The Dose-Dependent Effect of RSR13, a Synthetic Allosteric Modifier of Hemoglobin, on Physiological Parameters and Brain Tissue Oxygenation in Rats

  • Oleg Y. Grinberg
  • Minoru Miyake
  • Huagang Hou
  • Robert P. Steffen
  • Harold M. Swartz
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 530)


RSR13 is a synthetic allosteric modifier of hemoglobin that decreases the oxygen-binding affinity of hemoglobin, increasing the P50. As a result, tissue oxygen tension is expected to increase. Using the capabilities of in vivo EPR, we directly examined the effect of RSR13 on brain pO2 in rats and the relationship between any change in brain oxygenation and changes in physiological parameters, including blood gases. The brain pO2 and arterial blood paO2 were increased significantly (p<0.005) following RSR13 administration. The peak increase of brain tissue pO2 was 8.8±1.2 mm Hg in the animals receiving 150 mg/kg RSR13 and 13±3 mm Hg in the animals receiving 300 mg/kg RSR13. There was no difference among groups in MBP, heart rate, paCO2, pH, or HCO3. These data indicate that in anesthetized rats, RSR13 dose-dependently increases brain pO2 without affecting other physiologic parameters. This capability is likely to be very useful in circumstances where the pO2 of the brain is compromised.

Key words

Allosteric modifier RSR13 Cerebral pO2 EPR oximetry 


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  1. 1.
    Randad RS, Mahran MA, Mehanna AS, and Abraham DJ. Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents. J Med Chem 1991;34:752–757PubMedCrossRefGoogle Scholar
  2. 2.
    Wireko FC, Glen E. Kellogg GE, and Abraham DJ. Allosteric modifiers of hemoglobin. 2. Crystallographically determined binding sites and hydrophobic binding/interaction. Analysis of novel hemoglobin oxygen effectors. J Med Chem 1991;34:758–767.PubMedCrossRefGoogle Scholar
  3. 3.
    Abraham DJ, Wireko FC, and Randad RS. Allosteric modifiers of hemoglobin: 2-[4-[[(3,5Disubstituted anilino) carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats Biochemistry 1992;31:9141–9149.Google Scholar
  4. 4.
    Kunert MP, Liard JF, and Abraham DJ. RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats. Am J Physiol 1996;271:H602–613.PubMedGoogle Scholar
  5. 5.
    Khandelwal SR, Randad RS, Lin PS, Meng H, Pittman RN, Kontos HA, Choi SC, Abraham DJ, and RupertSchmidt-Ullrich. Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation. Am J. Physiol 1993;265:H1450–H1453.PubMedGoogle Scholar
  6. 6.
    Teicher BA, Ara G, Emi Y, et al. RSR:effects on tumor oxygenation and response to therapy. Drug Dev Res 1996;38:1–11.CrossRefGoogle Scholar
  7. 7.
    Pagel PS, Hettrick DA, Montgomery MW, Kersten JR, Steffen RP and Warltier DC. RSR 13, a synthetic modifier of hemoglobin-oxygen affinity, enhances the recovery of stunned myocardium in anesthetized dogs. J Pharmacology and Experimental Therapeutics 1998;2851–2858.Google Scholar
  8. 8.
    Jason A. Woods, Charles J. Storey, Evelyn E. Babcock and Craig R. Malloy.Right-shifting the oxyhemoglobin dissociation curve with rsrl3:effects on high-energy phosphates and myocardial recovery after low-flow ischemia J Cardiovascular Pharmacology 1998;31:359–364.Google Scholar
  9. 9.
    Wei EP, Randad RS, Levasseur JE, Abraham DJ, and Kontos HA. Effect of local change in 02 saturation of hemoglobin on cerebral vasodilution from hypoxia and hypotension. Am J Physiol 1993;265:H 1439-H1443.Google Scholar
  10. 10.
    Grocott HP, Bart RD, Sheng H, Miura Y, Steffen R, Pearlstein RD, and Warner DC. Effects of a synthetic allosteric modifier of hemoglobin oxygen affinity on outcome from global cerebral ischemia in the rat Stroke.1998;29:1650–1655.Google Scholar
  11. 11.
    Swartz HM, Boyer S, Gast P, Glockner JF, Hu H, Liu KJ, Moussavi M, Norby SW, Walczak T, Vahidi N, Wu M, and Clarkson RB. Measurements of pertinent concentrations of oxygen in vivo. Magn Reson Med. 1991;20:333–339.PubMedCrossRefGoogle Scholar
  12. 12.
    Swartz HM and Clarkson RB. The measurement of oxygen in vivo using EPR techniques. Phys Med Biol 1998;43:1957–1975.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu KJ, Gast P, Moussavi M, Norby SW, Vahidi N, Walczak T, Wu M, and Swartz HM. Lithium phthalocyanine:A probe for EPR oximetry in viable biological systems. Proc Natl Acad Sci 1993;90:5438–5442.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Oleg Y. Grinberg
    • 1
  • Minoru Miyake
    • 1
  • Huagang Hou
    • 1
  • Robert P. Steffen
    • 2
  • Harold M. Swartz
    • 1
  1. 1.EPR Center for the Study of Viable Systems, Dept. of RadiologyDartmouth Medical SchoolHanoverUSA
  2. 2.Allos Therapeutics, IncWestminsterUSA

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