RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

Kilgore, Kenneth S.; Shwartz, Charles F.; Gallagher, M.; Steffen, Robert P.; Mosca, Ralph S.; Bolling, Steven F.

doi:10.1161/01.cir.100.suppl_2.ii-351

Cited by 17 publications

(10 citation statements)

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“…All animals with increased P 50 subjected to global ischemia and cardiopulmonary bypass returned to normal sinus rhythm and doubled CO (22). 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).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…When such an agent becomes available, there are a myriad of both cardiac and general surgical applications that go far beyond simply that of a 'blood substitute.' phenoxy]2-methylpropionic acid) a synthetic allosteric modifier of hemoglobin (reproduced from Kilgore et al, [60] with permission).…”

Section: Resultsmentioning

confidence: 99%

“…[61] More importantly, RSR13 has been shown to increase brain oxygen tension and reduce infarct size in a cat model of stroke, [59] and to reduce cell damage, when given at reperfusion, in a rat model of global cerebral ischemia. [60] In a canine model of global myocardial ischemia during CPB, RSR13 improved myocardial function when given at reperfusion. [60] …”

Section: Global and Focal Ischemiamentioning

confidence: 99%

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Clinical Potential of Nonhemoglobin Oxygen Therapeutics in Cardiac and General Surgery

Wahr

2002

American Journal of Cardiovascular Drugs

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Significant efforts have been made over the past 70 years to find a solution that could substitute for blood. Over the years, the focus has shifted to developing a solution capable of delivering oxygen to the tissues. Fluorocarbons (FC) are highly inert solutions with a high solubility for all gases, making them a prime candidate to become such an oxygen delivery agent. Although clinical research efforts into the use of these agents as substitutes for blood transfusions continue at present, the rapid disappearance of emulsified FCs from the vascular space and accumulation in the liver and spleen may well limit their usefulness as transfusion substitutes. Because of their ability to dissolve significant quantities of oxygen and carbon dioxide, these agents may be more attractive as oxygen delivery agents during periods of local or global organ ischemia, including preservation of organs for transplantation. FCs have also been tested in animal models of cardiopulmonary bypass, and may be efficacious in adsorbing the gases present in air emboli. Recently a second class of oxygen therapeutics (allosteric modifiers) has been developed, and these agents enhance oxygen delivery by shifting the oxygen dissociation curve to the right, thus increasing tissue PO(2). Allosteric modifiers have been shown to effectively shift the p50 of hemoglobin 10mm Hg at clinically relevant dosages, and have been shown (in animal models) to reduce cerebral infarct size following carotid ligation and to improve myocardial performance following myocardial ischemia. Despite significant research efforts, however, none of the solutions under development are currently approved for clinical use by the Food and Drug Administration, with the exception of myocardial contrast imaging agents.

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“…Second, we have previously shown that, although RSR13 does not provide independent neuroprotection from a focal ischemic insult (33), when combined with other pharmacotherapy (e.g., dizocilpine), an increase in P 50 serves to reduce ischemic brain damage in normothermic animals (27). RSR13 also has been shown to augment hypothermic protection of the myocardium in a canine cardiopulmonary bypass model (25). As a result, we speculated that RSR13 might also enhance the neuroprotection provided by hypothermia.…”

Section: Discussionmentioning

confidence: 98%

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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RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

Abstract: Background-During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13,[2][3][4]

Cited by 17 publications

References 31 publications

Increasing P₅₀does not improve Do_2critor systemicV˙o₂in severe anemia

Increasing P₅₀does not improve Do_2critor systemicV˙o₂in severe anemia

Clinical Potential of Nonhemoglobin Oxygen Therapeutics in Cardiac and General Surgery

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

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RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

Abstract: Background-During hypothermic blood cardioplegia, oxygen delivery to myocytes is minimal with ineffective anaerobic metabolism predominating. RSR13,[2][3][4]

Cited by 17 publications

References 31 publications

Increasing P50does not improve Do2critor systemicV˙o2in severe anemia

Increasing P50does not improve Do2critor systemicV˙o2in severe anemia

Clinical Potential of Nonhemoglobin Oxygen Therapeutics in Cardiac and General Surgery

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

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