Theophylline Stimulates Fetal Breathing Movements during Hypoxia

Bissonnette, John M.; Hohimer, Roger; Chao, Conrad R.; Knopp, Sharon J.; NOTOROBERTO, NEIL F.

doi:10.1203/00006450-199008000-00002

Cited by 34 publications

(12 citation statements)

References 7 publications

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“…Adenosine administration to the fetus inhibits breathing activity, a depression which is very similar to that produced by hypoxia (Koos & Matsuda, 1990). Theophylline significantly attentuates the inhibitory effects of hypoxia on breathing movements (Bissonnette, Hohimer, Chao, Knopp & Notoroberto, 1990;Koos & Matsuda, 1990), indicating that adenosine contributes to hypoxic inhibition of fetal breathing. Because 8-SPT poorly crosses the blood-brain barrier, the failure of 8-SPT to blunt hypoxic inhibition of breathing is consistent with a central site of action of adenosine relative to hypoxic inhibition.…”

Section: Discussionmentioning

confidence: 94%

Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Koos¹,

Chau²,

Ogunyemi³

1995

The Journal of Physiology

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1. In seven unanaesthetized fetal sheep (> 80% term), isocapnic hypoxia (arterial partial pressure of O2, Pa,O2, approximately 15 mmHg) was induced for 1 h by lowering maternal inspired PO2. Fetal hypoxia was also produced during intra‐arterial administration of the adenosine receptor antagonist 8‐(p‐sulphophenyl)‐theophylline (8‐SPT). The fetal 8‐SPT infusion was begun just prior to hypoxia and was stopped when fetal Pa,O2 was returned to normal. 2. Hypoxia induced a progressive fetal acidosis, a rise in mean arterial pressure, a transient fall in heart rate and a decrease in breathing movements. 8‐SPT significantly reduced the metabolic acidosis and abolished the hypertension and bradycardia without altering hypoxic inhibition of fetal breathing. Administration of the vehicle for 8‐SPT during hypoxia did not significantly affect the normal fetal metabolic and cardiovascular responses to acute O2 deprivation. 3. It is concluded that adenosine mediates the fetal bradycardia and hypertension produced by hypoxia, indicating that adenosine modulates fetal autonomic responses to acute oxygen deficiency. Secondly, adenosine contributes to fetal metabolic acidaemia, suggesting that adenosine also modulates fetal glycolytic responses to hypoxia.

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Section: Discussionmentioning

confidence: 94%

Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Koos¹,

Chau²,

Ogunyemi³

1995

The Journal of Physiology

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“…ATP signalling is best considered as a three‐part system whose effects are determined from a dynamic interaction between the signalling actions of ATP and ADP at P2Rs, the spatial distribution of ectonucleotidases that differentially metabolize ATP into ADP, AMP and adenosine (ADO), and the signalling actions of ADO at P1 receptors (P1Rs). The dynamics of this interaction are highly relevant for respiratory control because ADO is implicated as a respiratory depressant in adult (Eldridge et al 1984; Yamamoto et al 1994), newborn (Runold et al 1989; Herlenius et al 1997) and especially fetal mammals (Bissonnette et al 1990). It is also implicated in the hypoxia‐induced depression of ventilation (Moss, 2000).…”

Section: Introductionmentioning

confidence: 99%

Purinergic modulation of preBötzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine

Zwicker

Rajani

Hahn

et al. 2011

The Journal of Physiology

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Non-technical summary Hypoxia causes an increase in breathing followed by a secondary depression that is most pronounced, and potentially life-threatening, in premature infants. Adenosine triphosphate (ATP) is released in brainstem respiratory networks during hypoxia, where it attenuates the secondary respiratory depression. Mechanisms are unknown but likely to be complex because ATP is degraded by enzymes into ADP, which is excitatory, and adenosine (ADO), which is inhibitory. We demonstrate in mouse, like rat, that ATP in the preBötzinger complex (preBötC), a site critical for inspiratory rhythm generation, increases frequency. Unlike rat, this increase is only observed in mouse if ADO receptors are blocked. Differential ATP sensitivity is likely to reflect that ADO is only inhibitory in mouse, and that mouse preBötC enzymes favour ADO production. Thus, purinergic signalling in preBötC networks appears balanced to favour inhibition in mouse but excitation in rat. Knowledge of purinergic signalling increases our understanding of processes underlying respiratory responses to hypoxia.Abstract ATP signalling in the CNS is mediated by a three-part system comprising the actions of ATP (and ADP) at P2 receptors (P2Rs), adenosine (ADO) at P1 receptors (P1Rs), and ectonucleotidases that degrade ATP into ADO. ATP excites preBötzinger complex (preBötC) inspiratory rhythm-generating networks where its release attenuates the hypoxic depression of breathing. Its metabolite, ADO, inhibits breathing through unknown mechanisms that may involve the preBötC. Our objective is to understand the dynamics of this signalling system and its influence on preBötC networks. We show that the preBötC of mouse and rat is sensitive to P2Y 1 purinoceptor (P2Y 1 R) activation, responding with a >2-fold increase in frequency. Remarkably, the mouse preBötC is insensitive to ATP. Only after block of A 1 ADORs is the ATP-evoked, P2Y 1 R-mediated frequency increase observed. This demonstrates that ATP is rapidly degraded to ADO, which activates inhibitory A 1 Rs, counteracting the P2Y 1 R-mediated excitation. ADO sensitivity of mouse preBötC was confirmed by a frequency decrease that was absent in rat. Differential ectonucleotidase activities are likely to contribute to the negligible ATP sensitivity of mouse preBötC. Real-time PCR analysis of ectonucleotidase isoforms in preBötC punches revealed TNAP (degrades ATP to ADO) or ENTPDase2 (favours production of excitatory ADP) as the primary constituent in mouse and rat, respectively. These data further establish the sensitivity of this vital network to P2Y 1 R-mediated excitation, emphasizing that individual components of the three-part signalling system dramatically alter network responses to ATP. Data also suggest therapeutic potential may derive from methods that alter the ATP-ADO balance to favour the excitatory actions of ATP.

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“…32 The inhibition of respiratory output in this preparation is exerted in the rostral ventrolateral medulla and appears to arise from a ventrolateral site in the caudal pons; this is unlikely to be equivalent to the site identified as FOS responsive in foetal sheep, which is more rostral and dorsal. 35 Experiments using drugs more specific for the A1 receptor subtype are required. 34 Theophylline, a non-specific adenosine receptor antagonist (but which also inhibits phosphodiesterases) not only blocks the hypoxia-induced decrease of FBM, but can result in a stimulation of FBM during hypoxia.…”

Section: Possible Receptor Mechanismsmentioning

confidence: 99%

“…34 Theophylline, a non-specific adenosine receptor antagonist (but which also inhibits phosphodiesterases) not only blocks the hypoxia-induced decrease of FBM, but can result in a stimulation of FBM during hypoxia. 35 Experiments using drugs more specific for the A1 receptor subtype are required. For example, infusion of ethanol inhibits FBM in foetal sheep, an effect blocked by the more specific antagonist 8cyclopentyltheophylline (8-CPT).…”

Section: Possible Receptor Mechanismsmentioning

confidence: 99%

Effect Of Hypoxia On Respiratory Activity In The Foetus

Walker

Lee

Nitsos

2000

Clin Exp Pharma Physio

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1. Breathing movements stop soon after the induction of hypoxia in foetal animals, a response attributed to the active inhibition of the respiratory centres. Separate studies using punctate lesions have identified lateral pontine and thalamic sites in foetal sheep from which respiratory inhibition may arise, but whether either of these loci are actually oxygen sensitive or whether they receive input from other regions responsive to hypoxia, has not been established. 2. FOS immunocytochemistry was used to identify neuronal pools activated by hypoxia in the brain of late-gestation foetal and newborn sheep. FOS-positive cells were found in the pons in regions corresponding to the medial parabrachial and Kolliker-Fuse nuclei and were shown to be catecholaminergic. Neurons in this pontine region were also activated by the piperizine drug almitrine, which, like hypoxia, inhibits respiratory output in the foetus but is a respiratory stimulant in the newborn and adult. Because these pontine neurons do not express FOS protein after challenge with hypoxia or almitrine in the newborn lamb, we argue that they are crucial to the hypoxic inhibition of respiratory activity in foetal life. 3. The role of the placenta in determining these foetal responses and how this may change at birth is discussed.

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Theophylline Stimulates Fetal Breathing Movements during Hypoxia

Abstract: The respiratory responses to theophylline during normoxia and hypoxia were determined in 13 unanesthetized fetal sheep. Theophylline (plasma levels-1 11 pmol/L) increased the incidence of fetal breathing movements measured over 120 min from 37.7 f 4.8% to 61.1 f

Cited by 34 publications

References 7 publications

Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Adenosine mediates metabolic and cardiovascular responses to hypoxia in fetal sheep.

Purinergic modulation of preBötzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine

Effect Of Hypoxia On Respiratory Activity In The Foetus

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