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Biomedical subjects

J A Neubauer

Publications and source records attributed to J A Neubauer.

At least 19 recordsLinked to original sources
PubMed2001

Invited review: Physiological and pathophysiological responses to intermittent hypoxia.

This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.

Adaptation, Physiological↗
PubMed2001

Expression of heme oxygenase in the oxygen-sensing regions of the rostral ventrolateral medulla.

Recently, unique regions in the rostral ventrolateral medulla (RVLM) have been found to be oxygen sensitive. However, the mechanism of sensing oxygen in these RVLM regions is unknown. Because heme oxygenase (HO) has been shown to be involved in the hypoxic responses of the carotid body and pulmonary artery, the aim of this study was to determine whether HO is present in the RVLM and whether expression of HO is altered by chronic hypoxia. Adult rats were exposed to hypoxia (10% O(2)) or normoxia (21% O(2)) for 10 days, and the mRNA for HO-1 and HO-2 was examined in the RVLM by using RT-PCR. Expression of HO-2 mRNA was seen in the RVLM of both control and hypoxic samples, whereas expression of HO-1 mRNA was only seen in the RVLM of hypoxic samples. HO-2 was immunocytochemically localized in brain sections (40 microm) to the C1 region and pre-Bötzinger complex of the RVLM. Together, these results indicate that HO-2 is present in the RVLM under control conditions and that HO-1 is induced in the RVLM during chronic hypoxia, consistent with a potential role for HO in the oxygen-sensing function of these cardiorespiratory RVLM regions.

Animals↗
PubMed2000

Hypoxic excitation in neurons cultured from the rostral ventrolateral medulla of the neonatal rat.

Neurons within cardiorespiratory regions of the rostral ventrolateral medulla (RVLM) have been shown to be excited by local hypoxia. To determine the electrophysiological properties of these excitatory responses to hypoxia, we developed a primary dissociated cell culture system to examine the intrinsic response of RVLM neurons to hypoxia. Neonatal rat neurons plated on medullary astrocyte monolayers were studied using the whole cell perforated patch-clamp technique. Sodium cyanide (NaCN, 0.5-10 mM) was used, and membrane potential (V(m)), firing frequency, and input resistance were examined. In 11 of 19 neurons, NaCN produced a V(m) depolarization, an increase in firing frequency, and a decrease in input resistance, suggesting the opening of a cation channel. The hypoxic depolarization had a linear dose response and was dependent on baseline V(m), with a greater response at more hyperpolarized V(m). In 8 of 19 neurons, NaCN produced a V(m) hyperpolarization, decrease in firing frequency, and variable changes in input resistance. The V(m) hyperpolarization exhibited an all-or-none dose response and was independent of baseline V(m). These differential responses to NaCN were retained after synaptic blockade with low Ca(2+)-high Mg(2+) or TTX. Thus hypoxic excitation 1) is maintained in cell culture, 2) is an intrinsic response, and 3) is likely due to the increase in a cation current. These hypoxia-excited neurons are likely candidates to function as central oxygen sensors.

Animals↗
PubMed2000

Pre-Bötzinger complex functions as a central hypoxia chemosensor for respiration in vivo.

Recently, we identified a region located in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) in which activation of ionotropic excitatory amino acid receptors using DL-homocysteic acid (DLH) elicits a variety of excitatory responses in the phrenic neurogram, ranging from tonic firing to a rapid series of high-amplitude, rapid rate of rise, short-duration inspiratory bursts that are indistinguishable from gasps produced by severe systemic hypoxia. Therefore we hypothesized that this unique region is chemosensitive to hypoxia. To test this hypothesis, we examined the response to unilateral microinjection of sodium cyanide (NaCN) into the pre-BötC in chloralose- or chloralose/urethan-anesthetized vagotomized, paralyzed, mechanically ventilated cats. In all experiments, sites in the pre-BötC were functionally identified using DLH (10 mM, 21 nl) as we have previously described. All sites were histologically confirmed to be in the pre-BötC after completion of the experiment. Unilateral microinjection of NaCN (1 mM, 21 nl) into the pre-BötC produced excitation of phrenic nerve discharge in 49 of the 81 sites examined. This augmentation of inspiratory output exhibited one of the following changes in cycle timing and/or pattern: 1) a series of high-amplitude, short-duration bursts in the phrenic neurogram (a discharge similar to a gasp), 2) a tonic excitation of phrenic neurogram output, 3) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a gasplike burst), or 4) an increase in frequency of phrenic bursts accompanied by small increases or decreases in the amplitude of integrated phrenic nerve discharge. Our findings identify a locus in the brain stem in which focal hypoxia augments respiratory output. We propose that the respiratory rhythm generator in the pre-BötC has intrinsic hypoxic chemosensitivity that may play a role in hypoxia-induced gasping.

Animals↗
PubMed1999

Patterns of phrenic motor output evoked by chemical stimulation of neurons located in the pre-Bötzinger complex in vivo.

The pre-Bötzinger complex (pre-BötC) has been proposed to be essential for respiratory rhythm generation from work in vitro. Much less, however, is known about its role in the generation and modulation of respiratory rhythm in vivo. Therefore we examined whether chemical stimulation of the in vivo pre-BötC manifests respiratory modulation consistent with a respiratory rhythm generator. In chloralose- or chloralose/urethan-anesthetized, vagotomized cats, we recorded phrenic nerve discharge and arterial blood pressure in response to chemical stimulation of neurons located in the pre-BötC with DL-homocysteic acid (DLH; 10 mM; 21 nl). In 115 of the 122 sites examined in the pre-BötC, unilateral microinjection of DLH produced an increase in phrenic nerve discharge that was characterized by one of the following changes in cycle timing and pattern: 1) a rapid series of high-amplitude, rapid rate of rise, short-duration bursts, 2) tonic excitation (with or without respiratory oscillations), 3) an integration of the first two types of responses (i.e., tonic excitation with high-amplitude, short-duration bursts superimposed), or 4) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a high-amplitude, short-duration burst). In 107 of these sites, the phrenic neurogram response was accompanied by an increase or decrease (>/=10 mmHg) in arterial blood pressure. Thus increases in respiratory burst frequency and production of tonic discharge of inspiratory output, both of which have been seen in vitro, as well as modulation of burst pattern can be produced by local perturbations of excitatory amino acid neurotransmission in the pre-BötC in vivo. These findings are consistent with the proposed role of this region as the locus for respiratory rhythm generation.

Animals↗
PubMed1997

Characterization of the rat carbonic anhydrase II gene structure: sequence analysis of the 5' flanking region and 3' UTR.

The rat carbonic anhydrase II gene was characterized and found to be approximately 15.5 kb in length and to contain 7 exons and 6 introns. All intron/exon junction and branch point sequences conform to consensus sequences, and the overall rat CA II genomic structure appears to be conserved upon comparison with mouse, human, and chicken CA II genes. The putative cis-acting elements within the analyzed 1014 bp 5' flanking region include: TATA box, 4 Sp1 binding sites, 2 AP2 sites and putative tissue-specific beta-globin-like repeat elements. A CpG island of approximately 800 bp was identified that begins about 600 bp upstream of exon 1 and extends about 200 bp into intron 1. In the 3' UTR, two polyadenylation signals (AATAAA) are present, the second of which is believed to be utilized. Northern blot analysis reveals that the 1.7 kb rat CA II mRNA is abundantly expressed in adult male brain and kidney, while negligible amounts are detected in heart and liver.

Animals↗
PubMed1996

Respiration and medullary blood flow during sinusoidal hypoxia in the peripherally chemodenervated cat.

The hypothesis that hypoxic respiratory depression is mediated by changes in medullary blood flow (MBF) was assessed in 18 anesthetized, paralyzed, vagotomized, peripherally chemodenervated, ventilated cats exposed to sinusoidal hypoxic hypoxia. In nine cats, the dynamic response of the central respiratory controller to hypoxia was studied by varying the cycle time of sinusoidal hypoxia (cycle time = 2.5, 4, 6, 10, and 15 min). Peak phrenic neurogram amplitude (PNA) followed sinusoidal oscillations in the hypoxic input [arterial O2 saturation (SaO2)] at all cycle times. The relationship between PNA and SaO2 was expressed as the transfer function of the system and was approximated as a first-order differential equation with a time constant of 78 +/- 1 s, a value consistent with a previous measurement of the time constant of the change in respiration following a change in brain blood flow. In a separate study, MBF was continuously measured during sinusoidal hypoxia (cycle time = 6 min; n = 9) with a laser-Doppler flow probe to directly assess the role of MBF in production of hypoxic respiratory depression. PNA and MBF followed SaO2 oscillations during sinusoidal hypoxia. Infusion of sodium nitroprusside (20 micrograms.kg-1.min-1 iv) increased MBF by 30-40% and abolished MBF oscillations during subsequent sinusoidal hypoxia but had no effect on PNA oscillations. We conclude that the increase in brain blood flow seen during sinusoidal hypoxia is not the primary cause of the accompanying central hypoxic respiratory depression.

Animals↗
PubMed1996

Respiratory and sympathetic activity during recovery from hypoxic depression and gasping in cats.

In peripherally chemodenervated, vagotomized, chloralose-anesthetized cats, hypoxia can produce central cardiorespiratory depression or excitation depending on severity. We monitored phrenic and cervical sympathetic neurograms during either hypoxic depression or gasping and 30 min of subsequent isocapnic reoxygenation to determine whether the response of these outputs during hypoxia predicts their activity during recovery. Three levels of hypoxic response were produced in cats: 1) reduction of phrenic neurogram amplitude (PNA) by 30% [fractional inspired O2 (FIO2) = 14-18%)]; 2) production of phrenic apnea (FIO2 = 9-10%); and 3) hypoxic gasping (FIO2 = 6-8%). Recovery from the milder levels of hypoxia was characterized by transient (< 10 min) depression of PNA and inspiratory synchronous sympathetic activity. Respiratory frequency was unaffected or only transiently depressed. Tonic sympathetic activity was unaffected. During reoxygenation after gasping, both PNA and inspiratory synchronous sympathetic activity were initially increased by 80% over control levels and respiratory frequency was depressed. Tonic sympathetic activity increased during hypoxia but returned to control levels after a brief undershoot on reoxygenation. All variables returned to control levels within 15 min. Measurement of medullary extracellular K+ concentration ([K+]e) in a separate group of cats indicated that a significant increase in this variable was associated with hypoxic gasping but was not correlated with PNA augmentation during reoxygenation. We hypothesize that increased [K+]e coincident with gasping may trigger a postanoxic potentiation of respiratory premotor neurons similar to that described in hippocampus.

Animals↗
PubMed1996

Autoregressive spectral analysis of phrenic neurogram during eupnea and gasping.

During hypoxic gasping, the phrenic neurogram (PN) has a steeper rate of rise, an augmented amplitude, and a shorter duration than is seen during eupnea. Because hypoxia reduces neuronal activity, we hypothesized that gasping would be characterized in the frequency domain by enhanced low-frequency power compared with eupnea. Autoregressive (AR) spectral analysis of the PN in chloralose-anesthetized, vagotomized, peripherally chemodenervated cats was performed during eupnea and hypoxic gasping. During eupnea, significant spectral peaks were seen at 41 +/- 2 and 93 +/- 2 (SE) Hz. In all cats, the 41-Hz spectral peak disappeared during hypoxic gasping and was replaced by a high-power, low-frequency peak at 26 +/- 1 Hz. No consistent change in the frequency or power of the high-frequency spectral peak was seen during gasping. To determine whether changes in the AR spectrum of the PN during gasping result from augmented respiratory output, we compared the AR spectra of the PN during gasping, hypercapnia (end-tidal CO2 fraction = 0.09), and carotid sinus nerve stimulation. Unlike during gasping, there was no shift in power toward lower frequencies during hypercapnia and carotid sinus nerve stimulation. We conclude that the spectral characteristics of gasping, loss of the medium-frequency peak and the appearance of low-frequency (< 30-Hz) power, are unique to this respiratory pattern.

Animals↗
PubMed1995

Mechanisms of apnea.

Instabilities in breathing pattern are a common feature of sleep, giving rise to a variety of syndromes that vary in the magnitude of respiratory disturbance but that all lead to frequent arousals and sleep fragmentation. Although these syndromes vary in intensity of respiratory disturbance, the underlying mechanism of each is determined to a large extent on the neural processes that promote periodicities in net respiratory output. This review focuses on recent publications that have evaluated central brainstem processes for their involvement in the initiation and resolution of an apneic episode. In particular, this review focuses on several neural processes that can play an important role in promoting respiratory instability. These include spontaneous oscillations within the respiratory network, instability in the chemical control system due to increased gain in the feedback controller, differences in the controller gains of the upper airway and pump muscle effectors, state-dependent instabilities, and loss of stabilizing processes (eg, poststimulus potentiation.)

Humans↗
PubMed1993

Phrenic and sympathetic nerve responses to glutamergic blockade during normoxia and hypoxia.

Because hypoxia increases brain extracellular glutamate levels, we hypothesized that gasping and increased sympathetic activity during severe hypoxia result from glutamergic excitation. To test this hypothesis, we exposed anesthetized paralyzed vagotomized glomectomized cats to hypoxia before and after N-methyl-D-aspartate (NMDA) glutamergic blockade (MK-801, 1 mg/kg iv) or non-NMDA blockade (NBQX, 3 mg/kg iv) while monitoring phrenic neurogram (PN) and inspiratory-synchronous (ISSN) and tonic (TSN) activity in cervical sympathetic neurogram (SN). Before hypoxia, MK-801 caused apneusis and reduced PN and ISSN amplitude by 38 and 84%, respectively, but TSN activity was unaffected. During hypoxia, MK-801 had no effect on PN gasping or TSN activity but reduced ISSN amplitude during gasping. Before hypoxia, NBQX reduced PN and ISSN amplitude by 54 and 60%, respectively but did not affect inspiratory timing or TSN activity. Gasping activity in PN and ISSN and TSN activity during hypoxia were unaffected by NBQX. We conclude that 1) ionotropic glutamergic receptor activation is important for eupneic phrenic patterning but is not involved in genesis of gasping, 2) NMDA receptor activation is involved in integration of respiratory and sympathetic activity, and 3) changes in TSN activity are independent of ionotropic glutamergic receptor activation.

Animals↗
PubMed1992

Triangularis sterni and phrenic nerve responses to progressive brain hypoxia.

Activity of the respiratory muscles that are not normally active during eupnea (genioglossal and abdominal) has been shown to be more vulnerable to hypoxic depression than inspiratory diaphragmatic activity. We hypothesized that respiratory muscles that are active at eupnea would be equally vulnerable to isocapnic progressive brain hypoxia (PBH). Phrenic (PHR) and triangularis sterni nerve (TSN) activity were recorded in anesthetized peripherally chemodenervated vagotomized ventilated cats. Hypercapnia [arterial PCO2 (PaCO2) = 57 +/- 3 (SE) Torr] produced parallel increases in peak PHR and TSN activity. PBH [0.5% CO-40% O2-59.5% N2, arterial O2 content (CaO2) reduced from 13.1 +/- 1.0 to 3.7 +/- 0.3 vol%] resulted in parallel decreases of peak PHR and TSN activity to neural apnea. PBH was continued until PHR gasping ensued (CaO2 = 2.9 +/- 0.2 vol%); TSN activity remained silent during gasping. After 6-12 min of recovery (95% O2-5% CO2; CaO2 = 7.8 +/- 0.8 vol%; PaCO2 = 55 +/- 2 Torr), peak PHR activity was increased to 110 +/- 18% (% of activity at 9% CO2) whereas peak TSN activity was augmented to 269 +/- 89%. The greater augmentation of TSN activity during the recovery period could not be explained solely by hypercapnia. In conclusion, we found that 1) TSN expiratory and PHR inspiratory activities are equally vulnerable to hypoxic depression and 2) recovery from severe hypoxia is characterized by a profound augmentation of TSN expiratory activity.

Animals↗
PubMed1992

Modulation of respiratory responses to carotid sinus nerve stimulation by brain hypoxia.

This study examines the effect of progressive isocapnic CO hypoxemia on respiratory afterdischarge and the phrenic neurogram response to supramaximal carotid sinus nerve (CSN) stimulation. Twelve anesthetized, vagotomized, peripherally chemodenervated, ventilated cats with blood pressure controlled were studied. During isocapnic hypoxemia, the amplitude of the phrenic neurogram was progressively depressed. In contrast, the increase in peak phrenic amplitude produced by CSN stimulation was unchanged, suggesting that the central respiratory response to CSN stimulation is unaffected by progressive hypoxemia. The time constant of respiratory afterdischarge (tau) was calculated from best-fit plots of phrenic amplitude vs. time after cessation of CSN stimulation. Under control conditions the value of tau was 57.7 +/- 3 (SE) s (n = 12). During progressive isocapnic hypoxemia, tau decreased as a linear function of arterial O2 content (CaO2) such that a 40% reduction of CaO2 resulted in a 48% reduction in tau. This reduction of respiratory afterdischarge may contribute to the genesis of periodic breathing during hypoxia.

Animals↗
PubMed1991

Chemosensitivity of medullary neurons in explant tissue cultures.

To determine whether cultured medulla contains chemosensitive neurons which are excited by CO2 and fixed acid and whether this function is specific to the ventral medulla, tissue explants of ventral and dorsal medulla were prepared from neonatal rats and incubated for two to three weeks. Cultures were superfused with artificial cerebrospinal fluid, maintained at 37 degrees C, and pH of the superfusate was varied either with PCO2 (14-71 Torr) at constant HCO3- (22 mM) or HCO3- (10-30 mM) at constant PCO2 (35 Torr). Spontaneous action potentials were recorded extracellularly in 51 ventral and 23 dorsal medullary neurons. Ventral medullary neurons exhibited a steady baseline firing frequency of 4 +/- 0.8 Hz. In contrast, dorsal medullary neurons exhibited two different patterns of spontaneous activity: 11 fired continuously (7.2 +/- 1.4 Hz) while 12 fired with a bursting pattern. Burst duration was 0.80 +/- 0.14 min and cycle time was 1.74 +/- 0.43 min. Decreasing pH with CO2 caused an increase in the activity of 10 of 27 ventral medullary neurons and two of six dorsal medullary neurons with a mean response of 7.5 Hz/pH unit. Varying pH by changing HCO3- had no effect on firing frequency. These results demonstrate that: (i) chemosensitive neurons are present in both ventral and dorsal medullary explant cultures; (ii) these cells only respond to changes in pH induced with CO2; and (iii) about half of the dorsal medullary neurons fire spontaneously with a regular bursting pattern of activity.

Action Potentials↗
PubMed1991

Extracellular potassium homeostasis in the cat medulla during progressive brain hypoxia.

Brain extracellular potassium [( K+]ec) in the ventral respiratory group of the medulla and the phrenic neurogram were recorded in anesthetized vagotomized peripherally chemodenervated ventilated cats during progressive isocapnic carbon monoxide (CO) hypoxia. During hypoxia, the phrenic neurogram was progressively depressed and became silent when arterial O2 content (CaO2) was reduced by 62 +/- 3% (SE). Gasping was seen in the phrenic neurogram when CaO2 was reduced by 78 +/- 1%. Medullary [K+]ec, an indicator of energy production failure due to O2 insufficiency, was 3.2 +/- 0.4 mM before hypoxia and was statistically unchanged at the onset of phrenic apnea during CO hypoxia (4 +/- 0.7 mM). By the onset of gasping, [K+]ec had increased to 6.1 +/- 1 mM, a value that tended to be different from control (P less than 0.1). After initiation of gasping, the rate of rise of [K+]ec increased, and [K+]ec reached a maximum value of 14.3 +/- 2.7 mM before hypoxia was terminated. With reoxygenation, [K+]ec returned to control levels within 20 min. On the basis of these results, we have drawn two major conclusions. 1) Hypoxic depression to the point of phrenic apnea does not appear to be caused by medullary energy insufficiency as measured by loss of [K+]ec homeostasis. 2) The rapid rise in [K+]ec in the medulla that characterizes severe hypoxia is closely associated with the onset of gasping in the phrenic neurogram, suggesting that gasping may serve as a marker for loss of medullary ionic homeostasis and thus onset of medullary energy insufficiency during hypoxia.

Animals↗