Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke

Joe C. Watson, Egon M R Doppenberg, Ross Bullock, Alois Zauner, Melody R. Rice, Donald Abraham, Harold F. Young

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background and Purpose: Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain during ischemia is to try to increase the delivery of oxygen via the residual blood flow through and around ischemic tissue. To test this hypothesis, we used a novel oxygen delivery agent, RSR-13 (2-[4-[[(3,5-dimethylanilino)-carbonyl]- methyl]phenoxy]-2-methylpropionic acid). Intravenous administration of RSR- 13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen dissociation curve in favor of oxygen delivery. Methods: We studied RSR-13 in a feline model of permanent middle cerebral artery occlusion to assess its effects on cerebral oxygenation and infarct size. A randomized, blinded study of RSR-13 (n=6) versus 0.45% saline (n=12) was conducted, after an RSR-13 dose-escalation study (n=4). Drug was administered as a preocclusion bolus followed by a continuous infusion for the duration of the experiment (5 hours). Brain oxygen was measured continuously with the use of a Clark oxygen electrode. Infarct size was measured at 5 hours after occlusion with computer-assisted volumetric analysis. Results: The drag treatment group had consistently higher mean brain oxygen tension than controls (33±5 and 27±6 mm Hg, respectively) and significantly smaller infarcts (21±9% versus 33±9%, respectively; P<.008). We observed an inverse relationship between the dose response of RSR-13 (the shift in the hemoglobin/oxygen dissociation curve) and infarct size. Conclusions: These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.

Original languageEnglish
Pages (from-to)1624-1630
Number of pages7
JournalStroke
Volume28
Issue number8
StatePublished - Sep 1 1997
Externally publishedYes

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Felidae
Hemoglobins
Stroke
Oxygen
Brain
Brain Ischemia
Middle Cerebral Artery Infarction
efaproxiral
Ion Channels
Intravenous Administration
Electrodes
Ischemia
Morbidity
Mortality

Keywords

  • Cats
  • Cerebral ischemia
  • Hemoglobin
  • Neuroprotection

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Watson, J. C., Doppenberg, E. M. R., Bullock, R., Zauner, A., Rice, M. R., Abraham, D., & Young, H. F. (1997). Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke. Stroke, 28(8), 1624-1630.

Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke. / Watson, Joe C.; Doppenberg, Egon M R; Bullock, Ross; Zauner, Alois; Rice, Melody R.; Abraham, Donald; Young, Harold F.

In: Stroke, Vol. 28, No. 8, 01.09.1997, p. 1624-1630.

Research output: Contribution to journalArticle

Watson, JC, Doppenberg, EMR, Bullock, R, Zauner, A, Rice, MR, Abraham, D & Young, HF 1997, 'Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke', Stroke, vol. 28, no. 8, pp. 1624-1630.
Watson JC, Doppenberg EMR, Bullock R, Zauner A, Rice MR, Abraham D et al. Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke. Stroke. 1997 Sep 1;28(8):1624-1630.
Watson, Joe C. ; Doppenberg, Egon M R ; Bullock, Ross ; Zauner, Alois ; Rice, Melody R. ; Abraham, Donald ; Young, Harold F. / Effects of the allosteric modification of hemoglobin on brain oxygen and infarct size in a feline model of stroke. In: Stroke. 1997 ; Vol. 28, No. 8. pp. 1624-1630.
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abstract = "Background and Purpose: Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain during ischemia is to try to increase the delivery of oxygen via the residual blood flow through and around ischemic tissue. To test this hypothesis, we used a novel oxygen delivery agent, RSR-13 (2-[4-[[(3,5-dimethylanilino)-carbonyl]- methyl]phenoxy]-2-methylpropionic acid). Intravenous administration of RSR- 13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen dissociation curve in favor of oxygen delivery. Methods: We studied RSR-13 in a feline model of permanent middle cerebral artery occlusion to assess its effects on cerebral oxygenation and infarct size. A randomized, blinded study of RSR-13 (n=6) versus 0.45{\%} saline (n=12) was conducted, after an RSR-13 dose-escalation study (n=4). Drug was administered as a preocclusion bolus followed by a continuous infusion for the duration of the experiment (5 hours). Brain oxygen was measured continuously with the use of a Clark oxygen electrode. Infarct size was measured at 5 hours after occlusion with computer-assisted volumetric analysis. Results: The drag treatment group had consistently higher mean brain oxygen tension than controls (33±5 and 27±6 mm Hg, respectively) and significantly smaller infarcts (21±9{\%} versus 33±9{\%}, respectively; P<.008). We observed an inverse relationship between the dose response of RSR-13 (the shift in the hemoglobin/oxygen dissociation curve) and infarct size. Conclusions: These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.",
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AU - Doppenberg, Egon M R

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AU - Zauner, Alois

AU - Rice, Melody R.

AU - Abraham, Donald

AU - Young, Harold F.

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AB - Background and Purpose: Cerebral ischemia and stroke are leading causes of morbidity and mortality. An approach to protecting the brain during ischemia is to try to increase the delivery of oxygen via the residual blood flow through and around ischemic tissue. To test this hypothesis, we used a novel oxygen delivery agent, RSR-13 (2-[4-[[(3,5-dimethylanilino)-carbonyl]- methyl]phenoxy]-2-methylpropionic acid). Intravenous administration of RSR- 13 increases oxygen delivery through allosteric modification of the hemoglobin molecule, resulting in a shift in the hemoglobin/oxygen dissociation curve in favor of oxygen delivery. Methods: We studied RSR-13 in a feline model of permanent middle cerebral artery occlusion to assess its effects on cerebral oxygenation and infarct size. A randomized, blinded study of RSR-13 (n=6) versus 0.45% saline (n=12) was conducted, after an RSR-13 dose-escalation study (n=4). Drug was administered as a preocclusion bolus followed by a continuous infusion for the duration of the experiment (5 hours). Brain oxygen was measured continuously with the use of a Clark oxygen electrode. Infarct size was measured at 5 hours after occlusion with computer-assisted volumetric analysis. Results: The drag treatment group had consistently higher mean brain oxygen tension than controls (33±5 and 27±6 mm Hg, respectively) and significantly smaller infarcts (21±9% versus 33±9%, respectively; P<.008). We observed an inverse relationship between the dose response of RSR-13 (the shift in the hemoglobin/oxygen dissociation curve) and infarct size. Conclusions: These results are evidence that allosteric hemoglobin modification is protective to the brain after acute focal ischemia, providing a new opportunity for neuroprotection and raising the possibility of enhancing the protective effect of thrombolysis and ion channel blockade.

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