Effects of a Synthetic Allosteric Modifier of Hemoglobin Oxygen Affinity on Outcome From Global Cerebral Ischemia in the Rat

Grocott, Hilary P.; Bart, Robert D.; Sheng, Huaxin; Miura, Yoshihide; Steffen, Robert P.; Pearlstein, Robert D.; Warner, David S.

doi:10.1161/01.str.29.8.1650

Cited by 20 publications

(8 citation statements)

References 35 publications

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“…In the presence of RBCs and nitrite, a further inhibition of respiration was observed. Importantly, the onset of inhibition occurred at oxygen tensions lower than the rat RBC P 50 (35-40 mmHg 33,34 ), consistent with the data presented in Figure 3. For personal use only.…”

Section: Nitrite-dependent Hypoxic Vasodilation By Rbcs Is No Dependentsupporting

confidence: 87%

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Crawford

Isbell

Huang

et al. 2006

Blood

449

467

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Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P 50 ). Concomitantly, vasodilation is initiated at the P 50 , suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved ␤93cys residue decreases the heme redox potential (ie, decreases E 1/2 ), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose "enzyme activity" couples hypoxia to increased NO-dependent blood flow. (Blood. 2006;107:566-574)

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Section: Nitrite-dependent Hypoxic Vasodilation By Rbcs Is No Dependentsupporting

confidence: 87%

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Crawford

Isbell

Huang

et al. 2006

Blood

449

467

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“…Right shifting the ODC also improved the recovery of stunned myocardium (32), reduced anemia-induced brain damage (12), and improved neurological outcome from brain ischemia (27). Although tissue PO 2 was not measured in these studies, the benefits were attributed to enhanced O 2 delivery with increased capillary and tissue PO 2 induced by the right-shifted ODC.…”

Section: Discussionmentioning

confidence: 95%

Increasing P₅₀does not improve Do_2critor systemicV˙o₂in severe anemia

Eichelbrönner

D'Almeida

Sielenkämper

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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binding affinity facilitates O2 unloading from Hb, potentially increasing tissue mitochondrial O2 availability. We hypothesized that a reduction of Hb-O2 affinity would increase O2 extraction when tissues are O2 supply dependent, reducing the threshold of critical O2 delivery (DO2 CRIT). We investigated the effects of increased O2 tension at which Hb is 50% saturated (P50) on systemic O2 uptake (V O2 SYS), DO2 CRIT, lactate production, and acid-base balance during isovolemic hemodilution in conscious rats. After infusion of RSR13, an allosteric modifier of Hb, P 50 increased from 36.6 Ϯ 0.3 to 48.3 Ϯ 0.6 but remained unchanged at 35.4 Ϯ 0.8 mmHg after saline (control, CON). Arterial O 2 saturations were equivalent between RSR13 and saline groups, but venous PO 2 was higher and venous O2 saturation was lower after RSR13. Convective O2 delivery progressively declined during hemodilution reaching the DO2 CRIT at 3.4 Ϯ 0.8 ml ⅐ min Ϫ1 ⅐ 100 g Ϫ1 (CON) and 3.6 Ϯ 0.6 ml ⅐ min Ϫ1 ⅐ 100 g Ϫ1 (RSR13). At Hb of 8.1 g/l V O2 SYS started to decrease (CON: 1.9 Ϯ 0.1; RSR13: 1.8 Ϯ 0.2 ml ⅐ min Ϫ1 ⅐ 100 g Ϫ1 ) and fell to 0.8 Ϯ 0.2 (CON) and 0.7 Ϯ 0.2 ml ⅐ min Ϫ1 ⅐ 100 g Ϫ1 (RSR13). Arterial lactate was lower in RSR13-treated than in control animals when animals were O 2 supply dependent. The decrease in base excess, arterial pH, and bicarbonate during O2 supply dependence was significantly less after RSR13 than after saline. These findings demonstrate that during O 2 supply dependence caused by severe anemia, reducing Hb-O2 binding affinity does not affect V O2 SYS Right shifting the ODC, or increasing the O 2 tension at which Hb is 50% saturated (P 50 ), favors release of O 2 from hemoglobin at higher tissue PO 2 (4, 13). As a consequence, the O 2 gradient between RBCs and the mitochondria is increased, and more of the O 2 transported in the blood is available for consumption in the tissues. This increased O 2 gradient between RBCs and mitochondria should allow O 2 to diffuse over longer distances or offering more O 2 for local mitochondrial metabolism.Recent research has led to the discovery of new allosteric modifiers of the Hb-O 2 affinity (1). RSR13, a 2- [4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-proprionic acid monosodium salt, reliably reduces the Hb-O 2 affinity in vivo. Because RSR13 binds to a site distinct from that of 2,3-diphosphoglycerate, the naturally occurring allosteric modifier of Hb, RSR13 generates an additive rightward shift of the ODC, which should facilitate added O 2 release (1). Superfusion of tissues with or infusion of RSR13 reduced hypoxia-induced vasodilation (44), increased tissue PO 2 (21), and reduced brain infarct size (43). During maximal exercise, low P 50 diminished maximal O 2 consumption (V O 2 max ) (14), whereas an increased P 50 by RSR13 enhanced maximal O 2 uptake (33). These findings suggest that modifications of the strength of the Hb-O 2 bond can effectively alter tissue O 2 availability.Under normal conditions, tissue O 2 availability and systemic V O 2 (V ...

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“…First, this dose has been shown to favorably alter outcome in studies of both global and focal normothermic ischemia (19,27,33,37). Second, this dose was found in experiment 1 to cause near-complete reversal of the P 50 reduction caused by mild hypothermia.…”

Section: Discussionmentioning

confidence: 88%

Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats

Wainwright

Sheng²,

Sato³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Pharmacological correction of hypothermic P 50 shift does not alter outcome from focal cerebral ischemia in rats. Am J Physiol Heart Circ Physiol 282: H1863-H1870, 2002; 10.1152/ajpheart.00863.2001.-Hypothermia decreases the arterial PO 2 at which hemoglobin is 50% saturated (P50), increasing hemoglobin O2-binding affinity. We used RSR13, a synthetic allosteric modifier of hemoglobin that increases P 50, to study the role of altered hemoglobin O2-binding affinity in mild hypothermic neuroprotection. RSR13 (150 mg/kg iv) restored P50 to normothermic values. Rats underwent 70 min of middle cerebral artery occlusion (MCAO) at 30.0, 34.0, or 37.5°C with hemoglobin saturation held at 98-100%. The 34.0°C group received RSR13 or vehicle before ischemia. After 7 days of recovery, infarct volumes were reduced in all hypothermic groups, without evidence of a detrimental effect on infarct size or neurological score as a result of P 50 correction. To examine for a beneficial effect of P50 correction, ischemia duration was increased to 120 min in rats maintained at 34.0°C. Correction of P50 by RSR13 did not alter cerebral infarct sizes or neurological scores. The decrease in P 50, caused by mild hypothermia, could not be associated with infarct size or neurological deficit resulting from ischemic brain hypoxia in rats.brain; allosteric modification; hypothermia; RSR13 IN LABORATORY MODELS of focal and global cerebral ischemia, mild (34.0°C) and moderate (30.0°C) hypothermia have been shown to reduce brain injury (8,14,17,30,31). Although the efficacy of induced hypothermia remains unproven in humans sustaining ischemic brain injury, intense investigation continues with the hope of defining conditions where benefits may be obtained (12,20,34,36,43).Mild hypothermia produces multiple effects on the ischemic brain. Cerebral metabolic rate is modestly reduced (29), as is the accumulation of glutamate in the extracellular space (9, 41). However, the importance of these effects has been questioned (32, 42). In vitro, mild hypothermia reduces calcium uptake by neurons (2, 6). Mild hypothermia has no effect on protein synthesis during early recirculation (4) but hastens recovery of protein synthesis several hours after reperfusion (39) and diminishes membranebound protein kinase C activity in selectively vulnerable regions (10). Hypothermia also reduces the cerebral formation of reactive oxygen species and nitric oxide (18,22,23,26). The frequency of peri-infarct spontaneous depolarizations is also decreased in hypothermic rats (11).Hypothermia exerts another biological effect, the significance of which has not been examined. The PO 2 at which 50% of hemoglobin (Hb) binding sites are occupied by oxygen (P 50 ) is reduced in a temperature-dependent fashion. It can be speculated that this effect on Hb O 2 -binding affinity may be either beneficial or detrimental to the ischemic brain. Because hypothermia increases the affinity of Hb for O 2 , release of O 2 into tissue could be reduced. In contrast, when Hb affinity for O 2 is incre...

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Effects of a Synthetic Allosteric Modifier of Hemoglobin Oxygen Affinity on Outcome From Global Cerebral Ischemia in the Rat

Cited by 20 publications

References 35 publications

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Increasing P₅₀does not improve Do_2critor systemicV˙o₂in severe anemia

Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats

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Effects of a Synthetic Allosteric Modifier of Hemoglobin Oxygen Affinity on Outcome From Global Cerebral Ischemia in the Rat

Cited by 20 publications

References 35 publications

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation

Increasing P50does not improve Do2critor systemicV˙o2in severe anemia

Pharmacological correction of hypothermic P50shift does not alter outcome from focal cerebral ischemia in rats

Contact Info

Product

Resources

About

Increasing P₅₀does not improve Do_2critor systemicV˙o₂in severe anemia

Pharmacological correction of hypothermic P₅₀shift does not alter outcome from focal cerebral ischemia in rats