Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model.

Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.

Prolactin selectively transported to cerebrospinal fluid from blood under hypoxic/ischemic conditions.

AIM: The aim of this study was to determine and to verify the correlation between the amount of prolactin (PRL) levels in the blood and in the cerebrospinal fluid (CSF) by various causes of death as an indicator for acute hypoxia in autopsy cases. It is to confirm the cause of the change in prolactin level in CSF by in vitro system. MATERIALS AND METHODS: In autopsy materials, the PRL levels in blood from the right heart ventricle and in the CSF were measured by chemiluminescent enzyme immunoassay, and changes in the percentage of PRL-positive cells in the pituitary gland were examined using an immunohistochemical method. Furthermore, an inverted culture method was used as an in vitro model of the blood-CSF barrier using epithelial cells of the human choroid plexus (HIBCPP cell line) and SDR-P-1D5 or MSH-P3 (PRL-secreting cell line derived from miniature swine hypophysis) under normoxic or hypoxic (5% oxygen) conditions, and as an index of cell activity, we used Vascular Endothelial Growth Factor (VEGF). RESULTS AND DISCUSSION: Serum PRL levels were not significantly different between hypoxia/ischemia cases and other causes of death. However, PRL levels in CSF were three times higher in cases of hypoxia/ischemia than in those of the other causes of death. In the cultured cell under the hypoxia condition, PRL and VEGF showed a high concentration at 10 min. We established a brain-CSF barrier model to clarify the mechanism of PRL transport to CSF from blood, the PRL concentrations from blood to CSF increased under hypoxic conditions from 5 min. These results suggested that PRL moves in CSF through choroidal epithelium from blood within a short time. PRL is hypothesized to protect the hypoxic/ischemic brain, and this may be because of the increased transportation of the choroid plexus epithelial cells.

Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia.

During sojourn to high altitudes, progressive time-dependent increases occur in ventilation and in sympathetic nerve activity over several days, and these increases persist upon acute restoration of normoxia. We discuss evidence concerning potential mediators of these changes, including the following: 1) correction of alkalinity in cerebrospinal fluid; 2) increased sensitivity of carotid chemoreceptors; and 3) augmented translation of carotid chemoreceptor input (at the level of the central nervous system) into increased respiratory motor output via sensitization of hypoxic sensitive neurons in the central nervous system and/or an interdependence of central chemoreceptor responsiveness on peripheral chemoreceptor sensory input. The pros and cons of chemoreceptor sensitization and cardiorespiratory acclimatization to hypoxia and intermittent hypoxemia are also discussed in terms of their influences on arterial oxygenation, the work of breathing, sympathoexcitation, systemic blood pressure, and exercise performance. We propose that these adaptive processes may have negative implications for the cardiovascular health of patients with sleep apnea and perhaps even for athletes undergoing regimens of "sleep high-train low"!

Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans.

Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P<0.0001) and jugular venous EPO displayed a similar response (to 22.2±6.0 mU/ml, n=11). Thus, the arterio-jugular venous EPO difference was unaffected by hypoxia and also in cerebrospinal fluid EPO remained stable following hypoxic exposure (0.33±0.15 mU/ml, n=9 in normoxia vs. 0.41±0.20 mU/ml, n=9 in hypoxia, P=0.40). No change in plasma EPO was observed when only skin was exposed to hypobaric hypoxia (n=8). Thus, neither dermal oxygen exposure nor cerebral EPO production appears to be important for the systemic EPO response to acute hypoxia in healthy humans.

[Lessening effect of hypoxia-preconditioned rat cerebrospinal fluid on oxygen-glucose deprivation-induced injury of cultured hippocampal neurons in neonate rats and possible mechanism].

The present study was to investigate the effect of cerebrospinal fluid (CSF) from the rats with hypoxic preconditioning (HPC) on apoptosis of cultured hippocampal neurons in neonate rats under oxygen glucose deprivation (OGD). Adult Wistar rats were exposed to 3 h of hypoxia for HPC, and then their CSF was taken out. Cultured hippocampal neurons from the neonate rats were randomly divided into four groups (n = 6): normal control group, OGD group, normal CSF group and HPC CSF group. OGD group received 1.5 h of incubation in glucose-free Earle's solution containing 1 mmol/L Na2S2O4, and normal and HPC CSF groups were subjected to 1 d of corresponding CSF treatments followed by 1.5 h OGD. The apoptosis of neurons was analyzed by confocal laser scanning microscope and flow cytometry using Annexin V/PI double staining. Moreover, protein expressions of Bcl-2 and Bax were detected by immunofluorescence. The results showed that few apoptotic cells were observed in normal control group, whereas the number of apoptotic cells was greatly increased in OGD group. Both normal and HPC CSF could decrease the apoptosis of cultured hippocampal neurons injured by OGD (P < 0.01). Notably, the protective effect of HPC CSF was stronger than that of normal one (P < 0.01). Compared to OGD group, normal and HPC CSF groups both showed significantly higher levels of Bcl-2 (P < 0.01), and Bcl-2 expression level in HPC CSF group was even higher than that in normal CSF group (P < 0.01). Whereas the expressions of Bax in normal and HPC CSF groups were significantly lower than that in OGD group (P < 0.01), and the Bax expression in HPC CSF group was even lower than that in normal CSF group (P < 0.01). These results suggest that CSF from hypoxic-preconditioned rats could degrade apoptotic rate of OGD-injured hippocampal neurons by up-regulating expression of Bcl-2 and down-regulating expression of Bax.

High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia.

Animal studies have highlighted the potentially neuroprotective role of vascular endothelial growth factor (VEGF). Low levels of this growth factor have been found in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). VEGF (and other proteins, such as erythropoietin (EPO)) are produced in response to hypoxia via a common pathway involving a specific transcription factor (hypoxia-inducible factor, HIF) and a hypoxia responsive element (HRE) in the respective genes' promoter regions. In this study, we report finding the expected, high levels of VEGF and EPO in CSF from hypoxemic neurological controls, whereas EPO (but not VEGF) levels are high in the CSF from hypoxemic ALS patients. Hence, the VEGF levels in CSF from patients with ALS were significantly lower than those seen in hypoxemic controls. There was a trend towards higher CSF levels of EPO in hypoxemic ALS patients than in hypoxemic controls. Our results suggest that VEGF may not be produced in sufficient amounts in chronically hypoxic ALS patients and that this dysfunction may participate in the pathogenesis of the disease. The high EPO levels in hypoxemic ALS patients nevertheless suggest an intact common oxygen-sensor pathway.

Excitatory amino acid release and electrocortical brain activity after hypoxemia in near-term lambs.

BACKGROUND: Energy failure due to insufficient cerebral O(2)-supply leads to excess accumulation of calcium ions in presynaptic neurons, followed by excess release of excitatory amino acids (EAAs), which are potent neurotoxins, into the synaptic cleft. AIM: The aim of the present study was to determine whether extracellular EAAs release after prolonged hypoxemia affects electrocortical brain activity (ECBA), as a measure of brain cell function, in near-term born lambs. METHODS: Ten near-term lambs (term: 147 days) were delivered at 131 days of gestation. After a stabilization period, prolonged hypoxemia (FiO(2): 0.10; duration 2.5h) was induced. Mean values of physiologic variables, including ECBA, were calculated over the last 3 min of normoxemia as well as of hypoxemia. Cerebral arterial and venous blood gases were determined at the end of the normoxemic and hypoxemic periods. Cerebrospinal fluid (CSF) was obtained at the end of the hypoxemic period. CSF from six normoxemic sibs was used for comparison. HPLC was used to measure EAAs in the CSF. RESULTS: During hypoxemia, aspartate and glutamate concentration increased significantly (4.8 and 6.0 times, respectively), while asparagine and glutamine did not. ECBA decreased to 30% of the normoxemic value. Glutamate was significantly higher in lambs with a flat cerebral function monitor (CFM) tracing than in lambs with a burst-suppression pattern. CONCLUSIONS: After prolonged hypoxemia aspartate and glutamate accumulated excessively in the CSF of near-term born lambs. Especially glutamate concentrations in CSF were related to the decline in brain cell function.

Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS.

Vascular endothelial growth factor (VEGF) is implicated in motor neurone degeneration. In normal individuals, hypoxia is known to induce an overexpression of VEGF, as measured in CSF. We show that patients with ALS do not manifest this VEGF overexpression in the presence of hypoxia. Although VEGF gene expression is mainly stimulated by hypoxia, we have measured lower VEGF levels in cerebrospinal fluid (CSF) from hypoxaemic patients with amyotrophic lateral sclerosis (ALS) than in CSF from normoxaemic patients with ALS. In contrast, hypoxaemic neurological controls displayed higher levels than normoxaemic neurological controls. There was a negative correlation between VEGF levels and the severity of hypoxaemia in patients with ALS, suggesting deregulation of VEGF in ALS.

Vascular endothelial growth factor in the cerebrospinal fluid of infants who died of sudden infant death syndrome: evidence for antecedent hypoxia.

OBJECTIVES: Recurrent hypoxemia has been proposed as an important pathophysiological mechanism underlying sudden infant death syndrome (SIDS). However, conflicting results emerged when xanthines were used as markers for hypoxia. The vascular endothelial growth factor (VEGF) gene is highly sensitive to changes in tissue partial oxygen tension, and changes in genomic and protein expression occur even after changes in oxygenation within the physiologic range. METHODS: For determining whether hypoxia precedes SIDS, VEGF levels were measured using an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) of 51 SIDS infants and in 33 additional control infants who died of an identifiable cause. In addition, 6 rats that had a chronically implanted catheter in the lateral ventricle were exposed to a short hypoxic challenge, and VEGF concentrations were measured in CSF at various time points for 24 hours. Another set of 6 rats were killed with a pentobarbital overdose, and VEGF CSF levels were obtained at different time points after death. RESULTS: Mean VEGF concentrations in CSF were 308.2 +/- 299.1 pg/dL in the SIDS group and 85.1 +/- 82.9 pg/dL in those who died of known causes. Mean postmortem delay averaged 22 hours for both groups. In rat experiments, hypoxic exposures induced time-dependent increases in VEGF, peaking at 12 hours and returning to baseline at 24 hours. Postmortem duration in the animals was associated with gradual increases in VEGF that reached significance only at 36 hours. CONCLUSIONS: We conclude that VEGF CSF concentrations are significantly higher in infants who die of SIDS. We postulate that hypoxia is a frequent event that precedes the sudden and unexpected death of these infants.

1H-NMR spectroscopy of cerebrospinal fluid of fetal sheep during hypoxia-induced acidemia and recovery.

The purpose of the study was to investigate the sequence of processes occurring during and after hypoxia-induced acidemia. We used proton nuclear magnetic resonance spectroscopy, which provides an overview of metabolites in cerebrospinal fluid (CSF), reflecting neuronal metabolism and damage. The pathophysiological condition of acute fetal asphyxia was mimicked by reducing maternal uterine blood flow in 14 unanesthetized pregnant ewes. CSF metabolites were measured during hypoxia-induced acidemia, and during the following recovery period, including the periods at 24 and 48 h after the hypoxic insult. Maximum values of the following CSF metabolites were reached during severe hypoxia (pH

Hypoxia in fetal lambs: a study with (1)H-MNR spectroscopy of cerebrospinal fluid.

In fetal lambs, severe hypoxia (SH) will lead to brain damage. Mild hypoxia (MH) is thought to be relatively safe for the fetal brain because compensating mechanisms are activated. We questioned whether MH, leading to mild acidosis, induces changes in cerebral metabolism. Metabolites in cerebrospinal fluid (CSF) samples, as analyzed by proton magnetic resonance spectroscopy, were studied in two groups of seven anesthetized near-term fetal lambs. In group I, SH leading to acidosis with an arterial pH <7.1 was achieved. In group II, MH with an intended pH of 7.23--7.27 was reached [start of MH (SMH)], and maintained during 2 h [end of MH (EMH)]. During SH, choline levels in CSF, a possible indicator of cell membrane damage, were increased. Both during SH and at EMH, CSF levels of lactic acid, alanine, phenylalanine, tyrosine, lysine, branched chain amino acids, and hypoxanthine were increased compared with control values and with SMH, respectively. At EMH, the hypoxanthine CSF-to-blood ratio was increased as compared with SMH. These results indicate that prolonged MH leads to energy degradation in the fetal lamb brain and may not be as safe as assumed.

Relationship between nociceptin/orphanin FQ and cerebral hemodynamics after hypoxia-ischemia in piglets.

This study was designed to characterize the role of the newly described endogenous opioid nociceptin/orphanin FQ (NOC/oFQ) in reduced cerebral blood flow (CBF) observed after ischemia-reperfusion (I/R) and combined hypoxia and ischemia-reperfusion (H-I/R), as a function of time after onset of reperfusion in newborn pigs equipped with a closed cranial window. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, whereas hypoxia (10 min) decreased PO(2) to 35 +/- 3 mmHg with unchanged PCO(2). I/R elevated cerebrospinal fluid (CSF) NOC/oFQ from 67 +/- 4 to 266 +/- 29 pg/ml within 1 h, whereas values returned to control level within 4 h of reperfusion. H-I/R elevated CSF NOC/oFQ to 483 +/- 67 pg/ml within 1 h, and such values returned slowly to control level within 12 h of reperfusion. Topical NOC/oFQ (10(-8) M, 10(-6) M)-induced vasodilation was attenuated by I/R and reversed to vasoconstriction by H-I/R at 1 h of reperfusion (control, 9 +/- 1 and 16 +/- 1%; I/R, 3 +/- 1 and 6 +/- 1%; H-I/R, -6 +/- 1 and -11 +/- 1%). Such altered dilation returned to control values within 4 h in I/R animals and within 12 h in H-I/R animals. Blood flow in the cerebrum was reduced from 58 +/- 4 to 33 +/- 2 ml x min(-1) x 100 g(-1) within 1 h and returned to control value within 4 h in I/R animals. In animals pretreated with [F/G]NOC/oFQ(1-13)-NH(2) (1 mg/kg iv), an NOC/oFQ antagonist, however, CBF only fell to 43 +/- 3 ml x min(-1) x 100 g(-1) at 1 h of reperfusion. Similar observations were made in H-I/R animals. These data suggest that an elevated CSF NOC/oFQ concentration and altered vascular responsiveness to this opioid contribute to reductions in CBF observed after either I/R or H-I/R.

CSF glutamate during hypoxia-ischemia in the immature rat.

Cerebrospinal fluid (CSF) glutamate was measured prior to and during the course of cerebral hypoxia-ischemia in the immature rat to estimate its concentration in the extracellular fluid (ECF). A preliminary experiment was conducted using [14C]glutamate injections into immature rat brain, which showed that equilibration between ECF and CSF occurred within 10 min. Seven-day postnatal rats underwent unilateral common carotid artery ligation followed by hypoxia with 8% oxygen for up to 2 h. Brain damage, in the form of selective neuronal necrosis or apoptosis, commences after 60 min, while infarction commences after 90 min of hypoxia-ischemia. During the course of hypoxia-ischemia, CSF was obtained from the cisterna magna and analyzed for glutamate. No statistically significant increases in CSF glutamate occurred until 105 min, at which time the concentration was 240% of control (20 micromol/l). By 120 min, CSF glutamate had increased over twofold above the control value. In rat pups exposed to 1 h of hypoxia-ischemia, no increases in CSF glutamate occurred for up to 6 h of recovery. In animals exposed to 2 h of hypoxia-ischemia, CSF glutamate decreased to the control value by 1 h of recovery, with a secondary rise at 6 h. Accordingly, the increase in CSF, and presumably ECF, glutamate is a late event, which better corresponds temporally to cerebral infarction than to selective neuronal death. The results suggest that glutamate excitotoxicity, although involved in the occurrence of infarction, neither causes or contributes to selected neuronal death. The secondary elevation in CSF glutamate at 6 h of recovery from 2 h of hypoxia-ischemia occurs coincident with the onset of tissue necrosis, seen histologically.

Arachidonic acid metabolites in CSF in hypoxic-ischaemic encephalopathy of newborn infants.

The aim of this study was to evaluate the cerebral synthesis of eicosanoids in the asphyctic newborn and to investigate the relation between the prostanoid profiles in cerebrospinal fluid (CSF) and the appearance and severity of hypoxic-ischaemic encephalopathy (HIE). Levels of 6-keto-PGF(1-alpha), TXB2, PGE2 and PGF(2-alpha), in CSF were measured in 40 full term newborns during the first day of life. Thirty of these newborns had birth asphyxia and were divided into three groups: 10 without HIE, 12 with mild HIE and 8 with moderate-severe HIE. They were compared to a control group of 10 non-hypoxic newborns. Determinations of the metabolites in CSF were performed by RIA and expressed as pg/ml (mean +/- SD). The CSF TXB2 (thromboxane A2 metabolite) in asphyxiated newborns was always higher than in the control group (28.12 +/- 10.6), and related to the severity of HIE (p = 0.005): without HIE (50.84 +/- 16.4; p = 0.02), mild HIE (80.65 +/- 12.64; p < 0.01) and moderate-severe HIE (178.14 +/- 20.5; p < 0.01). The CSF 6-keto-PGF(1-alpha) (prostacyclin metabolite) in asphyxiated newborns was always higher than in the control group (80.55 +/- 12.56), but indirectly related to the severity of HIE: without HIE (240.95 +/- 28.12; p < 0.01), mild HIE (183.65 +/- 30.1; p < 0.01) and moderate-severe HIE (140.55 +/- 25.12; p < 0.01). In the moderate-severe HIE group, the increase in TXB2 was higher than the rise in 6-keto-PGF(1-alpha).

Relationship between vasopressin and opioids in hypoxia induced pial artery vasodilation.

It has been observed that a vasopressin receptor antagonist attenuates hypoxic hyperemia in fetal sheep, whereas methionine enkephalin (Met) and leucine enkephalin (Leu) contribute to hypoxia-induced pial artery dilation in newborn pigs. This study was designed to investigate the relationship between vasopressin and opioids in hypoxia-induced pial artery dilation in the newborn pig by use of the closed cranial window technique. Hypoxia-induced pial artery dilation was attenuated during moderate [arterial Po2 (PaO2) approximately 35 mmHg] and severe hypoxia (PaO2 approximately 25 mmHg) by the vasopressin receptor antagonist, [beta-mercapto-beta beta-cyclopentamethylenepropionyl, 2-O-Me-Tyr2, Arg8]vasopressin (MeAVP, 5 micrograms/kg i.v.; 29 +/- 1 vs. 14 +/- 2 and 37 +/- 2 vs. 18 +/- 2% for moderate and severe hypoxia in absence vs. presence of MeAVP, respectively, n = 7). Hypoxia-induced dilation was accompanied by increased cerebrospinal fluid (CSF) vasopressin concentration (26 +/- 1 vs. 67 +/- 4 and 26 +/- 1 vs. 99 +/- 4 pg/ml for control vs. moderate and control vs. severe hypoxia, n = 5). Vasopressin increased CSF Met (895 +/- 28, 1,147 +/- 63, 1,327 +/- 48, and 1,600 +/- 75 pg/ml for control and 40, 400, and 4,000 pg/ml vasopressin, respectively, n = 7). CSF Leu concentration was similarly increased by vasopressin. Furthermore, MeAVP attenuated the release of Met during moderate hypoxia (910 +/- 38 and 2,682 +/- 49 vs. 911 +/- 38 and 2,110 +/- 84 pg/ml for control and moderate hypoxia in absence and presence of MeAVP, respectively, n = 5). MeAVP had similar effects on hypoxia-induced Leu release. These data show that vasopressin contributes to hypoxia-induced pial artery dilation and that vasopressin increases CSF Met and Leu concentrations. These data also suggest that elevated CSF vasopressin concentrations that occur during hypoxemia result in opioid release, which subsequently contributes to hypoxic pial artery dilation.

Cerebrospinal fluid concentrations of glutamate and GABA during perinatal cerebral hypoxia-ischemia and seizures.

Cerebrospinal fluid (CSF) concentrations of glutamate and gamma- aminobutyric acid (GABA), as estimates of levels in the extracellular compartment of brain, were determined in 7-day postnatal rats at the terminus of hypoxia-ischemia and during status epilepticus, induced with bicuculline, at 2 and 24 h of recovery. Hypoxia-ischemia was associated with increased CSF glutamate, which was not increased further during status epilepticus. In contrast, CSF GABA was increased by hypoxia-ischemia as well as by status epilepticus during recovery. CSF glutamate/GABA ratios in rat pups subjected to status epilepticus with or without prior hypoxia-ischemia were lower than control animals during recovery. The lack of any significant increase in glutamate or in the glutamate/GABA ratio during status epilepticus would preclude any neuronal injury from occurring in those immature rats sustaining seizures alone or any accentuation of brain damage in those animals subjected to prior cerebral hypoxia-ischemia.

Indicators of hypoxia in cerebrospinal fluid of hydrocephalic children with suspected shunt malfunction.

We used high performance liquid chromatography to determine the concentration of purine metabolites in the cerebrospinal fluid of three hydrocephalic children with a history of shunt malfunction. Hypoxanthine and xanthine levels were high in comparison with controls. We consider these purines to be valuable indicators of disturbance of neuronal metabolism following the sustained rise in intracranial pressure caused by shunt valve malfunction.

Vitreous humour and cerebrospinal fluid hypoxanthine concentration as a marker of pre-mortem hypoxia in SIDS.

AIMS: To assess the rate at which premortem hypoxia occurs in sudden infant death syndrome (SIDS) when compared with death in early childhood. METHODS: The hypoxanthine concentration was measured as a marker of premortem hypoxia in vitreous humour and cerebrospinal fluid samples obtained at necropsy from 119 children whose ages ranged from 1 week to 2 years. RESULTS: Increasing interval between death and necropsy was accompanied by an increase in the hypoxanthine concentration of vitreous humour for the first 24 hours, at a rate of 8.3 mumol/l/hour. Thereafter, there was little change with time, and the results wer corrected to 24 hours according to a regression equation. Cerebrospinal fluid concentrations showed no significant change with time following death. Patients were divided into three groups according to the cause of death: SIDS, cardiac or pulmonary disease, and others. Median values for the cerebrospinal fluid hypoxanthine concentrations were not significantly different among the groups and no difference could be shown between the vitreous humour hypoxanthine concentration in cases of SIDS and those children dying from other causes. Patients with established cardiac or pulmonary disease had a significantly reduced vitreous humour hypoxanthine concentration which may have reflected the premortem use of artificial ventilation. CONCLUSIONS: The results of this study do not support the view that pre-mortem hypoxia is a common feature in SIDS when compared with other causes of death.

Changes in pial arteriolar diameter and CSF adenosine concentrations during hypoxia.

We measured the changes in pial arteriolar diameter and CSF concentrations of adenosine, inosine, and hypoxanthine during hypoxia in the absence and presence of topically applied dipyridamole (10(-6) M) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 10(-5) M). Closed cranial windows were implanted in halothane-anesthetized adult male Sprague-Dawley rats for the observation of the pial circulation and collection of CSF. The mean resting arteriolar diameter in mock CSF was 31.2 +/- 5.9 microns. Topically applied dipyridamole and EHNA, in combination, caused a slight but significant (p < 0.05) increase in resting arteriolar diameter (33.8 +/- 4.3 microns). With mock CSF, moderate hypoxia caused a 22.1 +/- 9.7% increase in pial vessel diameter. Topically applied dipyridamole and EHNA significantly (p < 0.01) potentiated pial arteriolar vasodilation in response to hypoxia. Moreover, the potentiating effects of dipyridamole and EHNA during hypoxia were completely abolished by theophylline (0.20 mumol/g, i.p.; p < 0.05), an adenosine receptor antagonist. Resting concentrations of adenosine, inosine, and hypoxanthine in the subwindow CSF were 0.18 +/- 0.09, 0.35 +/- 0.21, and 0.62 +/- 0.12 microM, respectively. In the absence of dipyridamole and EHNA, these levels were not affected by sustained moderate hypoxia (PaO2 = 36 +/- 6 mm Hg). However, in the presence of dipyridamole and EHNA, the concentration of adenosine in the CSF during hypoxia was significantly (p < 0.05) increased. Our data indicate that dipyridamole and EHNA potentiate hypoxic vasodilation of pial arterioles while simultaneously increasing extracellular adenosine levels, thus supporting the hypothesis that adenosine is involved in the regulation of cerebral blood flow.