Transient NMDA receptor‐mediated hypoperfusion following umbilical cord occlusion in preterm fetal sheep

Abstract

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.

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia–ischaemia in near‐term fetal sheep

“…This suppression is an actively mediated, endogenous neuroprotective response that helps to limit the spread of neural injury (Dean et al . ; Jensen et al . ; Yawno et al .…”

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia–ischaemia in near‐term fetal sheep

“…This suppression is an actively mediated, endogenous neuroprotective response that helps to limit the spread of neural injury (Dean et al . ; Jensen et al . ; Yawno et al .…”

The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning—Effects on Heart Function and Oxidative Stress

“…The reactivity of coronary blood vessels remains one of the most important physiological properties of the heart. In an experimental setup designed to assess the effects of asphyxia in fetal sheep induced by umbilical cord occlusion, Dean et al showed that the increase in vascular resistance was reduced by MK-801 [51]. The role of NMDARs in the regulation of blood flow has been mainly examined in relation to the cerebral blood flow.…”

Motor Deficits Are Triggered by Reperfusion-Reoxygenation Injury as Diagnosed by MRI and by a Mechanism Involving Oxidants

“…Hippocampal reperfusion injury has been demonstrated in global antenatal H-I from transient umbilical cord occlusion in fetal sheep (Fujii et al, 2003). This model usually results in delayed biochemical changes in reperfusion that constitute secondary energy failure (Tan et al, 1996b; Dean et al, 2006). …”

“…In fetal sheep umbilical cord occlusion there is an initial cerebral hyper-perfusion that peaks at 6 min after end of occlusion followed by hypo-perfusion that reaches nadir at 90 min (Dean et al, 2006). The late hypo-perfusion was not observed with shorter occlusion in later gestation sheep (Fujii et al, 2003).…”

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia–ischaemia in near‐term fetal sheep

“…This suppression is an actively mediated, endogenous neuroprotective response that helps to limit the spread of neural injury (Dean et al . ; Jensen et al . ; Yawno et al .…”

The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning—Effects on Heart Function and Oxidative Stress

“…The reactivity of coronary blood vessels remains one of the most important physiological properties of the heart. In an experimental setup designed to assess the effects of asphyxia in fetal sheep induced by umbilical cord occlusion, Dean et al showed that the increase in vascular resistance was reduced by MK-801 [51]. The role of NMDARs in the regulation of blood flow has been mainly examined in relation to the cerebral blood flow.…”

Motor Deficits Are Triggered by Reperfusion-Reoxygenation Injury as Diagnosed by MRI and by a Mechanism Involving Oxidants

“…Hippocampal reperfusion injury has been demonstrated in global antenatal H-I from transient umbilical cord occlusion in fetal sheep (Fujii et al, 2003). This model usually results in delayed biochemical changes in reperfusion that constitute secondary energy failure (Tan et al, 1996b; Dean et al, 2006). …”

“…In fetal sheep umbilical cord occlusion there is an initial cerebral hyper-perfusion that peaks at 6 min after end of occlusion followed by hypo-perfusion that reaches nadir at 90 min (Dean et al, 2006). The late hypo-perfusion was not observed with shorter occlusion in later gestation sheep (Fujii et al, 2003).…”

Early sinusoidal heart rate patterns and heart rate variability to assess hypoxia–ischaemia in near‐term fetal sheep

“…This suppression is an actively mediated, endogenous neuroprotective response that helps to limit the spread of neural injury (Dean et al . ; Jensen et al . ; Yawno et al .…”

The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning—Effects on Heart Function and Oxidative Stress

“…The reactivity of coronary blood vessels remains one of the most important physiological properties of the heart. In an experimental setup designed to assess the effects of asphyxia in fetal sheep induced by umbilical cord occlusion, Dean et al showed that the increase in vascular resistance was reduced by MK-801 [51]. The role of NMDARs in the regulation of blood flow has been mainly examined in relation to the cerebral blood flow.…”

Motor Deficits Are Triggered by Reperfusion-Reoxygenation Injury as Diagnosed by MRI and by a Mechanism Involving Oxidants

“…Hippocampal reperfusion injury has been demonstrated in global antenatal H-I from transient umbilical cord occlusion in fetal sheep (Fujii et al, 2003). This model usually results in delayed biochemical changes in reperfusion that constitute secondary energy failure (Tan et al, 1996b; Dean et al, 2006). …”

“…In fetal sheep umbilical cord occlusion there is an initial cerebral hyper-perfusion that peaks at 6 min after end of occlusion followed by hypo-perfusion that reaches nadir at 90 min (Dean et al, 2006). The late hypo-perfusion was not observed with shorter occlusion in later gestation sheep (Fujii et al, 2003).…”