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Biomedical subjects

Vincent Joseph

Publications and source records attributed to Vincent Joseph.

11 recordsLinked to original sources

Progesterone increases hypoxic ventilatory response and reduces apneas in newborn rats.

We hypothesized that progesterone may enhance the hypoxic ventilatory response and reduce the occurrence of apneas in newborn male rats. We studied 10-day-old rats chronically exposed to progesterone (Prog) or vehicle through the milk of lactating mothers. Respiratory and metabolic recordings were performed using whole body plethysmography under normoxia and during hypoxic exposure (10% O(2)--30 min). While progesterone did not alter baseline breathing and metabolic rate, it increased hypoxic ventilatory response particularly by limiting the magnitude of the ventilatory roll-off during the second phase of the hypoxic ventilatory response (i.e. following 5 min of exposure). In parallel, progesterone lowered the number of spontaneous apneas and drastically reduced the occurrence of post-sigh apneas during hypoxic exposure by limiting the time of the post-sigh expiratory pause. Following domperidone injection (used to block peripheral D2 dopamine receptor), minute ventilation increased in Veh pups and the number of spontaneous apneas decreased. These responses were not observed in Prog pups, suggesting that progesterone reduces peripheral dopaminergic inhibition on breathing. We conclude that progesterone is a potent stimulant of hypoxic ventilatory response in newborn rats and effectively reduces the occurrence of apneas.

Animals↗

Expression of sex-steroid receptors and steroidogenic enzymes in the carotid body of adult and newborn male rats.

This study describes the localization and pattern of expression of estradiol and progesterone receptors as well as key enzymes for steroid synthesis (i.e. P450 side-chain-cleavage--P450scc, and P450 aromatase--P450Aro) in the carotid body (CB) and superior cervical ganglion (SCG) of adult, newborn and late fetal male rats, using immunohistochemistry, Western blot and real-time RT-PCR. Our results show a constitutive expression of the beta estradiol receptor (Erbeta) and the 80 kDa and 60 kDa progesterone receptors (PR-A and PR-C) isoforms in the CB, while in the SCG Eralpha, Erbeta, PR-A and PR-C are expressed. While P450Aro staining was negative, P450scc staining was strong both in the SCG and CB. In late fetal and newborn rats, Eralpha was not detected in the CB or SCG, but a slight staining appeared for P450 aromatase in the CB, and to a lesser extent in SCG. P450scc was strongly expressed in CB and SCG of late fetal and newborn rats. We conclude that the carotid body shows a constitutive expression of Erbeta and PR and may be able to synthesize steroids, including estradiol during late fetal life.

Age Factors↗

Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies.

Apart from its role in elevating red blood cell number, erythropoietin (Epo) exerts protective functions in brain, retina and heart upon ischaemic injury. However, the physiological non-erythroid functions of Epo remain unclear. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate Epo's impact on ventilation upon hypoxic exposure. Tg21 mice showed improved ventilatory response to severe acute hypoxia and moreover improved ventilatory acclimatization to chronic hypoxic exposure. Furthermore, following bilateral transection of carotid sinus nerves that uncouples the brain from the carotid body, Tg21 mice adapted their ventilation to acute severe hypoxia while chemodenervated wild-type (WT) animals developed a life-threatening apnoea. These results imply that Epo in brain modulates ventilation. Additional analysis revealed that the Epo receptor (EpoR) is expressed in the main brainstem respiratory centres and suggested that Epo stimulates breathing control by alteration of catecholaminergic metabolism in brainstem. The modulation of hypoxic pattern of ventilation after i.v. injection of recombinant human Epo in WT mice and the dense EpoR immunosignal observed in carotid bodies showed that these chemoreceptors are sensitive to plasma levels of Epo. In summary, our results suggest that Epo controls ventilation at the central (brainstem) and peripheral (carotid body) levels. These novel findings are relevant to understanding better respiratory disorders including those occurring at high altitude.

Adaptation, Physiological↗

Activation of NMDA receptors prevents excessive metabolic decrease in hypoxic rat pups.

We tested the hypothesis that glutamate NMDA receptors may help maintain metabolic rate and body temperature during acute or chronic hypoxic exposure in newborn rats. We recorded ventilation, metabolism ((.)V(O(2)) -- ((.)V(CO(2)) and rectal temperature, under normoxia, acute hypoxia (30 min -- 12% O(2)), or following 10 days of chronic hypoxia, in 10 days old male and female rats, receiving saline i.p. injection or the NMDA receptor antagonist MK-801. Acute hypoxia decreased rectal temperature and metabolism, and increased ventilation, and (.)V(E)/((.)V(O(2) and (.)V(E)/((.)V(CO(2) to the same extent in males and females. MK-801 injection amplified the metabolic decrease under acute (in males and females) and chronic (in males) hypoxia, prevented the increase of minute ventilation, while (.)V(E)/((.)V(O(2) or (.)V(E)/((.)V(CO(2)remained constant. Hence, NMDA glutamate receptors help to maintain metabolic rate, minute ventilation and body temperature at a determined level in acute (males and females) and chronic hypoxia (males only).

Analysis of Variance↗

Neonatal maternal separation enhances dopamine D(2)-receptor and tyrosine hydroxylase mRNA expression levels in carotid body of rats.

Adult male (but not female) rats previously subjected to neonatal maternal separation (NMS) are hypertensive and show a significant increase (25%) in their hypoxic ventilatory response. To begin investigating the mechanisms involved in this gender-specific disruption in cardiorespiratory regulation, we tested the hypothesis that NMS alters the expression of dopamine D(2)-receptors and tyrosine hydroxylase mRNA in 3 peripheral organs involved in cardio respiratory regulation: the carotid bodies, superior cervical ganglia, and adrenals. Pups subjected to NMS were placed in a temperature- and humidity-controlled incubator 3 h per day for 10 consecutive days (P3-P12). Control pups were undisturbed. Once they reached adulthood (8-10 weeks), male and female rats were anesthetised. The carotid bodies, superior cervical ganglia, and adrenals were harvested for semi-quantitative analyses of dopamine D(2)-receptors and tyrosine hydroxylase mRNA expression using reverse transcription-polymerase chain reaction (carotid bodies only) and Northern blot. In the carotid bodies, comparison of densitometric analyses showed that NMS enhanced tyrosine hydroxylase mRNA expression in male, but not female, rats. Neonatal maternal separation increased dopamine D(2)-receptor mRNA expression also, but the effect was not gender specific. No changes in mRNA expression related to dopaminergic neurotransmission were observed in superior cervical ganglia or the adrenals. These results indicate that subsequent mechanistic investigations should focus on the carotid bodies, as enhancement of dopaminergic neurotransmission within this organ likely contributes to the gender-specific effects of NMS on cardiorespiratory regulation.

Adrenal Glands↗

Differential regulation of short and long dopamine D2 receptor mRNA levels by hypoxia in the adrenals of 1-day-old and adult rabbits.

We tested the hypothesis that hypoxic exposure exerts distinct modulation on the mRNA level of the short and long isoform of the D2 dopamine (DA) receptor (D(2)r) and on tyrosine hydroxylase (TH) in the adrenals and superior cervical ganglion (SCG) of 1-day-old and adult rabbits. One-day-old and adult rabbits have been exposed to moderate (FiO(2): 0.15) or severe (FiO(2): 0.08) hypoxia for 0 (control), 6 or 24 h. At the end of the hypoxic exposure, the adrenals and SCG were rapidly dissected and kept frozen. Standard procedure for Northern blot and RT-PCR for evaluation of the short (D(2S)) or long (D(2L)) isoform of D(2)r and TH have been used. In the adrenals of adult rabbits, moderate and severe hypoxia decreased the D(2S) and D(2L) mRNA with a more prominent effect on the short isoform and increased TH mRNA. In 1-day-old rabbits, changes of D(2)r and TH mRNA levels were observed only after 24 h of severe or moderate hypoxic exposure and only the D(2S) receptor mRNA was significantly reduced. In the SCG, the expression level of both TH and D(2)r mRNA were not affected by hypoxic exposure in adult and newborn rabbits. Hence, sustained hypoxic exposure exerts distinct changes on mRNA level of D(2)r isoform and TH in an age- and tissue-dependent pattern.

Adrenal Glands↗

Prenatal hypoxia impairs circadian synchronisation and response of the biological clock to light in adult rats.

The aim of this study was to test the hypothesis that prenatal hypoxia in rats might lead to consistent changes in the entrainment of the circadian clock by light. Pregnant female rats were placed in a chamber provided with hypoxic gas (10 % O2--90 % N2) at gestational day 5 and returned to normoxia before delivery. Once adult, rats born to hypoxic mothers had significant alterations in their circadian rhythm of locomotor activity (recorded in freely accessible running wheels). Under a regular 12/12 light/dark (LD) cycle, they showed a phase advance of their rhythm of activity (mean phase advance of 87 min) and were less active than control rats. After an abrupt 6 h phase delay in the LD cycle, rats from the prenatal hypoxic group (PNH) took significantly more time to resynchronise to the new LD cycle compared to controls (+53 %; 6.0 +/- 1.5 vs. 9.2 +/- 0.5 days respectively). Under constant darkness, PNH and control rats had a similar period of activity (24.27 +/- 0.20 vs. 24.40 +/- 0.13) but the response of PNH rats to a light pulse in the early subjective night was less marked than that of control rats (101 +/- 9 vs. 158 +/- 13 min). When submitted to acute restraint stress, PNH rats had a prolonged secretion of corticosterone compared to controls. These results indicate that prenatal hypoxia is a factor that has long lasting consequences for the functional output of the biological clock and the hormonal response to stress.

Age Factors↗

Neurochemical perspectives on the control of breathing during sleep.

A specific depression of minute ventilation occurs during sleep in normal subjects. This sleep-related ventilatory depression is partially related to mechanical events and upper airway atonia but some data also indicate that it is likely to be centrally mediated. This paper reviews the anatomical and neurochemical connections between sleep/wake- and respiratory-related areas in an attempt to identify the potential implication of sleep-related neurochemicals (serotonin, catecholamines, GABA, acetylcholine) in the sleep-related hypoventilation. The review of available data suggests that the sleep-related ventilatory depression depends upon the enhanced GABAergic activity together with a loss of suprapontine influence depending on the cessation of activity of the reticular formation. During REM sleep, an additional inhibitory activity emerges from the pontine cholinergic neurons, which contributes to the breathing irregularities and the associated depression of minute ventilation and ventilatory response to chemical stimuli. This model may contribute to a better understanding of the neurochemical environment of respiratory neurons during sleep, which remains a question of importance regarding the numerous pathological states that are linked to specific perturbations of breathing control during sleep.

Animals↗

Dopaminergic metabolism in carotid bodies and high-altitude acclimatization in female rats.

We tested the hypothesis that ovarian steroids stimulate breathing through a dopaminergic mechanism in the carotid bodies. In ovariectomized female rats raised at sea level, domperidone, a peripheral D2-receptor antagonist, increased ventilation in normoxia (minute ventilation = +55%) and acute hypoxia (+32%). This effect disappeared after 10 daily injections of ovarian steroids (progesterone + estradiol). At high altitude (3,600 m, Bolivian Institute for High-Altitude Biology-IBBA, La Paz, Bolivia), neutered females had higher carotid body tyrosine hydroxylase activity (the rate-limiting enzyme for catecholamine synthesis: +129%) and dopamine utilization (+150%), lower minute ventilation (-30%) and hypoxic ventilatory response (-57%), and higher hematocrit (+18%) and Hb concentration (+21%) than intact female rats. Consistent signs of arterial pulmonary hypertension (right ventricular hypertrophy) also appeared in ovariectomized females. None of these parameters was affected by gonadectomy in males. Our results show that ovarian steroids stimulate breathing by lowering a peripheral dopaminergic inhibitory drive. This process may partially explain the deacclimatization of postmenopausal women at high altitude.

Acclimatization↗