Modulation of respiration during brain hypoxia

Neubauer, Judith A.; Melton, J. E.; Edelman, Norman H.

doi:10.1152/jappl.1990.68.2.441

Cited by 252 publications

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“…In Phox2a mutants, despite the reported atrophia of cranial sensory ganglia , the respiratory response to peripheral hypoxia is preserved in three of four fetuses. Second, if the respiratory response to peripheral hypoxia fails to restore blood normoxia, central hypoxia develops and depresses the RRG (Eden and Hanson, 1987;Neubauer et al, 1990;Gauda and Lawson, 2000). This depression has been studied mainly in neonatal (Kawai et al, 1995;Kato et al, 2000;Thoby-Brisson and Ramirez, 2000) and fetal in vitro preparations .…”

Section: Possible Contribution Of A6 Neurons To Rrg Prenatal Maturationmentioning

confidence: 99%

Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice

Viemari¹,

Bévengut²,

Burnet³

et al. 2004

J. Neurosci.

102

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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 ␣1 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 ␣1 adrenoceptors in wild-type dams during late gestation with daily injections of the ␣1 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.Key words: prenatal maturation of the respiratory network; Phox2a gene; fetal mice; in vivo ventilation; in vitro respiratory activity of brainstem; spinal cord preparations; noradrenaline; A6 neurons

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Section: Possible Contribution Of A6 Neurons To Rrg Prenatal Maturationmentioning

confidence: 99%

Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice

Viemari¹,

Bévengut²,

Burnet³

et al. 2004

J. Neurosci.

102

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“…It is well known that systemic hypoxia-induced ventilatory responses contain two components in both anesthetized and conscious species, including rats, i.e., peripheral chemoreceptor-mediated excitation and central hypoxic depression (29). Therefore, DVH could be the results of diminishing the carotid chemoreceptor-mediated excitatory response and/or strengthening hypoxic central depression.…”

Section: Dvh In Ova Guinea Pigs Involves At Least Partially the Supmentioning

confidence: 99%

Ovalbumin sensitization alters the ventilatory responses to chemical challenges in guinea pigs

Zhuang²,

Zhou³

et al. 2005

Journal of Applied Physiology

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tients with chronic bronchial asthma show a depressed ventilatory response to hypoxia (DVH), but the underlying mechanism remains unclear. We tested whether DVH existed in ovalbumin (Ova)-treated guinea pigs, an established animal model of asthma. Twelve guinea pigs were exposed to Ova (1% in saline) or saline aerosol (control) for 5 min, 5 days/wk, for 2 wk. After completing aerosol exposure, the animals were anesthetized and exposed to systemic hypoxia. Ova treatment had no effects on animal body weight, baseline cardiorespiratory variables, or arterial blood O 2 and CO2 tensions, but it attenuated the ventilatory response to hypoxia (10 breaths of pure N 2) by 65% (P Ͻ 0.05). When the animals were subjected to intracarotid injections of sodium cyanide (20 g) and doxapram (2 mg) to selectively stimulate carotid chemoreceptors, the ventilatory responses were reduced by 50% (P Ͻ 0.05) and 74% (P Ͻ 0.05), respectively. In contrast, Ova exposure failed to affect the ventilatory response to CO 2 (7% CO2-21% O2-balance N2 for 5 min; P Ͼ 0.05). Furthermore, the apneic response evoked by stimulating bronchopulmonary C fibers (PCFs) with right atrial injection of capsaicin (5 g) was markedly increased in the Ova-sensitized group (5.02 Ϯ 1.56 s), compared with the control group (1.82 Ϯ 0.45 s; P Ͻ 0.05). These results suggest that Ova sensitization induces a DVH in guinea pigs, which probably results from an attenuation of the carotid chemoreceptor-mediated ventilatory excitation and an enhancement of the PCF-mediated ventilatory inhibition. carotid body; bronchopulmonary C fibers; hypoxia; capsaicin; inflammation RESPIRATORY FAILURE FROM ASTHMA is a common clinical symptom and a primary cause of high mortality. A study through a period of 7 yr indicated that 68% of asthmatic patients had two or more episodes of respiratory failure that led to an ϳ10% death rate (30). Ventilatory arrest in the near-fatal nature of the exacerbations is dominant compared with cardiac arrest (26). It is generally recognized that patients with chronic bronchial asthma have a depressed ventilatory response to hypoxia (DVH) that may contribute to the respiratory failure (4, 11, 14 -16, 21, 33, 38), although an absence (27) of DVH or an increase of ventilatory response to hypoxia (20) was also reported. Hudgel and Weil (14,15) first reported a severe DVH in asthmatic individuals in 1974. Subsequent studies confirmed this observation and further indicated that the amplitude of minute ventilation (V E) in response to progressive isocapnic hypoxia was significantly attenuated in both young and adult patients compared with age-matched normal subjects (4,11,16,21,33,38). A severely diminished hypoxic perception was also found in asthmatic patients; a typical example is that the patients who had asthma displayed cyanosis but had no dyspnea at all (21). This blunted hypoxic perception could impair the behavioral control of breathing and worsen hypoxemia by reducing ventilatory augmentation. To date, the pathophysiological mechanisms underlying DVH i...

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“…Accordingly, a pathological respiratory pattern and loss of rhythmic activity could be expected in the isolated brainstem-spinal cord preparation if respiratory neurons were under oxygen deprivation (cf. Neubauer et al 1990). …”

Section: Introductionmentioning

confidence: 99%

Microenvironment of respiratory neurons in the in vitro brainstem‐spinal cord of neonatal rats.

Brockhaus

Ballanyi

Smith

et al. 1993

The Journal of Physiology

127

128

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SUMMARY1. O2-,K+-and pH-sensitive microelectrodes were used to measure extracellular oxygen pressure (Po2), K' activity (aK.) and pH (pH.) in ventral regions of the medulla oblongata containing respiratory neurons in the in vitro brainstem-spinal cord preparation from 0 to 4-day-old rats.2. The location of respiratory neurons was mapped by extracellular recordings with conventional microelectrodes, or with the reference barrel of ion-sensitive microelectrodes. The major populations of respiratory neurons were distributed in the ventrolateral reticular formation near the nucleus ambiguus at depths of 300-600 ,um. In this area, aK. baseline increased from 3-2 to 3-8 mm whereas steadystate values of Po2 and pHo fell from 120 to 7 mmHg and from 6-9 to 6-7, respectively.3. During rhythmic inspiratory discharges recorded with suction electrodes from ventral roots of spinal (C3-C5) and cranial (IX, X, XII) nerves, aKo transiently increased by up to 100 /M, and Po2 fell maximally by 0 4 mmHg. During episodes of non-rhythmic neuronal discharge, aKo increased by as much as 0-4 mm and Po2 decreased by about 10 mmHg. In contrast, no variations in pHo could be detected during such activities.4. Activation of medullary neurons by tetanic electrical stimulation of axonal tracts in the ventrolateral column of the spinal cord at the level of the phrenic motoneuron pool produced aKo elevations of up to 5 mm, decreases of Po2 by up to 50 mmHg, and pHo increases by a maximum of 0 07 pH units. These aKo and Po2 transients were reduced by more than 80 % during blockade of synaptic transmission with 5 mm manganese (Mn2+) and completely blocked by 1 ,tm tetrodotoxin (TTX).5. The tissue Po2 gradient as well as activity-related decreases of P2 were completely abolished after block of oxidative cellular metabolism by addition of 2-10 mm cyanide (CN-) to the bathing solution.6. Inhibition of the Na+-K+ pump by addition of 3-50 /M ouabain (3-10 min)caused a reversible increase of aKo by 0-8-3 mm, a delayed recovery of stimulusinduced aKo elevations, and produced a disturbance of the respiratory rhythm.7. The sensitivity of the respiratory network to oxygen depletion was tested by superfusing the neuraxis with hypoxic solutions gassed with N2 instead of 02(5-20 min). The response of the respiratory network to such hypoxic exposure MS 9830 J. BROCKHA US AND OTHERS consisted of an initial increase in frequency of respiratory motor output, followed by a depression of respiratory activity that terminated in a reversible loss of the respiratory rhythm.8 10. It is concluded that the oxygen supply of the ventral respiratory network is sufficient to maintain aerobic neuronal metabolism and metabolically driven Na+-K+ pump activity which allows respiratory rhythmogenesis and network function in the in vitro neonatal rat brainstem-spinal cord preparation.

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Modulation of respiration during brain hypoxia

Cited by 252 publications

References 0 publications

Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice

Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice

Ovalbumin sensitization alters the ventilatory responses to chemical challenges in guinea pigs

Microenvironment of respiratory neurons in the in vitro brainstem‐spinal cord of neonatal rats.

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