Brainstem Amino Acid Neurotransmitters and Ventilatory Response to Hypoxia in Piglets

Hehre, Dorothy; Devia, Carlos; Bancalari, Eduardo; Suguihara, Cleide

doi:10.1203/pdr.0b013e31815b4421

Cited by 25 publications

(16 citation statements)

References 38 publications

(51 reference statements)

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“…Application of a bicuculine/strychine mixture blocked both the HVR and the effect of the α 1 -agonist phenylephrine in isolated brainstem preparations. Hehre et al (2008) reported that the larger depression in ventilator response to hypoxia seen in younger piglets is mediated by a predominance of inhibitory neurotransmitters (GABA, glycine, taurine) in the nucleus tractus solitarius. A role for GABA in mediating the HVR has been reported by many investigators, but other neurotransmitters have been implicated as well (see review by Teppema and Dahan, 2010).…”

Section: Discussionmentioning

confidence: 99%

Chronic nicotine and ethanol exposure both disrupt central ventilatory responses to hypoxia in bullfrog tadpoles

Taylor

Brundage

McLane

2013

Respiratory Physiology & Neurobiology

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The central hypoxic ventilatory response (HVR) comprises a reduction in ventilatory activity that follows a peripherally mediated ventilatory augmentation. Chronic early developmental exposure to nicotine or ethanol are both known to impair the peripherally mediated HVR, and nicotine impairs the central HVR, but the effect of ethanol on the central HVR has not been investigated. Additionally, chronic nicotine and ethanol exposure are known to impair ventilatory responses to hypercapnia in bullfrog tadpoles but HVRs have not been tested. Here early and late metamorphic tadpoles were exposed to either 30 µg/L nicotine or 0.15 – 0.05 g/dL ethanol for 10 wk. Tadpole brainstems were then isolated and the neurocorrelates of ventilation were monitored in vitro over 180 min of hypoxia (PO2 = 5.05 ± 1.04 kPa). Both nicotine and ethanol exposure disrupted central HVRs. Nicotine impairments were dependent on development. Central HVRs were impaired only in early metamorphic nicotine-exposed tadpoles. Both early and late metamorphic ethanol-exposed tadpoles failed to exhibit central HVRs. Thus, central HVRs are impaired following both nicotine and ethanol exposure. Such failure to decrease ventilatory activity during hypoxia indicates that central hypoxic ventilatory depression is an active suppression of neural activity in response to hypoxia rather than a metabolic consequence of O2 limitation, and that exposure to ethanol (across development) or nicotine (during early development) disrupts mechanisms that normally induce active ventilatory depression.

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Section: Discussionmentioning

confidence: 99%

Chronic nicotine and ethanol exposure both disrupt central ventilatory responses to hypoxia in bullfrog tadpoles

Taylor

Brundage

McLane

2013

Respiratory Physiology & Neurobiology

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“…Acute hypoxemia is associated with increases in the extracellular concentration (measured with microdialysis) of both excitatory and inhibitory neurotransmitters and/or neuromodulators in the brain stem, including glutamate, GABA, taurine, adenosine, and serotonin in both anesthetized and conscious animals (33,36,63,66). Most of these studies have focused on respirationrelated areas, including the nucleus tractus solitarii (NTS) and ventrolateral medulla.…”

Section: Discussionmentioning

confidence: 99%

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

Darnall¹,

Schneider²,

Tobia³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Darnall RA, Schneider RW, Tobia CM, Zemel BM. Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms. Am J Physiol Regul Integr Comp Physiol 302: R551-R560, 2012. First published December 7, 2011; doi:10.1152/ajpregu.00506.2011Arousal is an important defense against hypoxia during sleep. Rat pups exhibit progressive arousal impairment (habituation) with multiple hypoxia exposures. The mechanisms are unknown. The medullary raphe (MR) is involved in autonomic functions, including sleep, and receives abundant GABAergic inputs. We hypothesized that inhibiting MR neurons with muscimol, a GABA A receptor agonist, or preventing GABA reuptake with nipecotic acid, would impair arousal and enhance arousal habituation and that blocking GABA A receptors with bicuculline would enhance arousal and attenuate habituation. Postnatal day 15 (P15) to P25 rat pups were briefly anesthetized, and microinjections with aCSF, muscimol, bicuculline, or nipecotic acid were made into the MR. After a ϳ30-min recovery, pups were exposed to four 3-min episodes of hypoxia separated by 6 min of normoxia. The time to arousal from the onset of hypoxia (latency) was determined for each trial. Latency progressively increased across trials (habituation) in all groups. The overall latency was greater after muscimol and nipecotic acid compared with aCSF, bicuculline, or noninjected controls. Arousal habituation was reduced after bicuculline compared with aCSF, muscimol, nipecotic acid, or noninjected pups. Increases in latency were mirrored by decreases in chamber [O2] and oxyhemoglobin saturation. Heart rate increased during hypoxia and was greatest in muscimol-injected pups. Our results indicate that the MR plays an important, not previously described, role in arousal and arousal habituation during hypoxia and that these phenomena are modulated by GABAergic mechanisms. Arousal habituation may contribute to sudden infant death syndrome, which is associated with MR serotonergic and GABAergic receptor dysfunction.␥-aminobutyric acid; sudden infant death syndrome; GABAA receptor; habituation IN HUMAN INFANTS, AROUSAL is an important protective mechanism against hypoxia during sleep. Spontaneous arousals and those in response to exogenous stimuli are affected by many factors: sleep position (3, 29, 37), sleep efficiency (30), prenatal exposure to cigarette smoking (28, 38), and stage of development (39). It has been hypothesized that arousal impairment may play an important role in the etiology of sudden infant death syndrome (SIDS) (32,40,43,46). Moreover, many SIDS infants have repeated episodes of apnea and hypoxia in the days or weeks prior to death (44,56). We propose that repeated exposure to hypoxia during sleep leads to progressive lengthening of the time to arousal in response to hypoxia that might contribute to sudden death.We and others have shown in newborn and infant rodents (17, 18, 21), lambs (25,41,42), and piglets (71) that repeated brief exposures to mild hypoxia result in...

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“…In infants and animal models, heart rate appears to initially increase during the same period when respiratory rate increases during hypoxia (Bamford et al, 1996; Horne et al, 2000; Nock et al, 2004; Horne et al, 2005; Hehre et al, 2008). As the respiratory rate decreases, bradycardia ensues with transient increases in heart rate during gasps (Hunt, 1992; Poets et al, 1999; Harper et al, 2000).…”

Section: Sids and Central Cardio-respiratory Controlmentioning

confidence: 99%

The physiological determinants of Sudden Infant Death Syndrome

Garcia¹,

Koschnitzky²,

Ramirez

2013

Respiratory Physiology & Neurobiology

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It is well-established that environmental and biological risk factors contribute to Sudden Infant Death Syndrome (SIDS). There is also growing consensus that SIDS requires the intersection of multiple risk factors that result in the failure of an infant to overcome cardio-respiratory challenges. Thus, the critical next steps in understanding SIDS are to unravel the physiological determinants that actually cause the sudden death, to synthesize how these determinants are affected by the known risk factors, and to develop novel ideas for SIDS prevention. In this review, we will examine current and emerging perspectives related to cardio-respiratory dysfunctions in SIDS. Specifically, we will review: (1) the role of the preBötzinger complex (preBötC) as a multi-functional network that is critically involved in the failure to adequately respond to hypoxic and hypercapnic challenges; (2) the potential involvement of the pre-BötC in the gender and age distributions that are characteristic for SIDS; (3) the link between SIDS and prematurity; and (4) the potential relationship between SIDS, auditory function, and central chemosensitivity. Each section underscores the importance of marrying the epidemiological and pathological data to experimental data in order to understand the physiological determinants of this syndrome. We hope that a better understanding will lead to novel ways to reduce the risk to succumb to SIDS.

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Brainstem Amino Acid Neurotransmitters and Ventilatory Response to Hypoxia in Piglets

Cited by 25 publications

References 38 publications

Chronic nicotine and ethanol exposure both disrupt central ventilatory responses to hypoxia in bullfrog tadpoles

Chronic nicotine and ethanol exposure both disrupt central ventilatory responses to hypoxia in bullfrog tadpoles

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

The physiological determinants of Sudden Infant Death Syndrome

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