Respiratory depression produced by activation of GABA receptors in hindbrain of cat

Yamada, Kathryn A.; Hamosh, Paul; Gillis, R. A.

doi:10.1152/jappl.1981.51.5.1278

Cited by 62 publications

(23 citation statements)

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“…Weil (69) has speculated that the HVD, in particular, may represent a vestige of this diving response with a possible mediating role for the neurotransmitter GABA. GABA depresses ventilation and metabolism (31,38,73), and the numerous GABA-receptor polymorphisms have been widely studied in various other contexts (e.g., Ref. 46).…”

Section: Discussionmentioning

confidence: 99%

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Brutsaert

Parra

Shriver

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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-Andean highaltitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O 2 saturation (SaO 2 ). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10 -12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia (r ϭ Ϫ0.36, P ϭ 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r ϭ Ϫ0.50, P ϭ 0.005) and ventilatory equivalent (VE/V O2, r ϭ Ϫ0.51, P ϭ 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the wellknown blunted HVR (10,35,36,57,62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua. genetic markers; admixture; arterial saturation; Andes THE HYPOXIC VENTILATORY RESPONSE (HVR) is the increase in ventilation (VE) that occurs when arterial blood oxygen partial pressure PO 2 decreases (60). Typically, on acute exposure to hypoxia, VE increases to a peak in the first few minutes and thereafter declines somewhat to a level higher than control depending on the level of hypoxia (13,49). This attenuation of VE has been termed the hypoxic ventilatory decline (HVD), and it is usually assessed by protocols that give a sustained hypoxic exposure greater than ϳ10 min. The sustained vs. acute response has not been systematically evaluated in Andean highland natives, but groups from this region appear to have a lower or "blunted" acute HVR and a lower effective alveolar ventilation compared with high altitude (HA)-acclimatized control groups from the lowlands (10,35,36,43,57,61,62). Andeans also have lower VE during exercise at HA compared with acclimatized lowland controls (7,32,55,66). These traits may be unique to Andeans, as many studies show normal HVR and higher VE in natives of the Himalayan plateau (2,21,25,29,75). However, little is known about the underlying genetic and/or environmental basis for ventilatory trait differences between populations. One possibility is that there are genes at which allele frequencies differ ...

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Section: Discussionmentioning

confidence: 99%

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Brutsaert

Parra

Shriver

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…GABA produces this inhibitor effect by causing hyperpolarization due to an increase in the influx of Cl -into the cardiorespiratory neurons (Anderson et al 1980;Neubauer et al 1990). Under normoxic conditions, centrally administrated exogenous GABA or GABA analogues depress ventilation (Yamada et al 1981(Yamada et al , 1982Kneussl et al 1986;Taveira-Da Silva et al 1987), whereas GABA antagonists bicuculline and baclofene cause an increase in phrenic activity (Taveira-Da Silva et al 1987;Melton et al 1990;Soto-Arape et al 1995). These findings suggest that GABAergic mechanisms are tonically effective in the regulation of respiratory activity under normoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…C e n t r a l l y a d m i n i s t e r e d G A B A a n d GABAergic agonists depress respiration in normoxic conditions (Yamada et al 1981(Yamada et al , 1982Kneussl et al 1986;Taveira-Da Silva et al 1987). Respiratory depression may be caused by disappearence of the activity of dorsal and ventral respiratory group of neurons as a result of neuronal hyperpolarization (Anderson et al 1980;Champagnat et al 1982;Bennet et al 1987).…”

Section: Methodsmentioning

confidence: 99%

“…The doses of bicuculline and MK-801 were performed as 0.2 mg/kg and 0.09 mg/kg respectively. These doses were selected on bases of earlier studies that showed complete antagonism of GABA and glutamate effects of the respiratory responses from the central nervous system (Yamada et al 1981;Ang et al 1992). These agents were dissolved in physiologic serum.…”

Section: Drugsmentioning

confidence: 99%

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The Role of Gamma-Aminobutyric Acid and Glutamate for Hypoxic Ventilatory Response in Anesthetized Rabbits

Yelmen

2004

Tohoku J. Exp. Med.

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Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed by a decrease in ventilation. Hypoxia causes changes in brain neurotransmitters depending on its severity and durations. The purpose of this study was to investigate the role of gamma-aminobutyric acid (GABA) and glutamate for hypoxic ventilatory response in rabbits. The experiments were performed in peripheral chemoreceptors intact and denervated rabbits anesthetized with Na-pentobarbitate. For intracerebroventricular (ICV) injections of reagents in each animal, cannula was placed in left lateral cerebral ventricle by stereotaxic method. After ICV injection of GABA (0.48 mg/kg), air breathing in both groups caused a depression of respiratory activity. On the other hand, after ICV injection of GABA, breathing of hypoxic gas mixture (8% O 2 -92% N 2 ) in both groups produced the hypoxic hyperventilation. After ICV injection of GABA, blockade of GABA A receptors with bicuculline (0.2 mg/kg) did not prevent the hypoxic hyperventilation. In contrast, after ICV GABA injection, blockade of glutamate NMDA receptors with MK-801 (0.09 mg/kg) completely abolished the hypoxic hyperventilation observed while the animals were breathing hypoxic gas mixture. Our findings suggest that ICV injection of GABA causes respiratory depression in normoxic conditions, and that it increases ventilation in hypoxic conditions with or without peripheral chemoreceptor impulses by increasing glutamate.GABA; hypoxia; control of breathing; bicuculline; MK-801

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“…which may be a respiratory inhibitor (1 1-16). Branched-chain AA may also compete with glutamate for decarboxylation, resulting in increased glutamate levels and consequently reducing the production of GABA, which is a n important respiratory depressant (17)(18)(19). Because a late ventilatory depression occurs in neonates during hypoxia (20)(21)(22)(23) and because this depression may in part be caused by an increase in inhibitory neurotransmitters, counterbalancing their effect by dietary intervention could reverse the ventilatory depression.…”

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confidence: 99%

Effect of Amino Acid Infusion on the Ventilatory Response to Hypoxia in Protein-Deprived Neonatal Piglets

et al. 1994

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Divisiorl o f R'c~ot~atolo,~.~~, Dcpurtrnolt ~f Pcdiutrics, Utliver.sitj3 ojl2liut~1i School oj'.\lc~clic.it~c~. ,\liut?~i, FIori(l(1 33101 ABSTRACT. Several amino acids (AA) act a s neurotransmitters and mediate the ventilatory response to carbon dioxide and hypoxia in adult human beings and animals.To evaluate the influence of AA on the neonatal ventilatory response to hypoxia, 29 newborn piglets less than 5 d old were randomly assigned to a control diet or protein-free diet for 7-10 d. Minute ventilation, arterial blood pressure, oxygen consumption, and arterial blood gases were measured in sedated, spontaneous breathing piglets while they breathed room air and at 1, 5 and 10 min of hypoxia p < 0.05). Changes in arterial blood pressure, oxygen consumption, and arterial blood gases during hypoxia were similar before and after AA infusion. The ventilatory response to hypoxia in both protein-free and control diet animals were similar before and after the 10% dextrose infusion. These results stress the importance of nutritional factors in the neonatal control of breathing. (Pediatr Res 35: 316-320, 1994) Abbreviations AA, amino acids D,oW, 10% dextrose ABP, arterial blood pressure BD, base deficit GABA, y-aminobutyric acid VE, minute ventilation Vo2, oxygen consumption VT, tidal volume hypercarbia (1). Furthermore, these respiratory changes were reversed by the administration of enteral or parenteral protein (1-3). In preterm infants, the basal VE and the ventilatory response to hypercarbia were increased after the administration of a standard AA solution (9). The mechanisms that can explain the ventilatory changes during nutritional intervention are not fully defined. Some of these changes may be mediated by the increase and/or decrease in inhibitory or excitatory neurotransmitters in the CNS (4, 10). One of the latter is glutamate, a central excitatory neurotransmitter that participates in the ventilatory response to hypoxia (5). Other AA that are not neurotransmitters may also influence the central respiratory output. For example, the administration of branched-chain AA to adult human beings resulted in an increase in basal ventilation and the ventilatory response to hypercarbia (6, 7). Branched-chain AA may compete with tryptophan at the blood brain bamer, limiting the entry of tryptophan to the CNS and thereby decreasing the production of serotonin. which may be a respiratory inhibitor (1 1-16). Branched-chain AA may also compete with glutamate for decarboxylation, resulting in increased glutamate levels and consequently reducing the production of GABA, which is a n important respiratory depressant (17)(18)(19). Because a late ventilatory depression occurs in neonates during hypoxia (20)(21)(22)(23) and because this depression may in part be caused by an increase in inhibitory neurotransmitters, counterbalancing their effect by dietary intervention could reverse the ventilatory depression. T o our knowledge, no studies have been conducted to evaluate the influence of AA infusion on the ventilatory re...

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Respiratory depression produced by activation of GABA receptors in hindbrain of cat

Cited by 62 publications

References 0 publications

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

The Role of Gamma-Aminobutyric Acid and Glutamate for Hypoxic Ventilatory Response in Anesthetized Rabbits

Effect of Amino Acid Infusion on the Ventilatory Response to Hypoxia in Protein-Deprived Neonatal Piglets

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