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1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; 2Consiglio Nazionale della Ricerca, Institute of Molecular Biology and Pathology and Department Biochemical Sciences University La Sapienza, Rome, Italy; and 3Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
Submitted 15 January 2003 ; accepted in final form 4 April 2003
With the objective of developing a recombinant oxygen carrier suitable for
therapeutic applications, we have employed an Escherichia coli
expression system to synthesize in high-yield hemoglobin (Hb) Minotaur,
containing 
-human and 
-bovine chains. Polymerization of Hb
Minotaur through S-S intermolecular cross-linking was obtained by introducing
a Cys at position 9 and substituting the naturally occurring Cys. This
homogeneous polymer, Hb Polytaur, has a molecular mass of 
500 kDa and was
resistant toward reducing agents present in blood. In mice, the circulating
half-time (3 h) was fivefold greater than adult human Hb (HbA). The half-time
of autooxidation measured in blood (46 h) exceeded the circulating retention
time. Hypervolemic exchange transfusion resulted in increased arterial blood
pressure similar to that with albumin. The increase in pressure was less than
that obtained by transfusion of cross-linked tetrameric Hb known to undergo
renovascular extravasation. The nitric oxide reactivity of Hb Polytaur was
similar to HbA, suggesting that the diminished pressor response to Hb Polytaur
was probably related to diminished extravasation. Transfusion of 3% Hb
Polytaur during focal cerebral ischemia reduced infarct volume by 22%.
Therefore, site-specific Cys insertion on the Hb surface results in uniform
size polymers that do not produce the large pressor response seen with
tetrameric Hb. Polymerization maintains physiologically relevant oxygen and
heme affinity, stability toward denaturation and oxidation, and effective
oxygen delivery as indicated by reduced cerebral ischemic damage.
hemoglobin recombinant; hemoglobin synthetic; hemoglobin polymeric; blood substitutes; transfusional fluids; artificial oxygen carriers; hemoglobin retention time; exchange transfusion; extravasation; focal cerebral ischemia
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