Fetal cardiovascular and breathing responses  to an adenosine A<sub>2a</sub> receptor agonist in sheep

Koos, Brian J.; Chau, Andrew

doi:10.1152/ajpregu.1998.274.1.r152

Cited by 22 publications

(12 citation statements)

References 23 publications

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“…This is in agreement with the observation that some, but not all, Atoh1 -dependent parabrachial neurons are activated during chemochallenges ( Figure 1 ). To our surprise, caffeine treatment actually decreased respiratory output in control animals, which might be caused by inhibition of A2 adenosine receptors that increase respiratory frequency ( Koos, 2011 ; Koos and Chau, 1998 ; Koos et al, 2001 ). Future studies with specific adenosine agonists and antagonists are needed to elucidate the specific effects of long-term caffeine treatment on respiratory control in neonatal mice.…”

Section: Discussionmentioning

confidence: 76%

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

Heijden

Zoghbi

2018

eLife

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Atoh1-null mice die at birth from respiratory failure, but the precise cause has remained elusive. Loss of Atoh1 from various components of the respiratory circuitry (e.g. the retrotrapezoid nucleus (RTN)) has so far produced at most 50% neonatal lethality. To identify other Atoh1-lineage neurons that contribute to postnatal survival, we examined parabrachial complex neurons derived from the rostral rhombic lip (rRL) and found that they are activated during respiratory chemochallenges. Atoh1-deletion from the rRL does not affect survival, but causes apneas and respiratory depression during hypoxia, likely due to loss of projections to the preBötzinger Complex and RTN. Atoh1 thus promotes the development of the neural circuits governing hypoxic (rRL) and hypercapnic (RTN) chemoresponses, and combined loss of Atoh1 from these regions causes fully penetrant neonatal lethality. This work underscores the importance of modulating respiratory rhythms in response to chemosensory information during early postnatal life.

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Section: Discussionmentioning

confidence: 76%

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

Heijden

Zoghbi

2018

eLife

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“…At least two discrete mechanisms are involved in the inhibition of ventilation by ADO. An A 2A R‐mediated excitation of GABAergic neurons that ultimately inhibits brainstem respiratory networks is a major contributor to the ADO‐mediated inhibition evoked in vivo in sheep (Koos et al 2005), lambs (Koos & Chau, 1998), piglets (Wilson et al 2004) and rat (Mayer et al 2006). Neither the source of the A 2A excitatory input to GABAergic neurons nor the GABAergic input to the brainstem is known, but both appear suprabulbar in origin and are therefore unlikely to be contributors to the brainstem mechanisms examined here.…”

Section: Discussionmentioning

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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“…The cardiovascular effects of adenosine include a myocardial A1 receptor-mediated bradycardia and, at higher concentrations, an A2 receptor-mediated vasodilatation of both cerebral and peripheral vessels (15). We deliberately chose to infuse adenosine at a rate that would not markedly alter fetal systemic hemodynamics, and, although there was a tendency for MAP to fall and for CaBF to rise, changes in fetal hemodynamics were not statistically significant.…”

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confidence: 99%

Adenosine Produces Changes in Cerebral Hemodynamics and Metabolism as Assessed by Near-Infrared Spectroscopy in Late-Gestation Fetal Sheep in Utero

2001

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Rises in fetal adenosine during hypoxia may have a metabolic inhibitory role that helps the fetus adapt to periods of low arterial partial pressure of oxygen (P a O 2 ). We examined the fetal cerebral hemodynamic and metabolic responses to exogenous adenosine infusion and compared this with previous studies. Six fetal sheep at ca. 125 d gestation were instrumented under general anesthesia with catheters, flow probes, and near-infrared optodes and allowed to recover. After 3 d, adenosine was infused at a level known to reproduce fetal levels during hypoxia. Fetal hemodynamics and cerebral near-infrared spectroscopic (NIRS) variables were monitored and paired blood samples taken for oxygen delivery and consumption calculation. Fetal heart rate, mean arterial pressure, and carotid flow showed no change during adenosine infusion. Cerebral oxyhemoglobin (HbO 2 ), deoxyhemoglobin (Hb), and blood volume rose, suggesting venous pooling in the brain. Cerebral cytochrome oxidase (CcO) became more oxidized, indicating reduction in electron flow down the mitochondrial electron transfer chain and, thus, a fall in metabolic rate. Blood sample analysis revealed that there was no change in oxygen delivery to the head but that cerebral oxygen consumption fell during adenosine infusion. These data indicate that fetal cerebral metabolism fell during infusion of adenosine at a level known to reproduce fetal plasma concentrations during hypoxia. Adenosine is a vasoactive purine metabolite produced during breakdown of high-energy phosphates in hypoxia. Tissue levels of adenosine are 2-3 times higher in the fetus than the adult (1) and have been shown to rise further within minutes of the onset of hypoxia in the ovine fetus (2). Plasma adenosine levels are also higher in hypoxemic, acidotic growth-retarded human fetuses than in appropriately grown fetuses (3). This may be seen as a direct consequence of the hypoxemia, but there is also the possibility that elevated tissue and plasma adenosine may form part of a protective fetal adaptation aimed at matching oxygen demand to availability (4, 5). Adenosine acting via A2 receptors is known to cause vasodilatation both in the peripheral and cerebral vascular beds, which improves cerebral blood flow and, thus, cerebral DO 2 (6, 7). Adenosine also inhibits fetal breathing and eye and body movements, depresses excitatory neurotransmission, and causes neuronal hyperpolarization, all of which will reduce fetal V O 2 (8, 9).We have previously reported that mild hypoxemia in the ovine fetus is associated with an increase in CBV and in the cerebral concentration of CcO as measured by near-infrared spectroscopy (10). We hypothesize that these changes are the result of the dual actions of endogenous adenosine on cerebral blood vessels and on cerebral metabolism. The aim of this study was, therefore, to determine whether adenosine administered exogenously to the chronically instrumented ovine fetus in utero would lead to similar changes in CBV and CcO redox state as those observed during moderate hyp...

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Fetal cardiovascular and breathing responses to an adenosine A_2a receptor agonist in sheep

Cited by 22 publications

References 23 publications

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

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

Adenosine Produces Changes in Cerebral Hemodynamics and Metabolism as Assessed by Near-Infrared Spectroscopy in Late-Gestation Fetal Sheep in Utero

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Fetal cardiovascular and breathing responses to an adenosine A2a receptor agonist in sheep

Cited by 22 publications

References 23 publications

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice

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

Adenosine Produces Changes in Cerebral Hemodynamics and Metabolism as Assessed by Near-Infrared Spectroscopy in Late-Gestation Fetal Sheep in Utero

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Fetal cardiovascular and breathing responses to an adenosine A_2a receptor agonist in sheep