Background. Low birth weight is associated with cardiovascular disease. The underlying mechanisms are unknown. We hypothesized that perinatal stress alters autonomic regulation of the cardiovascular system. In this study, catecholamines, heart rate (HR) and blood pressure (BP) were measured in healthy children with low birth weight.

In the premature infant, periventricular leukomalacia, usually related to hypoxicischemic white matter damage, is the main cause of neurological impairment. We hypothesized that protracted prenatal hypoxia might induce white matter damage during the perinatal period. Pregnant Sprague-Dawley rats were placed in a chamber supplied with hypoxic gas (10% O2-90% N2) from embryonic day 5 (E5) to E20. Neonatal rat brains were investigated by histology, immunocytochemistry, western blotting, in situ hybridization, DNA fragmentation analysis, and in vivo magnetic resonance imaging (MRI). Body weight of pups subjected to prenatal hypoxia was 10 to 30% lower from P0 to P14 than in controls. Specific white matter cysts were detected between P0 and P7 in pups subjected to prenatal hypoxia, in addition to abnormal extra-cellular matrix, increased lipid peroxidation, white matter cell death detected by TUNEL, and increased activated macrophage counts in white matter. Subsequently, gliotic scars and delayed myelination primarily involving immature oligodendrocytes were seen. In vivo MRI with T1, T2, and diffusion sequences disclosed similar findings immediately after birth, showing strong correlations with histological abnormalities. We speculate that protracted prenatal hypoxia in rat induces white matter damage occurring through local inflammatory response and oxidative stress linked to re-oxygenation during the perinatal period.

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To determine whether prenatal hypoxia increases the risk of developing cardiovascular disorders as an adult and, if so, the identity of the cell mechanisms involved in such dysfunction, we evaluated the sympathoadrenal system and central areas related to cardiovascular events during development and the cardiovascular parameters in adults. Pregnant rats were exposed to hypoxia (10% oxygen) from embryonic day (E) 5 to E20 and the offspring studied at 1, 3, 9 and 12 weeks of age for neurochemistry and at 12 weeks of age for cardiovascular analysis. In the 1-, 3- and 9-week-old offspring, the levels and utilization of catecholamines were reduced in sympathetic ganglia, in target organs, in adrenals and in the rostral part of the A2 cell group in the nucleus tractus solitarius, but were increased in the locus coeruleus. In the 12-week-old adult offspring, the lowered autonomic nervous activity was restricted to cardiac-related structures, i.e. the stellate ganglion, heart and adrenals. In adult rats, prenatal hypoxia did not affect the cardiac parameters under resting conditions but increased blood pressure and the variability of blood pressure and heart rate under stress conditions. The altered metabolic activity of the sympathoadrenal system and related central areas during development and at adulthood for most structures might be part of the potential mechanisms contributing to cardiovascular disorders in adults.

The effect of chronic hypoxia on gender differences in physiology and neurochemistry of chemosensory pathways was studied in prepubertal and adult rats living at sea level (SL; Lyon, France) or at high altitude (HA; La Paz, Bolivia, 3,600 m). HA adult rats had higher hematocrit (Ht%), Hb concentration, resting ventilatory rate (Ve(100)), and higher tyrosine hydroxylase (TH) activity in carotid bodies (CB) than SL animals. At HA and SL, adult females had lower Ht% (46.0 +/- 0.8 vs. 50.4 +/- 0.6% at HA, P < 0.05 and 43.8 +/- 0.9 vs. 47.1 +/- 0.8% at SL, P < 0.05) and Hb (16.1 +/- 0.3 vs. 17.7 +/- 0.2 g/dl at HA, P < 0.05 and 14.5 +/- 0.3 vs. 15.6 +/- 0.1 g/dl at SL, P < 0.05) than males. Females had higher Ve(100) [170 +/- 19 vs. 109 +/- 7 ml. min(-1). 100 g(-1) at HA, P < 0.05 and 50 +/- 3 vs. 40 +/- 2 ml. min(-1). 100 g(-1) at SL, not significant (NS)] and lower CB-TH activity (1.40 +/- 0.2 vs. 3.87 +/- 0.6 pmol/20 min at HA, P < 0.05 and 0.52 +/- 0.1 vs. 0.68 +/- 0.1 pmol/20 min at SL; NS) than males at HA only. The onset of hypoxic ventilatory response during development was delayed at HA. Prepubertal HA females had higher Ve(100) than males (2 wk old, +47%) and higher CB-TH activity (3 wk old, +51%). Medullary noradrenergic groups were sex dimorphic during development at SL. Rats raised at HA had a drop of TH activity between the second and the third postnatal week in all medullary groups. In conclusion, our data support the hypothesis that the CB is the major site for sexual differentiation of the ventilatory control. Ventilatory differences appeared before puberty, and the animals bred at HA had profound alterations in the developmental process of the chemoreflex and its neural pathways. Some of these alterations are under dependence of the sex of the animal, and there is an important interaction between gender and the hypoxic environmental condition during the developmental period.

To define the effects of prenatal hypoxia on the postnatal development of the chemoafferent pathway, ventilation and metabolism, pregnant rats were exposed to normobaric hypoxia (10 % oxygen) from embryonic day 5 to embryonic day 20. Offspring were studied at 1, 3 and 9 weeks of age in three separate protocols. Prenatal hypoxia decreased the dopamine content in the carotid bodies at all ages, and decreased the utilisation rate of noradrenaline in the caudal part of the A2 (A2c), A1 and A5 noradrenergic brainstem cell groups at 3 weeks after birth. At 9 weeks of age, the level of dopamine in the carotid bodies was still reduced but the utilisation rate of noradrenaline was enhanced in A1. Rats from dams subjected to hypoxia during pregnancy hyperventilated until 3 weeks after birth. In these rats, the biphasic hypoxic ventilatory response was absent at 1 week and the increase in minute ventilation was amplified at 3 weeks. Prenatal hypoxia disturbed the metabolism of offspring until 3 weeks after birth. A weak or absent hypometabolism in response to hypoxia was observed in these rats in contrast to control animals. Prenatal hypoxia impairs the postnatal development of the chemoafferent pathway, as well as the ventilatory and metabolic responses to hypoxia. These alterations were mostly evident until 3 weeks after birth.

The first step of this study was to determine the early time course and pattern of hypoxic ventilatory response (HVR) recovery following irreversible bilateral carotid sinus nerve transection (CSNT). The second step was to find out if HVR recovery was associated with changes in the neurochemical activity of the medullary catecholaminergic cell groups involved in the O2 chemoreflex pathway. The breathing response to acute hypoxia (10% O2) was measured in awake rats 2, 6, 10, 45 and 90 days after CSNT. In a control group of sham‐operated rats, the ventilatory response to hypoxia was principally due to increased respiratory frequency. There was a large reduction in HVR in the CSNT compared to the sham‐operated rats (−65%, 2 days after surgery). Within the weeks following denervation, the CSNT rats progressively recovered a HVR level similar to the sham‐operated rats (‐37% at 6 days, −27% at 10 days, and no difference at 45 or 90 days). After recovery, the CSNT rats exhibited a higher tidal volume (+38%) than the sham‐operated rats in response to hypoxia, but not a complete recovery of respiratory frequency. Fifteen days after CSNT, in vivo tyrosine hydroxylase (TH) activity had decreased in caudal A2C2 (−35%) and A6 cells (−35%). After 90 days, the CSNT rats displayed higher TH activity than the sham‐operated animals in caudal A1C1 (+51%), caudal A2C2 (+129%), A5 (+216%) and A6 cells (+79%). It is concluded that HVR following CSNT is associated with a profound functional reorganisation of the central O2 chemoreflex pathway, including changes in ventilatory pattern and medullary catecholaminergic activity.

METHODSAll experiments were carried out according to the ethical principles laid down by the French (Ministére de l'Agriculture) and EU Council directives for care of laboratory animals (No. 02889). At the end of the experiments, all animals were killed by exposure to a rising concentration of CO 2 . All the animals used in this study were sibling pups from a previously published study (Mamet et al. 2002). Gestational hypoxiaSixty pregnant Sprague-Dawley rats (IFFA-CREDO, l'Arbresle, France) were housed in a temperature-controlled room (26 ± 1°C) with a 12/12 light/dark cycle and allowed free access to food and water. The first day of gestation was determined on the basis of a vaginal smear. Pregnant rats were first exposed to hypoxia on the fifth day of gestation so as not to disturb implantation of the embryos. From the 5th to 20th day of gestation, the experimental group was housed in a Plexiglas chamber, with a normobaric hypoxic atmosphere consisting of 10 % O 2 -90 % N 2 . The O 2 and CO 2 contents of this atmosphere were monitored twice daily using Servomex analysers (Servomex Co., Norwood, MA, USA). The CO 2 expired by the rats was eliminated by circulating the atmosphere through soda lime, so that the atmospheric content of this gas never exceeded 0.1 %. The water contained in the expired gas was trapped in a chilled glass tank. On the 20th day of gestation, hypoxic pregnant rats were returned to normoxia (21 % O 2 ), under which they gave birth. Immediately after birth, the male pups were grouped together, and then randomly redistributed to nursing females (n = 60) which had never been exposed to hypoxic conditions (10-12 pups per female). This procedure was followed to avoid sex differences, eliminate variations between litters, ensure a standard nutritional status, and avoid any possible effect of hypoxia on the nutritional quality of the milk. These offspring were designated as the prenatal hypoxic (PNH) group. Pups from another 60 pregnant Sprague-Dawley rats, whose gestation occurred under normoxic conditions (21 % O 2 ), but were otherwise treated in the same manner and placed in a similar Plexiglas chamber, were designated as the control (cont) group.