Biphasic Ventilatory Response Research Articles

Influence of chronic hyperoxia on the developmental time course of the hypoxic ventilatory response relative to other traits in rats

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR) in which an initial increase in ventilation is followed by a decline back toward baseline levels. The magnitude of the secondary decline diminishes with postnatal age, but this transition occurs earlier in rat pups reared in moderate hyperoxia. This pattern is consistent with heterokairy, a form of developmental plasticity in which environmental factors alter the timing of developmental events. The present study investigated whether this plasticity is specific to the HVR or if hyperoxia instead accelerates overall development. Rat pups reared in 60 % O2 (Hyperoxia) exhibited a less biphasic ventilatory response to 12 % O2 than pups reared in 21 % O2 (Control) at 4 days of age (P4) and transitioned to a sustained HVR by P10-11; Control rats exhibited a biphasic HVR at both ages. However, the average ages at which pups attained other key developmental milestones (i.e., fur development at P5, incisor eruption at P9, and eye opening at P15) were similar between treatment groups. Moreover, growth rates and maturation of the metabolic response to cooling were not accelerated, and may have been delayed slightly, relative to Control rats. For example, the capacity for pups to increase their metabolic rate at low ambient temperatures increased with age, but this thermogenic capacity tended to be reduced in Hyperoxia pups at both P4 and P10-11 (i.e., lower CO2 production rates below the lower critical temperature). Collectively, these data support the conclusion that hyperoxia specifically advances the age at which rat pups exhibit a sustained HVR, altering the relative timing of developmental events rather than compressing the entire period of development.

Is Hyperoxic Hyperventilation Caused by Reduced Carbon Dioxide Washout or Disturbed Brain Redox Homeostasis?

Under oxygen‐enriched conditions, humans present a biphasic ventilatory response that is initially characterized by reduced ventilation (V̇E) as hyperoxia (HX) inhibits the peripheral chemoreceptors. This short‐lived response precedes a paradoxical increase in V̇E that has been termed hyperoxic hyperventilation. Proposed but untested mechanisms for this paradoxical response include central chemoreceptor stimulation via either an increased cerebral partial pressure of carbon dioxide (CO2), which would result from reductions in cerebral blood flow (CBF) and brain CO2–[H+] washout, or (2) an HX‐induced exaggerated production of reactive oxygen species (ROS). To determine the mechanism behind the paradoxical increase in V̇E during hyperoxemia, we submitted 8 healthy young men (24±1 yrs) to 10‐min trials of poikilocapnic HX under (1) saline or (2) ascorbic acid (AA) infusion. V̇E, arterial (a) and internal right jugular venous (Jv) PO2, PCO2, pH, oxidant (8‐isoprostane), and antioxidant (AA) markers, as well as volumetric CBF (Doppler ultrasound) responses, were quantified at the last minute of each trial. Under saline infusion, HX evoked an increase in PaO2 followed by a hyperventilatory response (+3.0 ± 1.2 L/min, p = 0.003) and arterial hypocapnia (−2.4 ± 0.9 mmHg, p = 0.03). HX also evoked a small but significant reduction in CBF (−219.6 ± 36.8 mL/min, p = 0.001) that was followed by unchanged PjvCO2 (−0.1 ± 0.7 mmHg, p = 0.619) and pH (0.001 ± 0.005, p = 0.957). HX under saline infusion also provoked an increase in arterial 8‐isoprostane (18.6 ± 7.5 pg/mL, p = 0.04). On the other hand, intravenous AA augmented arterial antioxidant markers (+584.1 ± 64.6, p = 0.0001 vs. saline) and blunted not only the increase in arterial 8‐isoprostane (−10.7 ± 9.5 pg/mL, p = 0.204) but also the HX‐induced hyperventilation (+0.87 ± 0.64 L/min, p = 0.232) and the arterial hypocapnia (−1.7 ± 0.5 mmHg, p = 0.04 vs. saline) observed during infusion of saline. HX under AA infusion also blunted CBF hypoperfusion (−41.8 ± 26.3 mL/min, p = 0.001 vs. saline) that, in turn, was followed by increases in PjvO2 (+5.3 ± 0.7 mmHg, p = 0.006 vs. saline), PjvCO2 (+1.1 ± 0.50 mmHg, p = 0.03 vs. saline) and a reduction in pH (−0.012 ± 0.004, p = 0.01) that may be explained by the Haldane effect. These findings suggest that hyperoxic hyperventilation is not a consequence of an increased cerebral CO2 partial pressure and a reduced brain CO2–[H+] washout but mediated by central chemoreceptor stimulation likely evoked by excessive production of ROS.Support or Funding InformationSupport: FaperRJ, CNPq, CAPES

Development of ventilatory chemoreflexes in Coturnix quail chicks

Compared to mammals, little is known about the development of the respiratory control system in birds. In the present study, ventilation and metabolism were measured in Coturnix quail chicks exposed to room air, hypoxia (11 % O2), and hypercapnia (4% CO2) at 0–1, 3–4, and 6–7 days posthatching (dph). Mass-specific ventilation and metabolic rate tended to increase between 0–1 and 3–4 dph and then decrease again between 3–4 and 6–7 dph. The magnitude of the hypoxic ventilatory response (HVR) increased with age. The HVR also exhibited a biphasic shape in younger quail: after the initial increase in ventilation, ventilation declined back to (0–1 dph), or toward (4 dph), baseline. Older chicks (6–7 dph) had a “sustained HVR” in which ventilation remained high throughout the hypoxic challenge. The biphasic HVR did not appear to be caused by a decline in metabolic rate; although hypoxic hypometabolism was observed in quail chicks in all three age groups, the metabolic response appeared to occur more slowly than the biphasic HVR. The biphasic ventilatory response was also specific to hypoxia since the hypercapnic ventilatory response (HCVR) was characterized by a sustained increase in ventilation in all three age groups. The magnitude of the HCVR decreased with age. These results point to several similarities in the development of ventilatory chemorflexes between Coturnix quail and newborn mammals, including age-dependent (1) increases in the HVR, (2) transitions from a biphasic to a sustained HVR, and (3) decreases in the HCVR. Whether homologous mechanisms underlie these developmental changes remains to be determined.

Rubral modulation of breathing.

What is the topic of this review? Rubral modulation of pontomedullary respiratory rhythm and pattern generating circuitry powerfully contributes to regulation of breathing. What advances does it highlight? Studies have demonstrated extensive rubromedullary and rubrospinal projections to zones generating and organizing the respiratory rhythm and pattern. Rubral modulation of respiratory output effects inspiratory expiratory phase transitions with stimulation generating inhibitory or excitatory responses of medullary inspiratory and expiratory units. The red nucleus mediates hypoxic ventilatory depression, integrates respiratory output with oromotor and locomotor activity, and modulates respiratory output during noxious stimulation. Although normal triphasic eupnoea can be produced by the pontomedullary respiratory network after pontomesencephalic transection, the midbrain provides important modulation of respiration. Specifically, stimulation of the red nucleus elicits inspiratory inhibition, as manifest in the phrenic neurogram, in addition to excitation and inhibition of individual medullary respiratory-related units, with the majority of premotor units that receive rubral modulation being inhibited. Stimulation of the red nucleus also induces respiratory phase transitions, which appear to be pontine independent. These effects might be mediated by rubrobulbar and/or rubrospinal tracts. Although lesioning of the red nucleus does not alter respiration in normoxic conditions, it eliminates hypoxic ventilatory depression, which is the second phase of the biphasic ventilatory response to low oxygen tension. The finding that the red nucleus also plays a role in anti-nociception suggests that it might coordinate respiratory responses during noxious stimulation and, given that the red nucleus regulates upper limb flexors, it might represent one region in a distributed bulbar network contributing to respiratory-locomotor integration. Modulation of jaw opening by the red nucleus would support a model whereby it coordinates oromotor activity with breathing. Thus, the multiplicity of roles played by the red nucleus aptly position it to coordinate respiration in a variety of behavioural states. In this review, we seek to highlight the different features and regional specializations of the rubral contribution to respiratory control and underscore its vital importance to breathing in the freely behaving mammal.

Postnatal Development of Hypoxic and Hypercapnic Ventilatory Responses in Coturnix Quail

Newborn mammals generally exhibit a biphasic hypoxic ventilatory response (HVR) in which the initial increase in ventilation is followed by a progressive decline toward (or below) baseline; the magnitude of the secondary decline diminishes with age. Considerably less is known about postnatal development of the HVR in birds, although a recent study did not detect a biphasic HVR in nestling red‐winged blackbirds (Dzialowski et al., Am J Physiol 311:R1105–R1112, 2016). We used head‐body plethysmography to characterize the ventilatory responses of Coturnix quail chicks to 15‐min challenges of 11% O2 or 4% CO2 at 0–1, 3–4, and 6–7 days of age. The magnitude of the HVR increased with postnatal age (21±4, 35±3, and 42±4 % increase from baseline, respectively; mean±SEM, P<0.01). The HVR was biphasic at P0–1 and (to a lesser extent) at P3–4, but not at P6–7. In contrast, the magnitude of the hypercapnic ventilatory response decreased with age (76±8, 54±4, 31±3 % increase from baseline, respectively; P<0.001). The hypercapnic ventilatory response was characterized by a relatively sustained increase in ventilation in all age groups, suggesting that the biphasic ventilatory response is specific to hypoxia. Additional experiments assessed hypoxic hypometabolism, and decreased metabolic rate does not appear to explain the biphasic HVR in the youngest quail chicks. We conclude that newborn quail exhibit a biphasic HVR similar to that observed in newborn mammals.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ventilation and diaphragm activity during sustained hypoxia in awake canines

In humans, isocapnic hypoxia sustained for 20–30min elicits a biphasic ventilatory response with an initial increased peak followed by a roll-off to a lesser, intermediate plateau. However, it is uncertain if this hypoxic roll-off is common for all mammals, as canines have been a notable exception. We examined the effect of moderate isocapnic hypoxia (SpO2 80%) sustained for 20min in 13 adult, awake, intact canines. The ventilatory response to sustained isocapnic hypoxia in these canines was not maintained: after an initial brisk response, ventilation declined significantly to an intermediate plateau. The hypoxic ventilatory decline occurred via a decrease in tidal volume, without change in breathing frequency. Distinct from airflow, costal diaphragm EMG showed a concurrent decline during sustained isocapnic hypoxia. However, the change in ventilation during sustained hypoxia in canines was very different from the response in humans. Although some decline in ventilation during sustained hypoxia may be common to all mammals, there are notable differences among species.

Time-Dependent Ventilatory Response to Poikilocapnic Hypoxia during Light and Dark Periods and the Role of Histamine H1 Receptors in Mice

We tested the hypothesis that the biphasic ventilatory response to poikilocapnic hypoxia shows circadian variation and contribution of histamine H1 receptors in mice. Initial increases in ventilation were augmented during dark periods. H1 receptors had no major relationship with circadian variation, but affected the declined phase.

Brainstem Amino Acid Neurotransmitters and Ventilatory Response to Hypoxia in Piglets

The ventilatory response to hypoxia is influenced by the balance between inhibitory (GABA, glycine, and taurine) and excitatory (glutamate and aspartate) brainstem amino acid (AA) neurotransmitters. To assess the effects of AA in the nucleus tractus solitarius (NTS) on the ventilatory response to hypoxia at 1 and 2 wk of age, inhibitory and excitatory AA were sampled by microdialysis in unanesthetized and chronically instrumented piglets. Microdialysis samples from the NTS area were collected at 5-min intervals and minute ventilation (VE), arterial blood pressure (ABP), and arterial blood gases (ABG) were measured while the animals were in quiet sleep. A biphasic ventilatory response to hypoxia was observed in wk 1 and 2, but the decrease in VE at 10 and 15 min was more marked in wk 1. This was associated with an increase in inhibitory AA during hypoxia in wk 1. Excitatory AA levels were elevated during hypoxia in wk 1 and 2. Changes in ABP, pH, and ABG during hypoxia were not different between weeks. These data suggest that the larger depression in the ventilatory response to hypoxia observed in younger piglets is mediated by predominance of the inhibitory AA neurotransmitters, GABA, glycine, and taurine, in the NTS.

Time Course of Air Hunger Mirrors the Biphasic Ventilatory Response to Hypoxia

Time Course of Air Hunger Mirrors the Biphasic Ventilatory Response to Hypoxia

Transient carbon monoxide inhibits the ventilatory responses to hypoxia through peripheral mechanisms in the rat

Hypoxia inhibits K + channels of chemoreceptors of the carotid body (CB), which is reversed by transient carbon monoxide (CO), suggesting an inhibitory effect of CO on hypoxic stimulation of carotid chemoreceptors. Therefore, we hypothesized that the ventilatory responses to hypoxic stimulation of the CB might be depressed in intact rats by transient inhalation of CO. Anesthetized, spontaneously breathing rats were exposed to room air, and 1 min of 11% O 2 (HYP) and CO (0.25–2%) alone and in combination (HYP + CO). We found that transient CO did not affect baseline cardiorespiratory variables, but significantly attenuated hypoxic ventilatory augmentation, predominantly via reduction of tidal volume. To distinguish whether this CO modulation occurs at the CB or within the central nervous system, the cardiorespiratory responses to electrical stimulation of the fastigial nucleus (FN), a cerebellar nucleus known excitatory to respiration, were compared before and during transient CO. Our results showed that the FN-mediated cardiorespiratory responses were not significantly changed by transient CO exposure. To evaluate the effect of CO accumulation, we also compared baseline cardiorespiratory responses to 5 min of 1% and 2% CO, respectively. Interestingly, only the latter produced a biphasic ventilatory response (initial increase followed by decrease) associated with hypotension. We conclude that eupneic breathing in anesthetized rat was not affected by transient CO, but was altered by prolonged exposure to higher levels of CO. Moreover, transient CO depresses hypoxic ventilatory responses mainly through peripherally inhibiting hypoxic stimulation of carotid chemoreceptors.

Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.

Regulation of breathing and body temperature of a burrowing rodent during hypoxic?hypercapnia

Burrowing mammals usually have low respiratory sensitivity to hypoxia and hypercapnia. However, the interaction between ventilation (V), metabolism and body temperature (Tb) during hypoxic–hypercapnia has never been addressed. We tested the hypothesis that Clyomys bishopi, a burrowing rodent of the Brazilian cerrado, shows a small ventilatory response to hypoxic–hypercapnia, accompanied by a marked drop in Tb and metabolism. V, Tb and O2 consumption (V̇O2) of C. bishopi were measured during exposure to air, hypoxia (10% and 7% O2), hypercapnia (3% and 5% CO2) and hypoxic–hypercapnia (10% O2+ 3% CO2). Hypoxia of 7% but not 10%, caused a significant increase in V, and a significant drop in Tb. Both hypoxic levels decreased V̇O2 and 7% O2 significantly increased V/V̇O2. Hypercapnia of 5%, but not 3%, elicited a significant increase in V, although no significant change in Tb, V̇O2 or V/V̇O2 was detected. A combination of 10% O2 and 3% CO2 had minor effects on V and Tb, while V̇O2 decreased and V/V̇O2 tended to increase. We conclude that C. bishopi has a low sensitivity not only to hypoxia and hypercapnia, but also to hypoxic–hypercapnia, manifested by a biphasic ventilatory response, a drop in metabolism and a tendency to increase V/V̇O2. The effect of hypoxic–hypercapnia was the summation of the hypoxia and hypercapnia effects, with respiratory responses tending to have hypercapnic patterns while metabolic responses, hypoxic patterns.

Regulation of breathing and body temperature of a burrowing rodent during hypoxic–hypercapnia

Burrowing mammals usually have low respiratory sensitivity to hypoxia and hypercapnia. However, the interaction between ventilation ( V), metabolism and body temperature (Tb) during hypoxic–hypercapnia has never been addressed. We tested the hypothesis that Clyomys bishopi, a burrowing rodent of the Brazilian cerrado, shows a small ventilatory response to hypoxic–hypercapnia, accompanied by a marked drop in Tb and metabolism. V, Tb and O 2 consumption (V̇O 2) of C. bishopi were measured during exposure to air, hypoxia (10% and 7% O 2), hypercapnia (3% and 5% CO 2) and hypoxic–hypercapnia (10% O 2+ 3% CO 2). Hypoxia of 7% but not 10%, caused a significant increase in V, and a significant drop in Tb. Both hypoxic levels decreased V̇O 2 and 7% O 2 significantly increased V/V̇O 2. Hypercapnia of 5%, but not 3%, elicited a significant increase in V, although no significant change in Tb, V̇O 2 or V/V̇O 2 was detected. A combination of 10% O 2 and 3% CO 2 had minor effects on V and Tb, while V̇O 2 decreased and V/V̇O 2 tended to increase. We conclude that C. bishopi has a low sensitivity not only to hypoxia and hypercapnia, but also to hypoxic–hypercapnia, manifested by a biphasic ventilatory response, a drop in metabolism and a tendency to increase V/V̇O 2. The effect of hypoxic–hypercapnia was the summation of the hypoxia and hypercapnia effects, with respiratory responses tending to have hypercapnic patterns while metabolic responses, hypoxic patterns.

Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants

Objective Correlate the ventilatory response of preterm infants to hypoxic exposure with incidence of neonatal apnea. Study design Seventeen stable convalescing premature infants underwent bedside cardiorespiratory monitoring of respiration using respiratory inductance plethysmography, heart rate, and oxygen saturation (SaO 2) for a 12-hour period. These studies were scored for number of apneas ≥15 and ≥20 seconds. Infants then underwent a 3-minute hypoxic exposure. Minute ventilation (V E) was calculated for 30-second epochs from the time inspired oxygen reached 15%. Linear regression analysis was used to correlate the change in V E normalized for decrease in SaO 2 (ΔV E/ΔSaO 2) during the first and third minutes of hypoxic exposure with the number of apneic episodes during the 12-hour study. Results The majority of infants exhibited an anticipated biphasic ventilatory response to hypoxia. There was a significant positive correlation between ΔV E/ΔSaO 2 during the first and third minutes of hypoxic exposure and number of apneic episodes ≥15 and ≥20 seconds during the preceding 12 hours. Conclusions Preterm infants with a greater number of apneic episodes exhibit an increased ventilatory response to hypoxic exposure, suggesting that apnea of prematurity may be associated with enhanced peripheral chemoreceptor activity.

Pathophysiologic Mechanisms Underlying Apnea of Prematurity

After completing this article, readers should be able to: 1. Characterize the unique features of neonatal respiratory control mechanisms. 2. Clarify how immature respiratory control contributes to neonatal apnea. 3. Identify the contribution of upper airway obstruction to episodes of mixed apnea. Idiopathic apnea of prematurity is a common disorder that requires therapeutic intervention to avoid potential morbidity in preterm infants who require neonatal intensive care. Severe, recurrent apneic episodes may lead to multiple investigations to rule out secondary disorders leading to apnea (see accompanying article in this issue). Although the incidence of neonatal apnea is inversely related to gestational age and is probably as high as 100% in the most immature preterm infants, the onset may be delayed by the presence of lung disease in the first days of life. Apnea of prematurity, especially if severe or persistent, has been associated with poor developmental outcome in school-age children, although a cause-and-effect relationship is difficult to establish. The definition of apnea varies among studies. Apnea of prematurity has been defined most widely as cessation of breathing in excess of 15 seconds’ duration, typically accompanied by desaturation and bradycardia. However, shorter episodes of apnea, and even periodic breathing, may be accompanied by bradycardia or hypoxemia. Prolonged desaturation episodes also have been reported in the absence of apnea or bradycardia, both in healthy preterm infants and in infants who have chronic lung disease. These episodes might represent obstructive apnea, hypoventilation, or possibly intrapulmonary right-to-left shunting, although episodes of desaturation and bradycardia almost always are preceded by apnea or hypoventilation. Apnea is classified traditionally into three categories based on the presence or absence of upper airway obstruction: central, obstructive, and mixed apneas. Central apnea is characterized by total cessation of inspiratory efforts with no evidence of obstruction. In obstructed apnea, the infant tries to breathe against …

Biphasic Ventilatory Response to Hypoxia in Unanesthetized Rats

To determine the role of postinspiratory inspiratory activity of the diaphragm in the biphasic ventilatory response to hypoxia in unanesthetized rats, we examined diaphragmatic activity at its peak (DI), at the end of expiration (DE), and ventilation in adult unanesthetized rats during poikilocapnic hypoxia (10 % O2) sustained for 20 min. Hypoxia induced an initial increase in ventilation followed by a consistent decline. Tidal volume (VT), frequency of breathing (fR), DI and DE at first increased, then VT and DE decreased, while fR and DI remained enhanced. Phasic activation of the diaphragm (DI - DE) increased significantly at 10, 15 and 20 min of hypoxia. These results indicate that 1) the ventilatory response of unanesthetized rats to sustained hypoxia has a typical biphasic character and 2) the increased end-expiratory activity of the diaphragm limits its phasic inspiratory activation, but this increase cannot explain the secondary decline in tidal volume and ventilation.

Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response.

The early phase of the biphasic ventilatory response to hypoxia in mammals is critically dependent on NMDA glutamate receptor activation within the nucleus of the solitary tract. However, the mechanisms underlying the subsequent development of the typical ventilatory roll-off are unclear and could underlie important roles in the functional and molecular adaptation to oxygen deprivation. Because the growth factor platelet-derived growth factor (PDGF)-BB can modulate the open channel probability of NMDA receptors by activating PDGF-beta receptors, its contribution to hypoxic ventilatory roll-off was examined. Administration of PDGF-BB, but not PDGF-AA, in the nucleus of the solitary tract was associated with significant attenuations of the early hypoxic ventilatory response in conscious rats. Furthermore, marked reductions in the magnitude of hypoxic ventilatory roll-off occurred in mice heterozygous for a mutation in the PDGF-beta receptor. Administration of a PDGF-beta receptor antagonist to wild-type littermates elicited similar declines in hypoxic ventilatory roll-off. The relative abundance of PDGF-beta receptors was confirmed in the nucleus of the solitary tract and other nuclei implicated in the hypoxic ventilatory response. In nucleus of the solitary tract lysates, PDGF-beta receptor tyrosine phosphorylation was temporally correlated with hypoxic ventilatory roll-off formation. Increased PDGF-B chain mRNA expression was induced by hypoxia in the nucleus of the solitary tract, and PDGF-B chain immunoreactivity colocalized with approximately 40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-beta receptor activation in the nucleus of the solitary tract are critical components of hypoxic ventilatory roll-off and may have important functional implications in processes underlying survival and acclimatization to hypoxic environments.

Behavioural correlates of conditioned ventilatory responses to hypoxia in rats

To examine the possible contribution of behavioural arousal to ventilatory conditioning, we performed a differential conditioning experiment using two odours as the paired conditioned stimulus (CS+) and unpaired conditioned stimulus (CS−) and a hypoxic mixture (7.5% O 2) as the unconditioned stimulus (US) in 24 adult male rats. Vanillin was the CS+ and rose the CS− in half the rats, and vice versa in the other half. Each rat underwent 26 paired CS+/hypoxia trials and 26 CS− trials in alternation, followed by two CS+ only and two CS− trials to test for conditioning. Analysis of breathing variables and behavioural scores during the test showed two qualitatively different conditioned responses. The initial conditioned response was characterised by short breath durations (TT), frequent sniffing episodes, and arousal responses. Following this, a specific, conditioned increase in tidal volume (VT) and levelling off of sniffing and motor activities occurred. The early TT-response and late VT-response to CS+ both contributed to an increase in ventilation (VI). The present data show that the association of an odour and hypoxia elicits a biphasic ventilatory conditioned response, of which the first component is integrated into conditioned arousal.

Effect of Increased Brain GABA Concentrations on Breathing in Unanesthetized Newborn Rabbits

Evidence suggests that γ-aminobutyric acid (GABA) is involved in control of breathing and in the hypoxia-related ventilatory depression in newborns. However, this evidence is obtained mainly from studies on anesthetized animals. Because anesthesia may interfere with the GABA system, the objectives of our study were to examine effects of GABA on ventilation (V_E) and ventilatory response to hypoxia and to reveal effects of repeated hypoxia on GABA concentrations in unanesthetized newborns. The study was performed in rabbits in two age groups: 1–3 days old (group I) and 10–14 days old (group II). To increase brain endogenous GABA concentrations, rabbits were injected with an inhibitor of GABA transaminase, aminooxyacetic acid (AOAA; 20 mg/kg i.p.). To prevent postmortem formation of GABA, at the end of experiments the rabbits received an inhibitor of glutamic acid decarboxylase, IP-3-mercaptopropionic acid (100 mg/kg i.p.). Animals were studied in normoxia alone, or they were exposed for 15 min to 8% O₂ before and 10 and 35 min after saline or AOAA. GABA concentrations were measured in brainstem, cerebrum, and cerebellum by means of a capillary electrophoresis. In group I, AOAA had no respiratory effects. In group II, AOAA decreased V_E, tidal volume, and mean inspiratory flow in normoxia and reversed V_E decline during hypoxia 10 min after the injection, GABA concentrations were not age dependent and the highest in the brainstem. Repeated hypoxia increased the cerebellar GABA concentrations and had no effect in group I. These results imply that in unanesthetized rabbits, GABAergic neurotransmission in the respiratory control network becomes functional by the 2nd week of life, but it does not contribute to the biphasic ventilatory response to moderate hypoxia. In contrast, GABA-evoked block of the cerebellar inhibitory input during hypoxia may be responsible for the reversal of the V_E decline in unanesthetized newborns.

Ventilatory Responses to Acute and Sustained Hypoxia During Sevoflurane Anesthesia in Women

We investigated the isocapnic hypoxic (i.e., pulse oximetry monitored arterial saturations 70%-75%) ventilatory response (HVR) for 20 min in the awake state and during sevoflurane anesthesia at an end-tidal concentration of 1.6% in eight healthy (ASA physical status I) women. Our aims were to determine if a prolonged isocapnic hypoxic period during sevoflurane anesthesia showed a biphasic response pattern (i.e., an initial acute HVR followed by a decline to a lowered sustained HVR) and, if so, to quantify to what extent the acute and sustained HVRs were depressed by anesthesia. The study was conducted before laparoscopic gynecological surgery. Pneumotachography and in-line infrared capnography were used. The pattern of awake biphasic HVR was maintained during anesthesia but was depressed during both the acute and the sustained phases by 60% and 70%, respectively. Further, HVR during anesthesia was accomplished by an increase in respiratory rate, in contrast to an increase in tidal volume in the awake state. In conclusion, sevoflurane anesthesia at 1.6% depresses HVR in women, but the biphasic response is maintained. Implications: Acute and sustained hypoxic ventilatory responses were investigated in eight women before and during sevoflurane anesthesia. A biphasic ventilatory response was persistent but blunted during anesthesia. (Anesth Analg 1999;89:209-14)