Abstract
RSR13 is a synthetic allosteric modifier of hemoglobin that decreases the oxygen binding affinity of hemoglobin, potentially increasing oxygen availability to hypoxic tissues. Using in vivo EPR to directly measure cortical pO2, we examined whether RSR13 would improve brain tissue pO2 following severe hemorrhagic shock in rats. Hemorrhagic shock was induced by withdrawing blood (2.7–2.8 mL/100 g/15 min). Following a 30 min shock period, resuscitation was performed by infusion with Ringer lactate plus RSR13 (150mg/kg) or saline (control). Following hemorrhage, brain pO2 decreased by about 14 mm Hg in both groups. Following crystalloid resuscitation brain pO2 remained depressed in the control group but returned to the pre-hemorrhage values in the rats that received RSR13. RSR13 immediately increased and maintained the paO2 while controls had a very gradual increase towards pre-hemorrhage values. There was no difference in the blood pressure or heart rate between groups. RSR13 may have useful applications to decrease the effects of acute hemorrhagic hypoxemia by increasing brain oxygenation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Heckbert RS, Vedder NB, Hoffman W, Winn RK, Hudson LD, Jurkovich GJ, Copass MK, Harlan JM, Rice CL, Maier RV. Outcome after hemorrhagic shock in trauma patients. J. Trauma 1998 Sep;45:545–549
Randad RS, MA, Mahran MA, Mehanna AS, 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;34:752–757.
Wireko FC, Kellogg GE, 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.
Abraham DJ, Wireko FC, 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 1991;31:9141–9149.
Wei EP, Randad RS, Levasseur JE, Abraham DJ, Kontos HA. Effect of local change in 02 saturation of hemoglobin on cerebral vasodilution from hypoxia and hypotension. Am J Physiol 1993;265:H1439–H1443.
Khandelwal SR, Randad RS, Lin P-S, Meng H, Pittman RN, Kontos HA, Choi SC, Abraham DJ, Schmidt-Ullrich R. Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation. Am J Physiol 1993;265:H1450–H1453.
Kunert MP, Liard JF, Abraham DJ. RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats. Am J Physiol 1996;271:H602–613.
Pagel PS, Hettrick DA, Montgomery MW, Kersten JR, Steffen RP, Warltier DC. RSR13, a synthetic modifier of hemoglobin-oxygen affinity, enhances the recovery of stunned myocardium in anesthetized dogs. J Pharmacology and Experimental Therapeutics, 1998;285:1–8.
Grocott HP, Bart RD, Sheng, H, Miura Y, Steffen, RP, Pearlstein RD, 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.
Woods JA, Storey CJ, Babcock EE, Malloy CR. Right-shifting the oxyhemoglobin dissociation curve with RSR13: effects on high-energy phosphates and myocardial recovery after low-flow ischemia. J Cardiovascular Pharmacology 1998;3I:359–364.
Swartz HM, Boyer S, Gast P, Glockner JF, Hu H, Liu KJ, Moussavi M, Norby SW, Walczak T, Vahidi N, Wu M, Clarkson RB. Measurements of pertinent concentrations of oxygen in vivo. Magn Reson Med. 1991;20:333–339.
Liu KJ, Gast P, Moussavi M, Norby SW, Vahidi N, Walczak T, Wu M, Swartz HM. Lithium phthalocyanine: a probe for EPR oximetry in viable biological systems. Proc Natl Acad Sci 1993;90:5438–5442.
Bacic G, Liu KJ, O’Hara JA, Harris RD, Szybinski K, Goda F, Swartz HM. Oxygen tension in a murine tumor: a combined EPR and MRI study. Magn Reson Med. 1993;30:568–572.
Liu KJ, Bacic G, Hoopes PJ, Jiang J, Du H, Ou LC, Dunn JF, Swartz HM. Assessment of cerebral pO2 by EPR oximetry in rodents: effects of anesthesia, ischemia, and breathing gas. Brain Res 1995;685:91–98.
Goda F., Bacic G, O’Hara JA, Gallez B, Swartz HM, Dunn JF. The relationship between pO2 and perfusion in two murine tumors after X-ray Irradiation: a combined Gd-DTPA dynamic MRI and in vivo EPR oximetry study. Cancer Res 1996;56:3344–3349.
James P, Grinberg O, Goda F, Panz T, O’Hara J, Swartz HM. Gloxy: an oxygen-sensitive coal for accurate measurement of low oxygen tensions in biological systems. Magn Reson Med 1997 138:48–58.
Swartz HM, Clarkson RB. The measurement of oxygen in vivo using EPR techniques. Phys Med Biol 1998;43:957–1975.
Liu KJ, Hoopes PJ, Rolett EL, Beerle BJ, Azzawi A, Goda F, Dunn JF, Swartz HM. Effect of anesthesia on cerebral tissue oxygen and cardiopulmonary parameters in rats. Adv Exp Med Biol 1997;428:33–39.
Taie S, Leichtweis SB, Liu KJ, Miyake M, Grinberg O, Demidenko E, Swartz HM. The effect of ketamine/xylazine and pentobarbital anesthesia on cerebral tissue oxygen tension, blood pressure, and arterial blood gas in rats. Adv Exp Med Biol 1999;471:189–198.
Rhee P, Waxman K, Clark L, Tominaga G, Soliman MH. Superoxide dismutase polyethylene glycol improves survival in hemorrhagic shock. The American Surgeon 1991;57:747–750.
Ismail H, Ulus B, Arslan Y, Savic V, Kiran K. Restoration of blood pressure by chroline treatment in rats made hypotensive by hemorrhage. British Journal of Pharmacology 1995;116:1911–1917.
Carillo P, Takatsu A, Safar P, Tisherman S, Stezoski W, Stolz G, Dixon CE, Radovsky A. Prolonged severe hemorrhagic shock and resuscitation in rats does not cause subtle brain damage. Journal of Trauma 1998;2:239–249.
Munchitsh E-M, Auer W, Pichler L. Effects of al acid glycoprotein in different rodent models of shock. Fundam Clin Pharmacol 1998;12:173–181.
Sazabo C. Potential role of the peroxynitrite-poly(ADP-RIBOSE) synthetase pathway in a rat model of severe hemorrhagic shock. Shock 1998;9:341–344.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer Science+Business Media New York
About this chapter
Cite this chapter
Miyake, M., Grinberg, O.Y., Hou, H., Steffen, R.P., Elkadi, H., Swartz, H.M. (2003). The Effect of RSR13, a Synthetic Allosteric Modifier of Hemoglobin, on Brain Tissue pO2 (Measured by Eproximetry) Following Severe Hemorrhagic Shock in Rats. In: Dunn, J.F., Swartz, H.M. (eds) Oxygen Transport to Tissue XXIV. Advances in Experimental Medicine and Biology, vol 530. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0075-9_30
Download citation
DOI: https://doi.org/10.1007/978-1-4615-0075-9_30
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4912-9
Online ISBN: 978-1-4615-0075-9
eBook Packages: Springer Book Archive