Role In Control Of Breathing Research Articles

Astrocytes mediate the post‐hypoxic persistent respiratory augmentation

Acute hypoxia increases ventilation. After brief hypoxic exposure, switchback of inspired gas to room air is accompanied by short-term potentiation of breathing, i.e., ventilation remains elevated above the baseline level. Short-term potentiation of breathing has been thought to play a stabilizing role in control of breathing, e.g., prevention of periodic breathing. However, the mechanism of this potentiation is unclear. We aimed to test the hypothesis that astrocytes mediate this potentiation, i.e., post-hypoxic persistent respiratory augmentation (PHRA), and performed a series of in vitro and in vivo experiments. In vitro, isolated brainstem-spinal cord preparations of neonatal rats were superfused with artificial cerebrospinal fluid (aCSF) without or with arundic acid (500 µM), an inhibitory modulator of astrocytic function. Both groups were sequentially superfused with oxygenated (95% O2, 5% CO2) and hypoxic (95% N2, 5% CO2) aCSF for 5 min, and again with oxygenated aCSF for 17 min. Hypoxia universally increased the respiratory burst rate. Without arundic acid, the burst rate transiently decreased with reoxygenation, and then recovered to and remained at the pre-hypoxic level until the end of the post-hypoxic observation. Contrarily, the burst rate steadily decreased throughout the post-hypoxic phase with arundic acid, declining below the pre-hypoxic level. In vivo, the hypoxic ventilatory response was investigated by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas (7% O2, 93% N2) for 2 min, and again room air for 10 min before and after i.p. administration of low (100 mg/kg) and high (300 mg/kg) doses of arundic acid. Minute ventilation in the post-hypoxic recovery was maintained above the pre-hypoxic level without arundic acid. However, it was suppressed with arundic acid. Notably with high dose arundic acid, it decreased below the pre-hypoxic level. Finally, we investigated the significance of the astrocytic TRPA1 channel, which is a ventilatory hypoxic sensor, in the PHRA using astrocyte-specific Trpa1 knockout (asTrpa1-/-) and floxed Trpa1 (Trpa1f/f) mice. Although the PHRA was observed in both Trpa1f/f and as Trpa1-/- mice, it was weaker in asTrpa1-/- as compared to Trpa1f/f mice. This observation indicates that the astrocytic TRPA1 channel plays a role in the PHRA but this by itself is not sufficient, suggesting the existence of additional key factors. These in vitro and in vivo experimental findings collectively demonstrate that astrocytes mediate the PHRA partially through the TRPA1 channel.

Effects of Fluoxetine on Inspiratory Motor Activity and Chemical Control of Breathing in Spontaneously Breathing Urethane‐Anesthetized 6‐OHDA MFB‐lesioned Parkinson’s Disease Rat Model

Breathing abnormalities are a common non‐motor symptom (NMS) of Parkinson’s Disease (PD), and multiple causes have been proposed, including impaired central respiratory control. While the loss of dopaminergic neurons is the primary pathology of PD, it is becoming better appreciated that serotonergic (5‐HT) dysfunction also plays a role in the development of motor and NMS and complications in PD. To this end, recent studies addressing the role of 5‐HT in PD symptoms have revealed that activation or antagonism of specific 5‐HT receptor subtypes may have therapeutic benefit. 5‐HT neurotransmission is also known to play a critical role in control of breathing; thus, respiratory abnormalities in PD may be further complicated by the progressive 5‐HT dysfunction in PD. Ongoing work in our laboratory has been focused on characterizing the respiratory phenotype of PD using 6‐hydroxydopamine (6‐OHDA) neurotoxin‐induced preclinical rat models of PD. Here, we evaluate potential contributions of 5‐HT dysfunction by assessing the effects of acute administration of the selective 5‐HT reuptake inhibitor fluoxetine hydrochloride (FLX) on basal inspiratory motor (diaphragm EMG) activity and hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses in spontaneously breathing urethane‐anesthetized adult female rats 2‐weeks after unilateral medial forebrain bundle (MFB) 6‐OHDA or vehicle/control injection. Basal (BL) diaphragm EMG activity was recorded for ≥30 min, the HVR (12% O2, 90s) and HCVR (7% CO2, 5 min) were assessed, acute FLX (10 mg/kg, iv) was injected and allowed 30 min to exert steady‐state effects, and then the HVR and HCVR were re‐assessed. We found that in both vehicle‐ and 6‐OHDA‐injected rats, administration of FLX produced an initial increase in burst frequency (by ~30%) and amplitude (by ~15%) above BL levels within ~60 s, after which burst frequency attenuated to a new steady‐state level of ~10% above BL levels while burst amplitude returned to slightly below BL levels in vehicle‐injected rats, but attained a new steady‐state level of ~10% above BL levels in 6‐OHDA‐injected rats. The effects of FLX on HVR and HCVR frequency behaviors were negligible in both control‐ and 6‐OHDA‐injected rats although a slight attenuation of the HVR frequency increase (by ~5%) was seen. The effects of FLX on HVR and HCVR amplitude behaviors, while underpowered, showed a trend of slightly enhanced of HVR amplitude (by ~5%) and HCVR amplitude (by ~9%) in 6‐OHDA‐injected rats; however, additional experiments are needed to determine the significance of these observations. While these preliminary observations suggest that (compared to control rats) MFB‐lesioned rats exhibit a difference in FLX‐induced effects on basal inspiratory burst amplitude alterations, acute FLX administration may not be able to fully correct chemical control of breathing deficits. We suggest that additional experiments are needed to better identify specific 5‐HT mechanisms that may contribute to chemical control of breathing deficits in this PD rat model.Support or Funding InformationNIH NS101737; Thomas Hartman Center for Parkinson’s Disease Research at Stony Brook University

Sigh-induced changes of breathing pattern in preterm infants.

Sighs are thought to play an important role in control of breathing. It is unclear how sighs are triggered, and whether preterm birth and lung disease influence breathing pattern prior to and after a sigh in infants. To assess whether frequency, morphology, size, and short-term variability in tidal volume (VT) before, during, and after a sigh are influenced by gestational age at birth and lung disease (bronchopulmonary dysplasia, BPD) in former preterm infants and healthy term controls measured at equivalent postconceptional age (PCA). We performed tidal breathing measurements in 143 infants during quiet natural sleep at a mean (SD) PCA of 44.8 (1.3) weeks. A total of 233 sighs were analyzed using multilevel, multivariable regression. Sigh frequency in preterm infants increased with the degree of prematurity and severity of BPD, but was not different from that of term controls when normalized to respiratory rate. After a sigh, VT decreased remarkably in all infants (paired t-test: P < 0.001). There was no major effect of prematurity or BPD on various indices of sigh morphology and changes in VT prior to or after a sigh. Short-term variability in VT modestly increased with maturity at birth and infants with BPD showed an earlier return to baseline variability in VT following a sigh. In early infancy, sigh-induced changes in breathing pattern are moderately influenced by prematurity and BPD in preterm infants. The major determinants of sigh-related breathing pattern in these infants remain to be investigated, ideally using a longitudinal study design.

Current management of apnea in premature infants: Is caffeine the magic bullet?

Apnea of prematurity is one of the most common problems observed in premature infants and it is associated with other morbidities including worse neurodevelopmental outcome. The incidence is higher in the more immature infants and it occurs in up to 90% of infants born under 28 weeks of gestation. The pathogenesis of apnea is due to immaturity of the respiratory control systems characterized by an abnormal ventilatory response to carbon dioxide and hypoxia combined with immature reflex responses. Upper airway obstruction due to airway instability is also a frequent component in apnea of prematurity. These abnormalities frequently persist until the infants reach 32–36 weeks corrected age or longer in the more immature infants. Severe apneic episodes are frequently associated with hypoxia and bradycardia and because of this they can lead to increased risk of CNS damage and neurological sequelae [1]. Infants who are mechanically ventilated also present frequently with episodes of hypoxemia but the mechanisms for these episodes differ from those of apnea of prematurity. The management of the infant with apnea episodes should start by identifying and correcting known conditions that can increase their incidence. These include metabolic abnormalities such as hypoglycemia, hypocalcemia and metabolic alkalosis, anemia and arterial hypotension, and any condition that increases the work of breathing. Medications that depress CNS activity also favor apnea and should be avoided. The level of arterial oxygenation plays a critical role in control of breathing in premature infants and low arterial oxygen tension increases the incidence of periodic breathing and apnea episodes [2].

Airway mechanoreceptor deactivation

Airway sensors play an important role in control of breathing. Recently, it was found that pulmonary slowly adapting stretch receptors (SARs) cease after a brief excitation following sodium pump blockade by ouabain. This deactivation can be explained by overexcitation. If this is true, mechanical stimulation of the SARs should also lead to a deactivation. In this study, we recorded unit activity of the SARs in anesthetized, open-chest, and mechanically ventilated rabbits and examined their responses to lung inflation at different constant pressures. Forty-seven of 137 units had a clear deactivation during the lung inflation. The deactivation threshold varied from unit to unit. For a given unit, the higher the inflation pressure, the sooner the deactivation occurs. For example, the SARs deactivated at 3.0 +/- 0.3 and 4.8 +/- 0.4 s when the lungs were inflated to constant pressures of 30 and 20 cmH(2)O, respectively (n = 25, P < 0.0001). The units usually ceased after a brief intense discharge. In some units, their activity shifted to a lower level, indicating a pacemaker switching. Our results support the notion that SARs deactivate due to overexcitation.

The effects of positioning on the Hering‐Breuer reflex in the preterm infant

The aim of this study was to determine the effect of positioning on the Hering-Breuer inflation reflex (HBIR) in the preterm infant. Seven, non-intubated, premature infants, ranging in birthweight from 732 to 1450 g with post-conceptual ages of 32-36 weeks were studied. In each infant, pulmonary function testing, including the HBIR was obtained using the SensorMedics 2600 during quiet sleep in the supine and prone position. The strength of the HBIR was quantified by the measurement of the percent prolongation of expiration after an occluded breath. Sleep states were categorized by the criteria of Prechtl. There was a significant difference in Hering-Breuer activity in the prone position versus the supine position with a consistently stronger reflex in the prone position. The mean percent prolongation of expiration was 237 +/- 108% in the prone position versus 95 +/- 32% in the supine position. Analysis of the data, using paired t-testing revealed a mean difference of 142 +/- 119% between prone and supine positions (P=0.028). Significant differences in the strength of the HBIR occur in relation to positioning in the preterm infant. Newborn positioning may affect pulmonary reflexes and may play a role in control of breathing.

Relation between Plasma β-Endorphin and the Ventilatory Response to Hypercapnia in Humans

1. Endogenous opioids have been implicated in the control of breathing in neonates, but their role in ventilatory control in adults remains unclear. 2. We studied the relationship between circulating immunoreactive beta-endorphin and the ventilatory and mouth occlusion pressure responses to hypercapnia in 12 healthy male subjects. In addition, we examined the effect of repetitive hypercapnia on plasma beta-endorphin and cortisol levels. 3. A weak but significant negative relationship between the ventilatory response to hypercapnia and basal plasma beta-endorphin levels was observed (r = -0.35, P less than 0.01). A similar negative relationship was noted between mouth occlusion pressure response to hypercapnia and basal plasma beta-endorphin levels (r = -0.36, P less than 0.01). 4. Repetitive hypercapnia prevented the fall in plasma cortisol that occurred under control conditions (P less than 0.02) but had no effect on plasma beta-endorphin. 5. We conclude that plasma beta-endorphin may play a role in the central chemical control of breathing in man.

Developmental aspects of the effect of naloxone on control of breathing in piglets

The respiratory effects of a stereospecific opiate antagonist, naloxone, were studied in two groups of paralyzed and vagotomized piglets who were servoventilated on 100% oxygen. Phrenic neural activity was used as the index of respiratory output. In 7 piglets less than 10 days of age naloxone infusion caused phrenic minute output to increase 122±36% (P < 0.01). This change was accounted for by a significant increase only in peak phrenic activity, the neural equivalent of tidal volume. Frequency did not change significantly. In 7 piglets 20–34 days of age naloxone infusion caused phrenic minute output to increase 54±12% (P < 0.025). Both peak phrenic activity and frequency were significantly increased. The increase in respiratory output observed in the younger piglets was significantly greater than that of the older piglets (P < 0.05). These findings indicate that endogenous endorphins have a significant, though changing, role in control of breathing in the developing piglet.