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Research ArticleArticle

O-Raffinose Cross-Linking Markedly Reduces Systemic and Renal Vasoconstrictor Effects of Unmodified Human Hemoglobin

Wilfred Lieberthal, Robert Fuhro, Jane E. Freedman, George Toolan, Joseph Loscalzo and C. Robert Valeri
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1278-1287;
Wilfred Lieberthal
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Robert Fuhro
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Jane E. Freedman
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George Toolan
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Joseph Loscalzo
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C. Robert Valeri
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Abstract

The hemodynamic effects of a 20% exchange-transfusion with different solutions of highly purified human hemoglobin A-zero (A0) were evaluated. We compared unmodified hemoglobin with hemoglobin cross-linked with O-raffinose. Unmodified hemoglobin increased systemic vascular resistance and mean arterial pressure more than the O-raffinose cross-linked hemoglobin solution (by ∼45% and ∼14%, respectively). Unmodified hemoglobin markedly reduced cardiac output (CO) by ∼21%, whereas CO was unaffected by the O-raffinose cross-linked hemoglobin solution. Unmodified and O-raffinose cross-linked hemoglobin solutions increased mean arterial pressure to comparable extents (∼14% and ∼9%, respectively). Unmodified hemoglobin increased renal vascular resistance 2-fold and reduced the glomerular filtration rate by 58%. In marked contrast, the O-raffinose cross-linked hemoglobin had no deleterious effect on the glomerular filtration rate, renal blood flow, or renal vascular resistance. The extents to which unmodified and O-raffinose cross-linked hemoglobin solutions inactivated nitric oxide also were compared using three separate in vitro assays: platelet nitric oxide release, nitric oxide-stimulated platelet cGMP production, and endothelium-derived relaxing factor-mediated inhibition of platelet aggregation. Unmodified hemoglobin inactivated or oxidized nitric oxide to a greater extent than the O-raffinose cross-linked hemoglobin solutions in all three assays. In summary, O-raffinose cross-linking substantially reduced the systemic vasoconstriction and the decrease in CO induced by unmodified hemoglobin and eliminated the deleterious effects of unmodified hemoglobin on renal hemodynamics and function. We hypothesize that O-raffinose cross-linking reduces the degree of oxidation of nitric oxide and that this contributes to the reduced vasoactivity of this modified hemoglobin.

Footnotes

  • Send reprint requests to: Wilfred Lieberthal, M.D., Renal Section, Evans Building, Room 428, Boston Medical Center, 88 East Newton St., Boston, MA 02118. E-mail: wliebert{at}bu.edu

  • ↵1 This work was supported by National Institutes of Health Grants DK375105, DK52898, HL53031, HL48743, HL53919, and HL55993; a Veterans Administration Merit Review award; and the U.S. Navy (Office of Naval Research Contract N00014–94-C-0149, with the funds provided by the Naval Medical Research and Development Command). The opinions or assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or Naval Service at large. One of the authors (C.R.V.) has commercial associations with Hemosol, Inc., Etobicoke, Canada; he is a member of the board of directors and a member of the Scientific Advisory Board and has stock in Hemosol, Inc.

  • Abbreviations:
    HBOC
    hemoglobin-based oxygen carrier
    HAS
    human serum albumin
    BAEC
    bovine aortic endothelial cell
    MAP
    mean arterial pressure
    CO
    cardiac output
    EDRF
    endothelium-derived relaxing factor
    ECB
    bovine endothelial cell on bead
    SVR
    systematic vascular resistance
    GFR
    glomerular filtration rate
    RPF
    renal plasma flow
    RBF
    renal blood flow
    FF
    filtration fraction
    RVR
    renal vascular resistance
    UV
    urine flow rate
    UNaV
    absolute excretion of sodium
    UKV
    absolute excretion of potassium
    FeNa
    fractional excretion of sodium
    FeK
    fractional excretion of potassium
    SNO-GSH
    S-nitrosoglutathione
    GFP
    gel-filtered platelets
    NO
    nitric oxide
    • Received April 3, 1998.
    • Accepted October 19, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

O-Raffinose Cross-Linking Markedly Reduces Systemic and Renal Vasoconstrictor Effects of Unmodified Human Hemoglobin

Wilfred Lieberthal, Robert Fuhro, Jane E. Freedman, George Toolan, Joseph Loscalzo and C. Robert Valeri
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1278-1287;

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Research ArticleArticle

O-Raffinose Cross-Linking Markedly Reduces Systemic and Renal Vasoconstrictor Effects of Unmodified Human Hemoglobin

Wilfred Lieberthal, Robert Fuhro, Jane E. Freedman, George Toolan, Joseph Loscalzo and C. Robert Valeri
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1278-1287;
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