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

Abstract

. 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...

Tissue Perfusion and Diffusion and Cellular Respiration: Transport and Utilization of Oxygen

“…Conversely, hypothermia increases Hb–O 2 binding affinity (lower P 50 ) and reduces O 2 release to match the reduction in tissue metabolic activity. 72 73 74…”

“…Hyperthermia increases molecular motion and reduces Hb-O 2 binding affinity (higher P 50 ), favoring O 2 release to meet the increased metabolic demand. Conversely, hypothermia increases Hb-O 2 binding affinity (lower P 50 ) and reduces O 2 release to match the reduction in tissue metabolic activity [72][73][74]. The 2,3-bisphosphoglycerate (2,3-BPG) effect, shown in ►Fig.…”