 April 2003

Previous experiments using cross-linked tetrameric hemoglobins (XLHb) to perfuse isolated rat kidneys showed that high-O₂-affinity XLHb improved proximal tubule function more effectively than low-O₂-affinity XLHb. To determine how function was improved, proximal tubule fragments were incubated with albumin, Hb₃₄ [half-saturation point (P₅₀) 34 Torr], or Hb₁₃ (P₅₀ 13 Torr) with PO₂ values ranging from 22 to 147 Torr. ATP content reflected O₂ delivery to mitochondria. Both XLHb increased ATP, Hb₃₄ with PO₂ 47 Torr and Hb₁₃ with PO₂ 47 Torr. XLHb increased Na-K-ATPase activity (⁸⁶Rb uptake) in similar PO₂-dependent patterns. O₂ consumption (O₂) was measured in a closed, well-stirred chamber. Ouabain- and oligomycin-inhibited O₂, reflecting Na-K-ATPase activity and oxidative phosphorylation, respectively, mirrored the PO₂-dependent patterns of ATP and ⁸⁶Rb uptake. As PO₂ fell below the midpoint of XLHb desaturation, O₂, uncoupled from oxidative phosphorylation, transiently increased. The increase was most pronounced with Hb₃₄. Nitro-L-arginine methyl ester had no effect on O₂. Inhibitors of NAD(P)H oxidases and diamine oxidase partially prevented the O₂ surge with Hb₃₄. In conclusion, facilitated diffusion accounts for PO₂-dependent XLHb effects on ATP content and Na-K-ATPase and for Hb₁₃'s effectiveness in hypoxic perfused kidneys. NO scavenging was not a factor. O₂-binding characteristics influence XLHb effects on mitochondria and O₂-sensitive enzymes such as oxidases.

ATP; Na-K-ATPase; Rb uptake; NAD(P)H oxidases; diphenyleneiodonium; aminoguanidine; nitro-L-arginine methyl ester; deferroxamine; oxidative phosphorylation

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