Transient NMDA receptor-mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep
Transient NMDA receptor-mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep
复制标题
DOI：
10.1113/expphysiol.2005.032375
复制
发表时间：
2006-03-01
影响因子：
2.7
通讯作者：
Bennet, L
中科院分区：
文献类型：
--
作者：
Dean, JM;Gunn, AJ;Bennet, L
暴露于严重缺氧导致迟发性脑和外周灌注不足。有证据表明，在非常不成熟的大脑中，在恢复的这一阶段可能会发生短暂的异常多巴胺能受体活性。因此，我们研究了N-甲基-D-天冬氨酸（NMDA）受体活性介导的继发性灌注不足的作用，在早产胎羊在70%的妊娠。胎仔接受假窒息或窒息，并研究12小时的恢复。特异性、非竞争性NMDA受体拮抗剂马来酸地佐环平（2 mg kg（-1）推注加0.07 mg kg h（-1）静脉注射）或生理盐水（溶剂）从窒息后15 min开始输注直至4 h。在窒息车辆组异常癫痫样脑电图瞬变过程中观察到的第一个4小时的再灌注，其峰值约对应于周围和脑灌注不足的最低点。地佐环平显著抑制这种活性（峰值频率时2.7 +/- 1.3与11.2 +/- 2.7计数min（-1），P < 0.05）并显着延迟和减弱窒息后观察到的外周和脑血管床血管阻力的上升，有效地防止了颈动脉血流和股动脉血流的初始深度低灌注期（P < 0.01）。然而，虽然持续输注确实减弱了随后的短暂性心动过速，但并不能阻止持续性但不太严重的灌注不足的第二阶段的发展。总之，目前的研究表明，在未成熟的大脑中，暴露于严重缺氧后的延迟性脑和外周低灌注的初始阶段是由NMDA受体活性介导的。脑循环中这种效应的时间与异常EEG活动密切相关，这表明我们推测与脑损伤进展有关的病理性多巴胺能激活。
Exposure to severe hypoxia leads to delayed cerebral and peripheral hypoperfusion. There is evidence in the very immature brain that transient abnormal glutaminergic receptor activity can occur during this phase of recovery. We therefore examined the role of N-methyl-D-aspartate (NMDA) receptor activity in mediating secondary hypoperfusion in preterm fetal sheep at 70% of gestation. Fetuses received either sham asphyxia or asphyxia and were studied for 12 h recovery. The specific, non-competitive NMDA receptor antagonist dizocilpine maleate (2 mg kg(-1) bolus plus 0.07 mg kg h(-1) I.V.) or saline (vehicle) was infused from 15 min after asphyxia until 4 h. In the asphyxia-vehicle group abnormal epileptiform EEG transients were observed during the first 4 h of reperfusion, the peak of which corresponded approximately to the nadir in peripheral and cerebral hypoperfusion. Dizocilpine significantly suppressed this activity (2.7 +/- 1.3 versus 11.2 +/- 2.7 counts min(-1) at peak frequency, P < 0.05) and markedly delayed and attenuated the rise in vascular resistance in both peripheral and cerebral vascular beds observed after asphyxia, effectively preventing the initial deep period of hypoperfusion in carotid blood flow and femoral blood flow (P < 0.01). However, while continued infusion did attenuate subsequent transient tachycardia, it did not prevent the development of a secondary phase of persistent but less profound hypoperfusion. In conclusion, the present studies suggest that in the immature brain the initial phase of delayed cerebral and peripheral hypoperfusion following exposure to severe hypoxia is mediated by NMDA receptor activity. The timing of this effect in the cerebral circulation corresponds closely to abnormal EEG activity, suggesting a pathological glutaminergic activation that we speculate is related to evolving brain injury.