Glial vascular endothelial growth factor overexpression in rat brainstem under tolerable hypoxia: evidence for a central chemosensitivity.

The ventilatory response to hypoxia is mediated by peripheral inputs arising from the arterial chemoreceptors. In their absence, hypoxic adaptation can be achieved, possibly as a result of central cellular reorganization. To study this reorganization, we used chemodenervated rats to investigate the expression and localization of vascular endothelial growth factor (VEGF) in the brainstem. VEGF is a target gene of hypoxia-inducible factor (HIF) that is responsible for the morphofunctional remodeling induced by hypoxia. Intact and chemodenervated rats were subjected to normoxia or hypoxia for 6 hr (10% O(2) in N(2)). VEGF protein was quantified in micropunches of brainstem tissue. Only chemodenervated animals showed an increased VEGF expression in response to hypoxia, whereas, in normoxia, VEGF expression was not modified by chemodenervation. The same hypoxic condition was repeated for 8 days before immunocytochemical staining with anti-VEGF; antiglial fibrillary acidic protein (GFAP), a marker of astrocytes; and anti-rat endothelial cell antigen-1 (anti-RECA-1) that recognizes endothelial cells. Confocal analysis showed a cellular colocalization of GFAP and VEGF, indicating that VEGF was overexpressed predominantly in astrocytes. Increased RECA-1 immunolabeling indicated an enhanced angiogenesis in chemodenervated rats subjected to hypoxia. These results indicate that glial cells and the vascular network contribute to the brainstem remodeling. The peripheral chemodenervation reveals a central O(2) chemosensitivity involving a cascade of gene expression triggered by hypoxia, which in intact animals may act synergically with peripheral chemosensory inputs.

[Anterior dislocation of the second and third carpometacarpal joints]. / Luxation carpométacarpienne antérieure des deuxième et troisième rayons.

Anterior dislocations of the second and third carpometacarpal joints are extremely rare. The authors report a case of an anterior dislocation of the bases of the second and third metacarpals of the right hand treated by closed reduction and percutaneous wiring. The result was excellent and the authors think that this type of carpometacarpal dislocation does not need open reduction.

Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice.

Although respiration is vital to the survival of all mammals from the moment of birth, little is known about the genetic factors controlling the prenatal maturation of this physiological process. Here we investigated the role of the Phox2a gene that encodes for a homeodomain protein involved in the generation of noradrenergic A6 neurons in the maturation of the respiratory network. First, comparisons of the respiratory activity of fetuses delivered surgically from heterozygous Phox2a pregnant mice on gestational day 18 showed that the mutants had impaired in vivo ventilation, in vitro respiratory-like activity, and in vitro respiratory responses to central hypoxia and noradrenaline. Second, pharmacological studies on wild-type neonates showed that endogenous noradrenaline released from pontine A6 neurons potentiates rhythmic respiratory activity via alpha1 medullary adrenoceptors. Third, transynaptic tracing experiments in which rabies virus was injected into the diaphragm confirmed that A6 neurons were connected to the neonatal respiratory network. Fourth, blocking the alpha1 adrenoceptors in wild-type dams during late gestation with daily injections of the alpha1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants. These results suggest that noradrenaline, A6 neurons, and the Phox2a gene, which is crucial for the generation of A6 neurons, are essential for development of normal respiratory rhythm in neonatal mice. Metabolic noradrenaline disorders occurring during gestation therefore may induce neonatal respiratory deficits, in agreement with the catecholamine anomalies reported in victims of sudden infant death syndrome.

Age-related sensitivity to lung oxidative stress during ozone exposure.

As immature and aged rats could be more sensitive to ozone (O(3))-linked lung oxidative stress we have attempted to shed more light on age-related susceptibility to O(3) with focusing our interest on lung mitochondrial respiration, reactive oxygen species (ROS) production and lung pro/antioxidant status. For this purpose, we exposed to fresh air or O(3) (500 ppb 12 h per day, for 7 days) 3 week- (immature), 6 month- (adult) and 20 month-old rats (aged). We determined, in lung, H(2)O(2) release by mitochondria, activities of major antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT)], heat shock protein (HSP(72)) content and 8-oxodG and dG-HNE nDNA contents, as DNA oxidative damage markers. In adult rats we did not observe alteration of pro/antioxidant status. In contrast to adults, immature rats exposed to O(3) higher nDNA 8-oxodG content and HSP(72) and without antioxidant enzymes modification. Aged rats displayed mild uncoupled lung mitochondria, increased SOD and GPx activities, and higher 8-oxodG content after O(3) exposure. Thus, in contrast to adults, immature and aged rats displayed lung oxidative stress after O(3) exposure. Higher sensitivity of immature to O(3) was partly related to ventilatory parameters and to the absence of antioxidant enzyme response. In aged rats, the increase in cytosolic SOD and GPx activities during O(3) exposure was not sufficient to prevent the impairment in mitochondrial function and accumulation in lung 8- oxodG. Finally, we showed that mitochondria seem not to be a major source of ROS under O(3) exposure.

[Arthroplasty for scaphotrapeziotrapezoidal arthrosis using a pyrolytic carbon implant. Preliminary results]. / Traitement de l'arthrose S.T.T. par un Implant en pyrocarbone. Premiers résultats.

INTRODUCTION: The authors propose a scaphotrapeziotrapezoidal (STT) arthroplasty using a discoid pyrocarbon implant. The aim of this prosthesis is to restore the scapho-trapezial mobility without destabilising the carpal bones (unlike with a simple resection of the distal scaphoid pole). METHOD: This technique was used in 15 cases from 1994 to 2002. 12 patients (10 females and 2 males), mean age 65 years) have been reviewed with a mean follow-up of 4 years (1 to 8). Surgical indication was pain refractory to medical treatment (average 8.5 on V.A.S.). Pre-operative mobility showed a loss of radial deviation and dorsal flexion. The severity of the pain did not allow evaluation of the pre-operative strength. Post-operative results were assessed with the EVAL computerised system, static and dynamic X rays were performed in all cases. RESULTS: Pain decreased to an average of 2. The mobility compared to the healthy side showed a slight loss of radial deviation (less than 10 degrees) and in wrist extension (less than 15 degrees). Grip strength was similar to the normal side, even during rapid exchanges. Pinch grip evaluation showed a slight decrease (0.8 kg) which did not compromise normal function of the first ray. No implant luxation was observed in the radiological study. Angular measurements did not show any modification in DISI and other static angles remained unchanged. Dynamic sagital and frontal views confirmed the good mobility of the prosthesis which adjusts its position to the scaphoid movements. CONCLUSION: The good results, the simple surgical procedure, the absence of complications, the lack of a need for any fixation or ligamentoplasty all confirm the advantages of this pyrocarbon implant in the treatment of STT arthrosis. Furthermore, in cases of failure, it is possible to use any other revision procedure.

Plasticity in the phenotypic expression of catecholamines and vasoactive intestinal peptide in adult rat superior cervical and stellate ganglia after long-term hypoxia in vivo.

Sympathetic ganglia in the adult rat contain various populations of nerve cells which demonstrate plasticity with respect to their transmitter phenotype. The plasticity of the neuronal cell bodies and of the small intensely fluorescent cells in the superior cervical and stellate ganglia in response to hypoxia in vivo (10% O2 for seven days) was assessed by studying the expression of catecholamines and vasoactive intestinal peptide. The levels of norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid and vasoactive intestinal peptide immunoreactivity were determined. In addition, the density of the immunohistochemical staining of cells for tyrosine hydroxylase and vasoactive intestinal peptide was evaluated. In the intact superior cervical ganglion, hypoxia increased the dopamine level as well as the density of small intensely fluorescent cells immunolabelled for tyrosine hydroxylase and vasoactive intestinal peptide. In the axotomized ganglion, hypoxia elicited a twofold rise in the level of the vasoactive intestinal peptide as well as enhancing the density of neuronal cell bodies immunostained for this peptide. Thus, the effect of hypoxia on the expression of vasoactive intestinal peptide expression in neurons was dependent on neural interactions. In the intact stellate ganglion, hypoxia alone induced a 1.5-fold increase in the density of neuronal cell bodies immunostained for vasoactive intestinal peptide. Thus, ganglia-specific factors appeared to play a role in determining changes in neuronal phenotype in response to hypoxia. The present study provides evidence for the involvement of dopamine and vasoactive intestinal peptide in ganglionic responses to long-term hypoxia as well as for differential responses by the two ganglionic cell populations, i.e. neuronal cell bodies and small intensely fluorescent cells. Changes in the expression of the vasoactive intestinal peptide during long-term hypoxia may be of energetic, trophic and/or synaptic significance. Hypoxia may be considered to be a vasoactive intestinal peptide-inducing factor in sympathetic ganglia.

Plasticity of tyrosine hydroxylase gene expression in the rat nucleus tractus solitarius after ventilatory acclimatization to hypoxia.

The aim of this study was to define the influence of long-term hypoxia on gene expression of tyrosine hydroxylase (TH) in the rat nucleus tractus solitarius (NTS). Animals were exposed to normobaric hypoxia (10% O2 in nitrogen) for 2 weeks. At this time, the hypoxia-induced hyperventilation reached a plateau, indicating ventilatory acclimatization. In horizontal brainstem sections, hypoxia-induced changes in TH protein and TH mRNA were assessed by immunocytochemistry and in-situ hybridization, respectively. Long-term hypoxia increased TH mRNA levels seen as both an increase in the number of grains per cell and an extension of the labeled area. The highest degree of labeling was found selectively located in caudal NTS. Hypoxia also enhanced TH immunoreactivity in the caudal NTS but this labeling extended more rostrally than that of TH mRNA. The data suggest that there is an hypoxia-induced plasticity of gene expression at the gene level in the NTS, which is associated with ventilatory acclimatization. The hypoxia model described in this study may serve as a framework for future regulatory studies.

Free and conjugated 3-methoxy-4-hydroxyphenylglycol in human urine: peripheral origin of glucuronide.

The aim of our study was to investigate the endogenous origin of the three forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) present in human urine and to further examine the hypothesis of an independent (peripheral or central) origin of glucuronide and sulfate conjugates. The urinary levels of free, sulfate, and glucuronide MHPG were determined in control subjects under normal conditions in relation to age, sex, and diet and in two experimental situations known to alter sympathetic activity. The mean daily excretion of total MHPG in a group of 14 men and 14 women was 1780 +/- 122 micrograms, with the free, sulfate, and the glucuronide representing 8% +/- 0.5%, 40% +/- 1.5%, and 52% +/- 1.6%, respectively. No influence of sex, age, or diet was observed on any form. Strong physical activity and anticipatory stress increased norepinephrine excretion and selectively increased MHPG glucuronide levels without changing the free or the sulfate excretion. We conclude that the total amounts of free, sulfate, and glucuronide MHPG found in urine originate from endogenous body pools with no interference of dietary components. The sympathetic nervous system seems to be the main source of glucuronide and arguments are given supporting the central origin of sulfate.

Relationships between catecholamine or 3-methoxy 4-hydroxy phenylglycol changes and the mental performance under submaximal exercise in man.

Eleven young students were tested to determine the relationship between the improvement of mental performances observed under prolonged submaximal work and central or peripheral catecholamine changes. The subjects pedaled a bicycle ergometer for 1 h at a work load individually calculated to approximate 75% of maximal oxygen uptake. The mental test, consisting of 1-h sessions of time-limited word tests and arithmetical calculations, required a high degree of concentration (vigilance and short-term memory). Catecholamines [epinephrine (E), norepinephrine (NE), dopamine (DA)], metanephrine (MN), normetanephrine (NMN) and the glucuronide conjugate of 3-methoxy 4-hydroxyphenylglycol (MHPG) were assayed in urine to assess peripheral activity: E and MN as indexes of adrenomedullary secretion, NE, NMN and MHPG glucuronide as markers of NE metabolism in sympathetic nerves. Urinary MHPG sulfate was determined as a possible marker of central noradrenergic metabolism. When compared to the effect of single tests, the combination of prolonged submaximal work and mental task induced significant increases in MHPG sulfate and E + MN excretions. Both these increases were correlated each to one another and also correlated to the number of discriminated words. Altogether, the present data show that prolonged submaximal work under mental load activates catecholamine systems and suggest that a relationship exists between adrenomedullary activation and the improvement of mental performance. Based on literature data, the possible modulatory role of peripheral E on mental processes and central noradrenergic activity is discussed.

Differential effects of long-term hypoxia on norepinephrine turnover in brain stem cell groups.

The influence of long-term hypoxia on noradrenergic cell groups in the brain stem was assessed by estimating the changes in norepinephrine (NE) turnover in A1, A2 (subdivided into anterior and posterior parts), A5, and A6 groups in rats exposed to hypoxia (10% O2-90% N2) for 14 days. The NE turnover was decreased in A5 and A6 groups but failed to change significantly in A1. The NE turnover was increased in the posterior part of A2 and remained unaltered in the anterior part. In normoxic rats, the hypotensive drug dihydralazine induced a reverse effect, namely increased NE turnover in anterior A2 and no change in posterior A2. The neurochemical responses to hypoxia were abolished by transection of carotid sinus nerves. The results show that long-term hypoxia exerts differential effects on the noradrenergic cell groups located in the brain stem. Peripheral chemosensory inputs control the hypoxia-induced noradrenergic alterations. The A2 cell group displays a functional subdivision: the posterior part is influenced by peripheral chemosensory inputs, whereas the anterior part may be concerned with barosensitivity.

Free dopamine in dog plasma: lack of relationship with sympathoadrenal activity.

To investigate the relationship between dopamine (DA) released into the bloodstream and sympathoadrenal activity, levels of free DA, norepinephrine (NE), and epinephrine (E) in plasma were recorded in four dogs subjected to three tests: treadmill exercise at two work levels [55 and 75% maximal O2 uptake; 15 min], normobaric hypoxia (12% O2; 1 h), combined exercise and hypoxia. Normoxic exercise induced slight nonsignificant decreases in the arterial partial pressure of O2 (PaO2), increases in NE [median values and ranges during submaximal work vs. rest: 1086 (457-1,637) vs. 360 (221-646) pg/ml; P less than 0.01] and E [277 (151-461) vs. 166 (95-257) pg/ml; P less than 0.05], but it failed to alter the DA level. Hypoxia elicited large decreases in PaO2 [hypoxia vs. normoxia: 42.8 (40.3-50.0) vs. 97.6 (83.2-117.6) Torr; P less than 0.01], increases in DA [230 (105-352) vs. 150 (85-229) pg/ml; P less than 0.01] and NE [383 (219-1,165) vs. 358 (210-784) pg/ml; P less than 0.05], but it failed to alter the E level. Combined exercise and hypoxia further increased NE levels but did not alter the DA response to hypoxia alone. The data indicate that free DA in plasma may vary independently of the sympathoadrenal activity.

Adrenal response to long-term hypoxia is still increased after carotid body denervation in rat.

This study investigated the effects of long-term normobaric hypoxia (10% O2 in N2 for 2, 7, 14, and 28 days) on the metabolism of catecholamines in rat adrenals and the role of the carotid body chemoreceptors in the adrenal response. The content and utilization of dopamine were significantly increased from the 7th day of hypoxia and remained enhanced thereafter. The content of norepinephrine and epinephrine decreased after 2 days of hypoxia and increased thereafter; after 28 days of hypoxia the norepinephrine amounts remained enhanced but the epinephrine levels were no longer significantly increased. In vivo tyrosine hydroxylation increased after 7 days of hypoxia. Bilateral transection of the carotid sinus nerve 1 wk before hypoxia failed to abolish the increase in the content and utilization of dopamine after 7, 14, or 21 days of hypoxic exposure. These results indicate that long-term normobaric hypoxia elicits a long-lasting increase in the metabolism of catecholamines in adrenals, especially as assessed by dopamine measurement, and that this response does not involve a carotid body chemoreflex pathway.

Inhibitory effect of almitrine on dopaminergic activity of rat carotid body.

Almitrine increases ventilation by stimulating the peripheral arterial chemoreceptors. This study assessed the effects of acute and chronic almitrine treatments on the dopamine (DA) and norepinephrine (NE) contents and utilization rates in the rat carotid body. Almitrine (5 mg/kg ip) caused a 34% reduction in DA content after 30 min. Extending the almitrine treatment for 15 days (one daily ip injection) produced a further progressive diminution in DA stores (-55%; P less than 0.01). The utilization rate of DA measured after inhibiting catecholamine biosynthesis by alpha-methyl-p-tyrosine was strongly reduced by almitrine (-98% after 15 days; P less than 0.01). The effects of almitrine were dose dependent. The noradrenergic activity was much less altered by the drug. The data showed that almitrine can modify the dynamics of DA in rat carotid body producing a decrease in both content and utilization rate.

Glucose administration before exercise modulates catecholaminergic responses in glycogen-depleted subjects.

In glycogen-depleted subjects (GD) a nonlinear increase in epinephrine (Epi) and norepinephrine (NE) parallels blood lactate (La) during graded exercise. The effect of glucose (Glc) supplementation and route of administration on these relationships was studied in 26 GD athletes who were randomly assigned to receive 1.3 g/kg Glc by slow intravenous infusion (IV; n = 9), oral administration (PO; n = 9), or artificially sweetened placebo in 1 liter of water (Asp; n = 8) in the 2 h preceding a graded maximal exercise. Performance and La were similar among the three groups in normal glycogen (NG) or GD conditions. However, slightly improved performances were observed in GD compared with NG and were associated with a shift to the right in La curves. Blood Glc concentrations were higher in IV and PO before exercise, but they rapidly decreased to lowest levels in IV, gradually decreased over time in PO, and remained stable in Asp or NG. Insulin concentrations were highest in IV and lowest in Asp and NG at onset of exercise, rapidly decreasing in IV and PO although remaining at higher levels than in Asp or NG. In contrast, higher serum levels of free fatty acids were measured during exercise in Asp with no significant differences in glucagon or glycerol among the three groups. Free and sulfated NE increases were smaller in IV than in PO and Asp on exhaustion. In contrast, free and conjugated Epi were most increased in IV, with smallest increases in Asp. Dopamine levels were most increased in IV at exhaustion. We conclude that the changes of Epi and NE concentrations, associated with the activation of glucoregulatory mechanisms, including hyperinsulinemia, display different magnitude and time courses during exercise in GD subjects who receive oral vs. intravenous load of Glc before exercise. We speculate that the magnitude of insulin surge after acutely increased Glc before exercise in GD subjects may exert dissociative effects on adrenal-dependent glycogenolysis and on sympathetic responses.

Epinephrine, norepinephrine, and dopamine during a 4-day head-down bed rest.

Head-down bed rest at an angle of 6 degrees was used as an experimental model to simulate the hemodynamic effects of microgravity, i.e., the shift of fluids from the lower to the upper part of the body. The sympathoadrenal activity during acute (from 0.5 to 10 h) and prolonged (4 days) head-down bed rest was assessed in eight healthy men (24 +/- 1 yr) by measuring epinephrine (E), norepinephrine (NE), dopamine (DA), and methoxylated metabolite levels in their plasma and urine. Catecholamine (CA) and methoxyamine levels were essentially unaltered at any time of bed rest. Maximal changes in plasma were on the second day (D2): NE, 547 +/- 84 vs. 384 +/- 55 pg/ml; DA, 192 +/- 32 vs. 141 +/- 16 pg/ml; NS. After 24 h of bed rest, heart rate decreased from 71 +/- 1 to 63 +/- 3/min (P less than 0.01). Daily dynamic leg exercise [50% maximum O2 uptake (VO2 max)] used as a countermeasure did not alter the pattern of plasma CA during bed rest but resulted in a higher urinary NE excretion during postexercise recovery (+45% on D2; P less than 0.05). The data indicate no evident relationship between sympathoadrenal function and stimulation of cardiopulmonary receptors or neuroendocrine changes induced by central hypervolemia during head-down bed rest.

Effects of hypoxia on carotid body dopamine content and release in developing rabbits.

Hypoxia induces dopamine (DA) release from the carotid body (CB), but the role of DA during hypoxia in the postnatal maturation of carotid chemosensory discharge remains controversial. The aim of this study was to evaluate changes in CB content and release of DA evoked by hypoxia at different stages of development in the rabbit. Five groups of rabbits aged < or = 24 h (n = 9), 5 days (n = 27), 15 days (n = 18), 25 days (n = 16), and > or = 1 yr (n = 11) were studied. CBs were surgically removed and immediately incubated at 37 degrees C for 1 h in a surviving medium equilibrated with 100% O2 or 8% O2 in N2. The content of DA in the CB ([DA]CB) and the DA released in the surviving medium ([DA]r) were measured by high-performance liquid chromatography. [DA]CB was significantly larger in adults than in all pup groups in both 100% O2 [385.5 +/- 74.1 (SE) pmol/CB in adults and 43.6 +/- 6.0 pmol/CB in pups; P < 0.01] and hypoxia (518.1 +/- 99.9 pmol/CB in adults and 24.7 +/- 3.2 pmol/CB in pups; P < 0.01), presumably because of the larger CB mass. [DA]r was significantly larger in hypoxia than in 100% O2 only in 25-day-old rabbits (19.8 +/- 4.2 and 3.6 +/- 1.1 pmol/h, respectively; P < 0.01) and in adults (183.9 +/- 57.7 and 7.9 +/- 1.7 pmol/h, respectively; P < 0.01). The average ratio of [DA]r in hypoxia to [DA]r in 100% O2 ranged from 1.3 to 2.2 in the three younger age groups and was 5.5 and 23.3 in 25-day-old and adult rabbits, respectively. We conclude that the release of DA evoked by hypoxia is weak at birth and develops during the first weeks of life in rabbits.

Regional specificity of the long-term regulation of tyrosine hydroxylase in some catecholaminergic rat brainstem areas. I. Influence of long-term hypoxia.

The present study was carried out to investigate the influence of long-term hypoxia on tyrosine hydroxylase (TH) protein quantity in some catecholaminergic rat brainstem areas such as the dorsomedial medulla (DMM), the ventrolateral medulla (VLM) and the locus coeruleus (LC). TH protein quantity was also measured in a dopaminergic structure, the substantia nigra (SN). Male Sprague-Dawley rats were exposed to normobaric hypoxia (10% O2/90% N2) for 3, 7, 14 or 22 days. Controls were kept in normoxia for the same period. This study demonstrates that: (1) 3 days of hypoxia produced a 50% and a 26% increase in the quantity of TH protein in the rostral and caudal LC, respectively; (2) 14 days of hypoxia produced a 44% increase of TH protein content exclusively in the caudal part of DMM and a 31% increase in the VLM area; and (3) the stimulus failed to alter the TH protein quantity in the SN. After 14 and 22 days of hypoxia respectively, the TH protein content in the LC and DMM returned to the level of controls. To determine whether the increase in TH protein quantity could be related to a change in norepinephrine (NE) content, the rate constant of disappearance (k) of NE was measured in the catecholaminergic areas of intact or chemodenervated rats submitted to long-term hypoxia. Our results show that hypoxia causes an increase of TH protein quantity within the subpopulations of catecholaminergic areas additionally with an elevation in the NE content. These data suggest a selective response of the TH regulation to long-term hypoxia within the caudal DMM catecholaminergic area which receives chemosensory inputs.

Regional specificity of long-term regulation of tyrosine hydroxylase in some catecholaminergic rat brainstem areas. II. Effect of a chronic dihydralazine treatment.

Dihydralazine, which is used in the treatment of hypertension, causes a long-lasting hypotensive action by a direct vasodilator effect on arteriolar smooth muscle. The present study was carried out to investigate the effect of a daily single injection of dihydralazine (20 mg/kg, s.c.) for 14 days on the tyrosine hydroxylase (TH) protein quantity in some catecholaminergic rat brainstem areas such as the dorsomedial medulla (DMM), the ventrolateral medulla (VLM) and the locus coeruleus (LC). This study demonstrates that the dihydralazine produced (1) an 85% increase in TH protein quantity exclusively in the rostral part of DMM, (2) a 58% increase of TH protein content exclusively in the rostral part of the LC, and (3) a 37% increase of the TH protein quantity in VLM catecholaminergic area. To determine whether the increase in TH protein quantity could be related to a change in norepinephrine (NE) content, the rate constant of disappearance (k) of NE was measured in the catecholaminergic regions of the same rats treated with dihydralazine. Our results show that dihydralazine causes an increase of the TH protein, in addition to an elevation of NE content, within the subpopulations of catecholaminergic structures. These data suggest a selective response of the TH regulation to dihydralazine within the rostral DMM area which receives barosensory inputs.

Activity of tryptophan hydroxylase and content of indolamines in discrete brain regions after a long-term hypoxic exposure in the rat.

The influence of long-term hypoxia (10% O2, 14 days) on in vivo activity of tryptophan hydroxylase and on 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentration in discrete brain regions of rats was assessed. The activity of tryptophan hydroxylase was determined through 5-hydroxytryptophan accumulation (5-HTPacc) following the administration of NSD 1015. The 5-HTPacc was significantly decreased in the dorsal and median raphe (56 and 42%, respectively) and in the striatum (62%). Both 5-HTPacc and the ratio of the concentrations of 5-HIAA to 5-HT were decreased in the nucleus raphe magnus (46 and 27%, respectively), the dorsomedian medulla oblongata (52 and 51%), the locus coeruleus (62 and 40%) and the anterior hypothalamic nucleus (30 and 50%). In contrast, 5-HTPacc was increased in the ventrolateral medulla oblongata (55%) and the preoptic area (83%), but the 5-HIAA/5-HT ratio was lower in these two regions. Finally, 5-HIAA/5-HT ratio was also decreased in the periventricular nucleus and in the frontal cortex. Since various patterns of variations in 5-HTPacc and in 5-HIAA/5-HT ratio were observed, the factors affecting serotonin metabolism in hypoxic rats can be different among brain regions. These results show that, in the rat, long-term hypoxia induces changes in in vivo activity of tryptophan hydroxylase and in 5-HT and 5-HIAA content of some brain structures; some of these biochemical changes may be linked to adaptative mechanisms.

Alteration in central and peripheral substance P- and neuropeptide Y-like immunoreactivity after chronic hypoxia in the rat.

The influence of long-term hypoxia on substance P (SP) and neuropeptide Y (NPY)-like immunoreactivity (LI) in discrete brain areas and peripheral structures was assessed by radioimmunoassay. Rats were exposed to normobaric hypoxia (10% O2 in nitrogen) for 14 days. In the carotid bodies of hypoxic animals, NPY-LI was significantly increased (56% vs. normoxic controls) while SP-LI was unchanged. In the brain, NPY-LI was increased in the ventrolateral medulla oblongata (23%) and in the striatum (53%); however, SP-LI was unaltered in these two regions. In the anterior pituitary, NPY-LI was increased (99%), while SP-LI was decreased (37%). No significant alteration in NPY-LI and SP-LI was observed in other discrete brain areas or peripheral structures studied. These results show that, in the rat, long-term hypoxia induces changes in NPY-LI or SP-LI in a few central and peripheral structures; these biochemical alterations may be linked to adaptative mechanisms involving morphological changes in carotid bodies or alterations in sympathetic control and neuroendocrine function.