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1 Department of Physiology, University of Auckland, Auckland, New Zealand
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(Received 29 September 2005;
accepted after revision 28 November 2005; first published online 29 November 2005)
Corresponding author L. Bennet: Department of Physiology, Faculty of Medicine and Health Science, The University of Auckland, Private Bag 92019, Auckland, New Zealand. Email: 1.bennet{at}auckland.ac.nz
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Introduction |
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In the preterm fetal lamb we have shown that delayed cerebral hypoperfusion occurs during the early hours of recovery from asphyxia in utero (Bennet et al. 1999) and is associated with the appearance of abnormal EEG activity in the form of epileptiform transients (George et al. 2004). The observation of evolving epileptiform transients, despite profound suppression of background activity, is consistent with in vitro evidence that glutamate receptor-mediated excitatory responses are increased for many hours after hypoxia (Mitani et al. 1998; Kalemenev et al. 2002), despite rapid normalization of extracellular levels of excitatory neurotransmitters after reperfusion from hypoxia–ischaemia (Tan et al. 1996).
There are now data in adult species to suggest that glutamate may play a role in mediating postischaemic cerebrovascular dysfunction via NMDA receptors (Armstead, 2005). Under physiological conditions NMDA receptor activation has been shown to elicit cerebrovascular dilatation, and may promote coupling of cerebral blood flow and metabolism (Faraci & Breese, 1993; Lu et al. 1997; Zonta et al. 2003). However, recent studies have demonstrated that following hypoxia there may be a reversal of the actions of the NMDA receptor from vasodilatation to vasoconstriction (Armstead, 2002, 2005; Philip & Armstead, 2003b). This may contribute to the impaired cerebral haemodynamic response to hypotension following severe hypoxia, particularly in the immature brain (Rosenberg, 1988; Armstead, 2002, 2005).
These data suggest the possibility that abnormal central excitatory activity may contribute to delayed hypoperfusion. Supporting this hypothesis, preinsult treatment with the highly selective non-competitive NMDA receptor antagonist dizocilpine has been shown to attenuate delayed cerebral hypoperfusion after cerebral ischaemia and traumatic injury in adult animals (Meyer et al. 1990; Stevens & Yaksh, 1990; Kurihara et al. 1992). However, these effects may have been related, at least in part, to reduced neural injury owing to pretreatment with dizocilpine (Stevens & Yaksh, 1990). Further, there are currently no data examining the role of NMDA receptor activation in mediating delayed hypoperfusion in the preterm fetus or newborn.
The aim of this study was to test the hypothesis that NMDA receptor activation contributes to cerebral and peripheral vasoconstriction after severe hypoxia in preterm fetal sheep.
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Methods |
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All procedures were approved by the Animal Ethics Committee of the University of Auckland, New Zealand. Twenty-four Romney x Suffolk fetal sheep were instrumented using sterile techniques at 97–98 days of gestation (term, 147 days). In terms of cerebral maturity the sheep fetus at this age is comparable to the human at 28–32 weeks of gestation (McIntosh et al. 1979), prior to the onset of cortical myelination (Barlow, 1969).
Food but not water was withdrawn 18 h before surgery. Ewes were given 5 ml of Streptocin (procaine penicillin 250 000 U and dihydrostreptomycin, 250 mg ml–1; Stockguard Laboratories Ltd, Hamilton, New Zealand) intramuscularly for prophylaxis 30 min prior to the start of surgery. General anaesthesia was induced by intravenous injection of Alfaxan (alphaxalone, 3 mg kg–1, Jurox, Rutherford, Australia) and maintained using 2–3% halothane in O2. Ewes were not ventilated, and the depth of anaesthesia, maternal heart rate and respiration were constantly monitored by trained anaesthetic staff. Under anaesthesia a 20 gauge catheter was placed in a maternal front leg vein for the duration of surgery, and the ewes received a constant infusion isotonic saline drip (at a rate of approximately 250 ml h–1) to maintain maternal fluid balance.
All surgical procedures were performed using sterile techniques (Quaedackers et al. 2004a,b). Catheters were placed in the left femoral artery and vein, the right brachial artery and vein, and the amniotic sac. Two pairs of electroencephalograph (EEG) electrodes (AS633-5SSF, Cooner Wire Co., Chatsworth, CA, USA) were placed on the dura mater over the parasagittal parietal cortex (5 and 10 mm anterior to bregma and 5 mm lateral) and secured with cyanoacrylate glue. A reference electrode was sewn over the occiput. Ultrasonic blood flow probes (Transonic Systems Inc., Ithaca, NY, USA) were placed around the right femoral artery (size 2R) and the left carotid artery (size 3S) for the measurement of femoral blood flow (FBF) and carotid blood flow (CaBF). CaBF is an index of cerebral blood flow (CBF) and correlates well with microsphere and laser Doppler measurements of CBF under both physiological and pathophysiological conditions (van Bel et al. 1994; Gratton et al. 1996; Gonzalez et al. 2005). Electrocardiogram (ECG) electrodes were sewn across the chest to record fetal heart rate (FHR). An inflatable silicone occluder was placed around the umbilical cord of all fetuses (In Vivo Metric, Healdsburg, CA, USA). The fetus was returned to the uterus, and the maternal uterine and abdominal incisions were repaired.
All fetal leads were exteriorized through the maternal flank. After surgery, all exteriorized catheters and leads were kept in an enclosed Perspex box suspended from the side of the ewe's metabolic cage. The maternal long saphenous vein was catheterized to provide access for postoperative maternal care. Antibiotics were administered into the amniotic sac prior to closure of the uterus (80 mg Gentamicin, Pharmacia and Upjohn, Perth, Australia). The maternal skin incision was infiltrated with a long-acting local anaesthetic, Marcain (Bupivacaine hydrochloride 0.25% with adrenaline 1:400 000; Astra Zeneca, North Ryde, NSW, Australia).
Following surgery, sheep were housed together in separate metabolic cages with access to water and food ad libitum. They were kept in a temperature-controlled room (16 ± 1°C, humidity 50 ± 10%), in a 12 h–12 h light–dark cycle. A period of 4–5 days postoperative recovery was allowed before experiments commenced, during which time antibiotics were administered daily for 4 days I.V. to the ewe (600 mg benzylpencillin sodium, Novartis Ltd, Auckland, New Zealand, and 80 mg gentamicin Novartis Ltd). Fetal brachial arterial blood was sampled daily for blood gas analysis for the assessment of fetal health. Catheters were maintained patent by continuous infusion of heparinized isotonic saline (20 U ml–1, 0.2 ml h–1).
Experimental design and recordings
Experiments were conducted at 103–104 days of gestation (70% gestation). Fetal mean arterial (MAP) and venous pressure (corrected for maternal position by subtraction of amniotic fluid pressure), FHR, CaBF, FBF and EEG were recorded continuously from 12 h before asphyxia until 12 h afterwards. Data were stored to disk using custom software for off-line analysis (Labview for Windows, National Instruments Ltd, Austin, TX, USA).
Fetuses were randomized to either sham asphyxia–vehicle (sham-control; n= 9), asphyxia–vehicle (n= 8) or asphyxia–dizocilpine groups (n= 7). Fetal asphyxia was induced by rapid inflation of the umbilical cord occluder for 25 min with isotonic saline of a defined volume known to completely inflate the occluder (Bennet et al. 1999). Successful occlusion was confirmed by observation of a rapid fall in FHR and a sharp rise in MAP. In all groups fetal arterial blood was taken from the brachial artery catheter at 15 min prior to asphyxia, 20 min during asphyxia, and 10 min, 2, 4 and 12 h after asphyxia for pH and blood gas measurement (Ciba-Corning Diagnostics 845 Blood Gas Analyser/Co-oximeter, East Walpole, MA, USA) and for glucose and lactate determination (YSI 2300, Yellow Springs Instruments, Yellow Springs, OH, USA). Dizocilpine (dizocilpine hydrogen maleate, Sigma-Aldrich, Sydney, NSW, Australia) was dissolved in sterile isotonic saline at a concentration of 1 mg ml–1. Dizocilpine or the same volume of vehicle was given in a 2 mg kg–1 bolus followed by a 0.07 mg kg h–1 constant I.V. infusion following the end of occlusion from 15 min until 4 h.
On completion of the experiment the ewes and fetuses were killed with an intravenous overdose of sodium pentobarbitone to the ewe via the saphenous vein catheter (9 g; Pentobarb 300, Chemstock International, Christchurch, New Zealand).
Data analysis and statistics
Off-line analysis of the physiological data was performed using analysis programs developed using Labview. The raw EEG record was assessed for epileptiform transient activity, specifically the presence of spikes and sharp waves (George et al. 2004). A spike was defined as having a sharp outline and a duration of less than 70 ms. Sharp waves were assessed as single or repeated mono- or diphasic transients lasting 100–250 ms, with an amplitude greater than 10 µV, typically superimposed on a flat EEG background (Scher, 2003). Epileptiform transient activity was calculated as 10 min averages from the end of occlusion until 4 h. Carotid and femoral vascular resistance (CaVR and FVR) were calculated using the formula:
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For the analysis of changes during recovery from asphyxia, these data were calculated as 30 min averages from the end of occlusion until 12 h. The baseline period was taken as the mean of the 12 h before occlusion. Treatment effects were evaluated by analysis of variance with time as a repeated measure (ANOVA, SPSS v12, SPSS Inc., Chicago, IL, USA) followed by Fisher's protected least-significant difference (LSD) post hoc test when a significant overall effect was found. Statistical significance was accepted when P < 0.05. Data are presented as means ±S.E.M.
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Results |
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Arterial pH, blood gas, glucose and lactate values for the control and asphyxia groups are presented in Table 1.
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There was no significant difference in CaBF and CaVR between groups in the baseline period, and in the asphyxia groups during the occlusion (Fig. 1A and B). During occlusion CaBF fell to 7.0 ± 1.0 ml min–1 in the asphyxia–vehicle group and to 9.0 ± 1.6 ml min–1 in the asphyxia–dizocilpine group (P < 0.001 both groups versus the sham-control group, 33.0 ± 3.4 ml min–1).
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In the asphyxia–dizocilpine group the fall in CaBF after the brief immediate postasphyxial hyperperfusion was attenuated for the first 30 min of dizocilpine infusion, with CaBF transiently increasing during this time (peak CaBF, 41.5 ± 2.5 versus 30.0 ± 2.1 ml min–1 in the sham-control group, P < 0.05; Fig. 1A). This attenuation in CaBF was associated with a significant reduction in CaVR (CaVR nadir of 0.8 ± 0.1 versus 1.4 ± 0.1 mmHg min ml–1 in the sham-control group, P < 0.01; Fig. 1B). Thereafter, CaBF gradually fell, reaching a nadir approximately 165 min after asphyxia (19.0 ± 1.2 versus 31.5 ± 2.7 ml min–1 in the sham-control group, P < 0.01), and remained significantly lower than that in the sham-control group for the duration of the study (P < 0.05). The fall in CaBF was associated with a sustained significant increase in CaVR (P < 0.05).
Femoral arterial blood flow and vascular resistance
There was no significant difference in FBF and FVR between groups during the baseline period, and in the asphyxia groups during the occlusion (Fig. 2A and B). During occlusion FBF fell to 2.8 ± 0.6 ml min–1 in the asphyxia–vehicle group and to 2.1 ± 0.5 ml min–1 in the asphyxia–dizocilpine group (P < 0.001 both groups versus the sham-control group, 11.2 ± 1.4 ml min–1).
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In the asphyxia–dizocilpine group, the fall in FBF after the brief return to baseline was attenuated for the first 53 min of dizocilpine infusion, with FBF transiently increasing again to sham-control values (Fig. 2A). This attenuation in FBF was associated with a significant reduction in FVR to sham-control levels (Fig. 2B). Thereafter, FBF gradually fell, reaching a nadir approximately 3 h after asphyxia (4.7 ± 1.5 versus 12.0 ± 0.7 ml min–1 in the sham-control group; P < 0.005), and remained significantly lower than that in the sham-control group for the duration of the study (P < 0.01). The fall in FBF was associated with a sustained significant increase in FVR (P < 0.05).
Fetal heart rate and mean arterial pressure
There were no significant differences in FHR between groups in the baseline period, or in the asphyxia groups during the asphyxia period (Fig. 3A). The nadir of FHR during occlusion was 55 ± 3 beats min–1 in the asphyxia–vehicle group and 54 ± 5 beats min–1 in the asphyxia–dizocilpine group (P < 0.001 both asphyxia groups versus the sham-control group, 181 ± 3 beats min–1).
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There was no significant difference in MAP between groups in the baseline period, or in the asphyxia groups during the asphyxia period (Fig. 3B). During occlusion MAP fell to 10.6 ± 0.7 mmHg in the asphyxia–vehicle group and to 10.5 ± 0.5 mmHg in the asphyxia–dizocilpine group (P < 0.001 both asphyxia groups versus the sham-control group, 36.3 ± 0.5 mmHg).
During recovery the postasphyxial rise in MAP peaked around 7 min in both asphyxia groups. MAP then transiently returned to sham-control group values. In the asphyxia–vehicle group MAP then significantly increased from 25 min after asphyxia and remained elevated compared to the sham-control group for the duration of the experiment (P < 0.05; Fig. 3B). Similarly, in the asphyxia–dizocilpine group MAP significantly increased from 1 h 30 min after asphyxia and remained significantly elevated compared to the sham-control group for the duration of the experiment (P < 0.05; Fig. 3B).
Epileptiform activity
In fetuses of the asphyxia–vehicle group the raw EEG signal after reperfusion showed epileptiform activity consisting of frequent high-voltage transients (epileptiform transients; Fig. 4). The peak frequency of EEG transient activity occurred at approximately 50 min after asphyxia (11.2 ± 2.7 counts min–1; Figs 4 and 5). There was a significant overall effect of treatment (P < 0.01) in the first 4 h after asphyxia, with a significant reduction in epileptiform transient frequency in asphyxia–dizocilpine versus asphyxia–vehicle fetuses between 30 min and 4 h after asphyxia (P < 0.05).
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Discussion |
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In the present study, central and peripheral blood flow fell in the vehicle-treated group after the initial rapid reperfusion phase. The hypoperfusion in both vascular beds was mediated by an increase in vascular resistance, and this probably contributed to the brief period of mild hypertension seen in that group. We suggest that the fall in central blood flow is likely to be related in large part to reduced metabolic demand, as previously demonstrated in similar protocols in the fetal sheep (Rosenberg et al. 1986; Gunn et al. 1997). Further, we have previously presented evidence that peripheral vasoconstriction, particularly in the gut, is important in maintaining blood pressure at a time of transiently impaired myocardial function (Quaedackers et al. 2004a). A similar phenomenon is seen in the adult during shock (Reilly et al. 2001; Ceppa et al. 2003), and both clinical and experimental data show that reversible myocardial injury and associated cardiac dysfunction are common during recovery from exposure to perinatal asphyxia (Gunn et al. 2000; Lumbers et al. 2001; Hunt & Osborn, 2002).
In the present study, non-competitive NMDA receptor blockade prevented the acute increase in blood pressure after the end of occlusion, corresponding to prevention of the initial acute fall in blood flow that occurred in the asphyxia–vehicle group. There was also a trend for blood pressure to fall below the asphyxia–vehicle group values at the peak of vasodilatation, with no compensatory changes in heart rate. This provides further support for the proposition that there is impaired cardiac function during the early recovery phase from severe hypoxia–ischaemia in the preterm fetus, and that at this time blood pressure is supported more by changes in vascular resistance than in combined ventricular output.
In a previous study of the mechanisms of delayed posthypoxic hypoperfusion in the immature fetal sheep, we demonstrated a key role for the sympathetic nervous system (SNS) in actively mediating gut hypoperfusion. Blockade by the mixed 
-adrenergic receptor antagonist phentolamine prevented the secondary fall in superior mesenteric artery blood flow after asphyxia (Quaedackers et al. 2004a). Thus, the SNS is likely to be a major mediator of increased peripheral and cerebral vasoconstriction after hypoxia, as it is during moderate and severe hypoxia (Wagerle et al. 1983; Jensen et al. 1987; Jones et al. 1988; Goplerud et al. 1991; Jensen & Lang, 1992; Giussani et al. 1993). This would account for the failure of dizocilpine to prevent the eventual development of delayed hypoperfusion.
However, the present study suggests a role for the NMDA receptor in promoting the initial part of the fall in central and peripheral blood flow, shortly after the reperfusion phase. These findings are highly consistent with many observations that neurogenic stimuli can act through perivascular nerve endings as rapid initiators of dynamic adjustment of CBF (Sandor, 1999). It is unknown whether the same effect would be found with a competitive antagonist; however, in practice, non-competitive antagonists appear to be more effective in reducing post-NMDA receptor-mediated excitotoxicity (Levy & Lipton, 1990). Although there are no direct data in the normal fetus, it is improbable that the effects of NMDA blockade to prevent initial vasoconstriction were a non-specific effect of neuronal suppression, since in adult animals dizocilpine is known to reduce EEG activity even in non-anaesthetic doses (Haberny & Young, 1995) and, as discussed below, NDMA causes vasodilatation in the normal, non-hypoxic newborn brain (Bari et al. 1998), in contrast to the present findings. It remains unclear whether the NMDA receptor activation is: (1) acting to initiate the process of delayed hypoperfusion in support of the more generalized SNS response, which takes time to establish; or (2) acting independently and coincidentally due to a posthypoxic change in local responses, as discussed below, which can lead to reversal of the effects of NMDA receptor activation (Domoki et al. 2002; Armstead, 2005).
In adult animals, stimulation of NMDA receptors on cortical neurones results in dose-dependent pial arteriolar dilatation via a mechanism involving neuronal nitric oxide synthase (nNOS) activation and subsequent NO release (Busija & Leffler, 1989; Faraci & Brian, 1995; Meng et al. 1995; Domoki et al. 2002). Although the vascular effects of NMDA in the preterm fetus are unknown, in piglets hypoxia, asphyxia and global ischaemia attenuate NMDA receptor-induced vasodilatation in a dose- and time-dependent manner (Bari et al. 1998) via reactive oxygen species (ROS) produced by cyclo-oxygenase activity (Armstead et al. 1988; Pourcyrous et al. 1993). NMDA receptors are reportedly very sensitive to ROS (Hoffman et al. 1994; Marro et al. 1998), and ROS activity following reperfusion may lead to impaired NMDA receptor activity. For example, Armstead and colleagues have shown that protein tyrosine kinase and mitogen-activated protein kinase activation contribute to the opioid nociceptin/orphanin FQ-induced impairment of NMDA receptor-mediated dilatation, particularly in the presence of ROS generated during the reperfusion phase (Philip & Armstead, 2003a,b; Armstead, 2005). Thus, taken together, these data highlight the potential for marked changes in control of vascular responses under pathophysiological conditions compared with normal physiology.
Alternatively, there is some evidence that NMDA receptors may play an important role in initiating postasphyxial secondary vasoconstriction by direct neural mediation of sympathetic outflow. Within the rostral ventrolateral medulla (RVLM), for example, sympathoexcitatory neurones directly innervate sympathetic preganglionic neurones in the spinal cord, and are critical to the tonic and reflex regulation of sympathetic tone and, therefore, of arterial blood pressure (Lipski et al. 1996; Guyenet, 2000; Dampney et al. 2003). The RVLM receives tonic glutamatergic excitatory inputs from medullary and supramedullary regions, and glutamate has been shown to be the fast synaptic transmitter mediating the activity of sympathetic preganglionic neurones through both non-NMDA and NMDA receptors (Reis et al. 1994; Sun & Reis, 1994, 1995; Deuchars et al. 1995, 2003; Ito & Sved, 1997; Horiuchi et al. 2004; Sved, 2004). Similarly, the paraventricular nucleus (PVN) in the hypothalamus has major direct and indirect connections with sympathetic efferents, and the level of activity in efferent sympathetic nerves is altered after PVN microinjection of glutamate (Katafuchi et al. 1988; Kannan et al. 1989; Li et al. 2001). Collectively, these data suggest an important role for glutamate receptors in mediating sympathetic outflow, and thus, potentially, during the early posthypoxic phase, glutamate may play a role in triggering or enhancing sympathetic activity. Further ex vivo studies of NMDA receptor-mediated modulation of adrenergic responses in isolated central and peripheral arteries are needed to help resolve these questions.
Finally, this study has also demonstrated that NMDA receptor activation plays a role in mediating the appearance of transient epileptiform activity in the latent phase. This abnormal EEG transient activity is not the same as the high-amplitude stereotypically evolving seizures seen after resolution of the latent phase, from 6 to 12 h from reperfusion (Gunn et al. 1997; Quaedackers et al. 2004a), but rather subtle discrete, fast, sharp and slow-wave spikes; typically high-frequency, low-amplitude events occurring under 400 ms (Scher, 2002). In the present study, dizocilpine substantially reduced the numbers of these EEG transient events. The tachycardia which we have previously reported to be associated with these events was also prevented (George et al. 2004). However, dizocilpine did not completely eliminate EEG transient activity, suggesting a potential role for the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors in also mediating these events.
These EEG transients are similar to neural depolarizations which have been reported in adult ischaemia models (Somjen, 2001). In these models cerebral infarct volume correlates with the number of depolarizing events (Mies et al. 1993) and with the total duration of events (Dijkhuizen et al. 1999). Consistent with the concept that both AMPA/kainate and NMDA receptors are involved in their occurrence, antagonists for both types of receptors have been shown to suppress depolarizations and improve neuronal outcome (Mies et al. 1994; Busch et al. 1996; Jensen & Wang, 1996; Obrenovitch & Zilkha, 1996; Hartings et al. 2003). Similarly, we have previously demonstrated in sheep fetuses at 60% of gestation that these EEG transients were only seen in fetuses which developed neural injury (George et al. 2004). In the preterm newborn infant epileptiform EEG transients have also been documented, but their significance is not well understood. Overall, however, the appearance of these events is also strongly associated with adverse neural outcome (Rowe et al. 1985; Hughes & Guerra, 1994; Vecchierini-Blineau et al. 1996; Marret et al. 1997; Biagioni et al. 2000; Okumura et al. 2003).
In conclusion, this study has demonstrated that NMDA receptor activation during the very early hours of recovery after an asphyxial insult in utero plays a role in the induction of delayed hypoperfusion in both central and peripheral vascular beds. It remains to be determined whether NMDA receptor activity directly induces hypoperfusion, or whether hypoperfusion is secondary to changes in the endothelial responses to NMDA receptor activation. This study has shown, however, that the NMDA receptors are not the primary mediators of posthypoxic delayed hypoperfusion. Finally, this study confirms a role for NMDA receptors in the appearance of transient epileptiform activity during the latent phase of recovery. Given the potential importance of these epileptiform events in mediating injury, further study is now required to determine whether suppression of this activity can significantly improve neural outcome.
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) and the asphyxia–dizocilpine group (•)