Dopamine transporters are involved in the onset of hypoxia-induced dopamine efflux in striatum as revealed by in vivo microdialysis.

Although many studies have revealed alterations in neurotransmission during ischaemia, few works have been devoted to the neurochemical effects of mild hypoxia, a situation encountered during life in altitude or in several pathologies. In that context, the present work was undertaken to determine the in vivo mechanisms underlying the striatal dopamine efflux induced by mild hypoxaemic hypoxia. For that purpose, the extracellular concentrations of dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid were simultaneously measured using brain microdialysis during acute hypoxic exposure (10% O(2), 1h) in awake rats. Hypoxia induced a +80% increase in dopamine. Application of the dopamine transporters inhibitor, nomifensine (10 microM), just before the hypoxia prevented the rise in dopamine during the early part of hypoxia; in contrast the application of nomifensine after the beginning of hypoxia, failed to alter the increase in dopamine. Application of the voltage-dependent Na(+) channel blocker tetrodotoxin abolished the increase in dopamine, whether administered just before or after the beginning of hypoxia. These data show that the neurochemical mechanisms of the dopamine efflux may change over the course of the hypoxic exposure, dopamine transporters being involved only at the beginning of hypoxia.

Central and peripheral changes in catecholamine biosynthesis and turnover in rats after a short period of ozone exposure.

We investigated in rat the effects of ozone exposure (0.7 ppm) for 5 h on the catecholamine biosynthesis and turnover in sympathetic efferents and various brain areas. For this purpose, the activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, was assessed in superior cervical ganglia and in two major noradrenergic cell groups, A2 and A6 (locus coeruleus). Tyrosine hydroxylase activity was estimated in vivo by measuring the accumulation of l-dihydroxyphenylalanine after pharmacological blockade of L-aromatic acid decarboxylases by NSD-1015 (100 mg/kg i.p.). The catecholamine turnover rate was measured after inhibition of tyrosine hydroxylase by alpha-methyl-para-tyrosine (AMPT, 250 mg/kg, i.p., 2.5 h) in peripheral sympathetic target organ (heart and lungs) as well as in some brain catecholamine terminal areas (cerebral cortex, hypothalamus and striatum). Ozone caused differential effects according to the structure. Catecholamine biosynthesis was stimulated in superior cervical ganglia (+44%, P < 0.05) and caudal A2 subset (+126%, P < 0.01), whereas catecholamine turnover was increased in heart (+183%, P < 0.01) and cortex (+22%, P < 0.05). On the other hand, catecholamine turnover was inhibited in lungs (-53%, P < 0.05) and striatum (-24%, P < 0.05). A brief exposure to ozone, at a concentration chosen to mimic pollution level encountered in urban areas, can modulate catecholamine biosynthesis and utilization rate in the sympathetic and central neurones.

Hormonal profile heterogeneity and short-term physical risk in restrictive anorexia nervosa.

CONTEXT: The relevance of hormonal assessment in anorexia nervosa (AN) management is still unclear. The short-term physical risk during undernutrition period of the disease is partially predicted by anthropometric and electrolytic parameters. OBJECTIVE: The objective of the study was to evaluate hormonal profiles in a large cohort of AN and their relationship with critical states. DESIGN AND SETTING: This was an observational monocentric cross-sectional study performed in the endocrinological unit. PATIENTS AND OTHER PARTICIPANTS: Participants included 210 young female subjects with restrictive-type AN and 42 female controls of comparable age. MAIN OUTCOME MEASURES: The following hormonal parameters were measured: thyroid hormones, GH, IGF-I, cortisol, oestradiol, FSH, LH, SHBG, dehydroepiandrosterone sulfate, plasma metanephrines, and bone markers. Their relation with registered short-term evolution of AN subjects after hormonal assessment was evaluated. RESULTS: Except for metanephrines and dehydroepiandrosterone sulfate, most of the hormonal abnormalities previously reported in AN were confirmed. The manifestation of these hormonal abnormalities started below different body mass index (BMI) levels, ranging between 17 and 15 kg/m(2), even though an important percentage of normal values for every parameter was still noticed for very low BMIs. All patients who developed critical states during the 3 months after the hormonal assessment presented with BMI less than 15 kg/m(2) and a very increased level of cortisol, GH, and increased values of metanephrines. CONCLUSIONS: The hormonal response to undernutrition is heterogeneous in a large population with restrictive AN. In clinical practice, metanephrines, GH, and/or cortisol data could be used as important predictors for severe short-term outcome.

Folate deficiency alters melatonin secretion in rats.

The final step of melatonin (MLT) synthesis is methylation of N-acetyl-serotonin, with S-adenosylmethionine as a methyl donor provided by a metabolic pathway involving sulfur-containing amino acids (homocysteine and methionine). Remethylation of homocysteine to methionine requires folate. The present study was undertaken to test the influence of folate deficiency on MLT secretion. Severe folate deficiency was induced in rats by feeding them a synthetic diet containing (per kg diet) 0 mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, erythrocyte folate concentrations were significantly lower and plasma homocysteine levels were greater in folate-deficient rats than in controls. Pineal MLT concentration and urinary excretions of MLT, 6 sulfatoxymelatonin (the main hepatic MLT metabolite) and methoxylated catechol compounds were lower in the folate-deficient group than in the controls, whereas plasma catecholamine concentrations did not differ. Decreases generally were more marked at wk 2 than at wk 4 for the urinary metabolite excretions. These findings indicate that folate deficiency dramatically alters MLT secretion in rats.

Metabolic characteristics and body composition in a model of anti-obese rats (Lou/C).

OBJECTIVE: The aims of this study were to investigate some features of the metabolic profile and the body composition of male Lou/C rats and to examine whether these characteristics are strictly related to the food-intake reduction. RESEARCH METHODS AND PROCEDURES: Fourteen-week-old male Lou/C rats were compared with age-matched male Wistar rats fed ad libitum (WAL) and another group of male Wistar rats whose food was chronically restricted (WFR) to the same amount as the Lou/C rats from weeks 3 to 14. RESULTS: Food intake and body weight were significantly (p < 0.01) reduced in Lou/C compared with WAL rats, whereas these reductions were perfectly reproduced in WFR rats. Lou/C rats demonstrated lower relative weights of retroperitoneal (0.97 +/- 0.07 vs. 1.67 +/- 0.16 and 1.88 +/- 0.15 g/100 g body) and epididymal (1.01 +/- 0.02 vs. 1.62 +/- 0.12 and 1.80 +/- 0.11 g/100g body) fat depots than did the two other groups and no decrease in the percentage of carcass proteins, which was observed in the WFR rats. In addition, compared with the WFR group, the Lou/C rats showed lower plasma glucose levels (3.65 +/- 0.14 vs. 4.72 +/- 0.15 and 4.7 +/- 0.19 mM); a tendency (p < 0.1) for lower liver glycogen concentrations; and similar levels of glycerol, free fatty acids, and beta-hydroxybutyrate concentrations. Epinephrine and the relative weight of the adrenal glands were significantly (p < 0.01) lower in the Lou/C rats than in the WAL rats and the two other groups, respectively. DISCUSSION: The ability of the Lou/C rats to accumulate less body fat than their equally food-restricted Wistar counterparts (WFR) suggests a difference in basal metabolism in this strain of rats that resembles obesity-resistant rats.

Delayed maturation of catecholamine phenotype in nucleus tractus solitarius of rats with glial angiotensinogen depletion.

Cerebral catecholamines and angiotensins are both involved in the regulation of cardiovascular function. Recent in vitro studies have suggested that angiotensin II modulates noradrenergic neurotransmission by controlling both the expression and neuritic trafficking of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. To assess the potential existence of such mechanisms in vivo, we compared TH phenotype ontogeny in the nucleus tractus solitarius (NTS), which is the first central relay of the baroreflex, between control Sprague-Dawley rats and TGR(ASrAOGEN) rats (TG) with glial specific angiotensinogen (AOGEN) depletion. TG displayed a delayed increase in both TH-mRNA and TH protein levels, which sharply rises in the NTS of control rats within the fourth week. The delayed maturation of TH phenotype also affected the presence of TH protein in the neuropil, not only within the NTS region but also within the ventrolateral medulla. This was evidenced by a large decrease in the density of TH-containing neuronal processes in TG at 4 weeks only, without noticeable modification of the labeling of the neuritic marker MAP2, suggesting that neuritic trafficking of TH protein was transiently altered. These results indicate that glial AOGEN is crucial to coordinate within the fourth week the mechanisms driving the maturation of NTS catecholaminergic neurons and suggest that impairment of the central angiotensinergic system early in development can lead to cardiovascular dysfunction related to altered maturation of catecholaminergic neurons located in both the dorsal and the ventrolateral medulla.

Control of erythropoiesis after high altitude acclimatization.

Erythropoiesis was studied in 11 subjects submitted to a 4-h hypoxia (HH) in a hypobaric chamber (4,500 m, barometric pressure 58.9 kPa) both before and after a 3-week sojourn in the Andes. On return to sea level, increased red blood cells (+3.27%), packed cell volume (+4.76%), haemoglobin (+6.55%) ( P<0.05), and increased arterial partial pressure of oxygen (+8.56%), arterial oxygen saturation (+7.40%) and arterial oxygen blood content ( C(a)O(2)) (+12.93%) at the end of HH ( P<0.05) attested high altitude acclimatization. Reticulocytes increased during HH after the sojourn only (+36.8% vs +17.9%, P<0.01) indicating a probable higher reticulocyte release and/or production despite decreased serum erythropoietin (EPO) concentrations (-46%, P<0.01). Hormones (thyroid, catecholamines and cortisol), iron status (serum iron, ferritin, transferrin and haptoglobin) and renal function (creatinine, renal, osmolar and free-water clearances) did not significantly vary (except for lower thyroid stimulating hormone at sea level, P<0.01). Levels of 2,3-diphosphoglycerate (2,3-DPG) increased throughout HH on return (+14.7%, P<0.05) and an inverse linear relationship was found between 2,3-DPG and EPO at the end of HH after the sojourn only ( r=-0.66, P<0.03). Inverse linear relationships were also found between C(a)O(2) and EPO at the end of HH before ( r=-0.63, P<0.05) and after the sojourn ( r=-0.60, P=0.05) with identical slopes but different ordinates at the origin, suggesting that the sensitivity but not the gain of the EPO response to hypoxia was modified by altitude acclimatization. Higher 2,3-DPG levels could partly explain this decreased sensitivity of the EPO response to hypoxia. In conclusion, we show that altitude acclimatization modifies the control of erythropoiesis not only at sea level, but also during a subsequent hypoxia.

Prolonged daytime exercise repeated over 4 days increases sleeping heart rate and metabolic rate.

The aim of this study was to determine the influence of prolonged exercise repeated for 4 days on sleeping heart rate (SHR) and metabolic rate (SMR). Eleven young untrained men exercised at moderate intensity 5 hrs daily for 4 days, alternately on a cycle ergometer (57.0 +/- 1.3% .VO2max) and a treadmill (64.7 +/- 1.6% .VO2max). They spent the night prior to the exercise period (control, C) and the 4 nights following exercise days (N1 to N4) in room calorimeters for the measurement of SHR, SMR, and respiratory quotient (RQ) from midnight until 6 a.m. Every morning, before the exercise bouts, plasma-free epinephrine (E) and norepinephrine (NE) levels were measured. After exercise, all SHR values were significantly higher than at C level (52 +/- 1 bpm, p < 0.001) and the highest value was observed on N2 (61 +/- 2 bpm). SMR increased by 11.2 +/- 1.5% from C to N1, p < 0.001, and then plateaued up to N4, whereas RQ decreased from C (0.833 +/- 0.009) to N2 (0.798 +/- 0.005) and then plateaued. Plasma NE levels were higher the morning after each day of exercise and peaked on N2, whereas no significant variations were found for E. Variations of SHR between C and N2, and N3 and N4 were correlated with changes of SMR. No significant relationships were found between morning plasma NE, and either SMR or SHR variations. To conclude, prolonged exercise repeated for 4 days was associated with increases in SHR and SMR during the night following each day of exercise concomitantly with an enhanced lipid oxidation. The sustained stimulation of the sympathetic nervous system may be partly responsible for these effects.

Long-term prenatal hypoxia alters maturation of adrenal medulla in rat.

Catecholamine release from the adrenal medulla glands plays a vital role in postnatal adaptation. A number of pathologic situations are characterized by oxygen deficiency. The objective of the present study was to determine the influence of long-term prenatal hypoxia on maturation of the adrenal medulla. Pregnant rats were subjected to hypoxia (10% O2) from the fifth to the 20th d of gestation. The offspring were examined on the 19th d of gestation (E19), the day of birth (P0), and at postnatal (P) day of life P3, P7, P14, P21, and P68. The catecholamine content and activity of tyrosine hydroxylase (TH) in vivo were assayed by HPLC with electrochemical detection. Cellular expression of TH and phenylethanolamine N-methyl transferase was evaluated by protein immunohistochemistry and in situ hybridization of the corresponding mRNA species. Exposure to prenatal hypoxia reduced the epinephrine content of the adrenal medulla on E19, P0, P3, and P7 while increasing the norepinephrine content on E19, P0, and P14. Furthermore, the peak epinephrine to norepinephrine ratio appearing between P7 and P10 in the normoxic offspring was absent in the hypoxic offspring. The in vivo TH activity was increased on P3 and P14 and decreased on P68. The percentage of chromaffin cells in the medulla expressing TH and phenylethanolamine N-methyl transferase was lowered on E19, P0, and P7. TH and phenylethanolamine N-methyl transferase mRNA levels were reduced on P7. Clearly prenatal hypoxia results in major changes in adrenal catecholamine stores and synthesis during the perinatal period, which persist into adulthood. The capacity to cope with postnatal stress might be disturbed as a consequence of prenatal hypoxia.