Ionotropic excitatory amino acid receptors in pre-Botzinger complex play a modulatory role in hypoxia-induced gasping in vivo.

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-B?tzinger complex (pre-B?tC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-B?tC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-B?tC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-B?tC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased (P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure (P < 0.05), the duration of gasps was prolonged (P < 0.05), and the duration between gasps was increased (P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-B?tC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-B?tC as the primary locus of respiratory rhythm generation.     

Power spectra of inspiratory nerve activity with lung inflations in cats

To investigate the effect of lung inflations on the high-frequency synchrony (70-122 Hz) observed in the inspiratory activity of respiratory motor nerves of decerebrate cats, I applied a step increase in lung inflation pressure at fixed delays into the inspiratory phase and computed power spectra of phrenic neurograms before and during inflation. In 25 decerebrate paralyzed cats the frequency of the high spectral peak was 92.3 +/- 11.1 Hz before and 105.3 +/- 12.1 Hz during the step in inflation pressure, shifting upward by 13.0 +/- 6.0 Hz. For 8 of the 25 cats, the recurrent laryngeal and phrenic neurograms were recorded simultaneously. The high spectral peak was present during inspiration in the recurrent laryngeal power spectra and coherent with the high peak in the phrenic power spectra. In response to lung inflation, the high peak disappeared from the power spectra of the recurrent laryngeal nerve as the inspiratory activity was inhibited; a shift upward in frequency was not detectable. Comparing inspiratory times (TI, based on the phrenic neurograms) for breaths with no lung inflations to those for breaths with lung inflations, I found that lung inflations early in inspiration caused a decrease in TI, lung inflations at intermediates times had no effect on TI, and lung inflations late in inspiration caused an increase in TI. Despite lung inflation decreasing, not affecting, or increasing inspiratory duration and amplitude of the phrenic neurogram, lung inflation always caused a shift upward in the high-frequency peak of the phrenic power density. The fact that lung inflation, a powerful respiratory stimulus, affected the frequency of the high peak in a consistent manner suggests that the high-frequency synchrony is an important and robust feature of the central respiratory pattern generator.     

Comparison of phrenic motoneuron activity during eupnea and gasping

Single-fiber phrenic nerve action potentials were recorded together with activity of contralateral whole phrenic nerve rootlets during eupnea and gasping in decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats. Gasping was reversibly produced by cooling a fork thermode positioned through the pontomedullary junction. In eupnea, phrenic motoneurons were distributed into "early" and "late" populations relative to their onset of activity during inspiration. During gasping, however, both fiber types typically commenced activity at the beginning of the phrenic nerve burst. Moreover, late fibers, but not early units, exhibited an augmentation of discharge frequency with the onset of gasping. The concentration of activity of all phrenic motoneurons at the beginning of inspiration and the increase in late-unit discharge frequency account for the faster rise of the gasp as compared with the eupneic breath. It is concluded that the pattern of phrenic nerve activation during gasping differs fundamentally from that during eupnea. These results support the concept that mechanisms underlying the neurogenesis of gasping and eupnea may not be identical.     

Characterization by stimulation of medullary mechanisms underlying gasping neurogenesis

Our purpose was to evaluate the hypothesis that neurons in the lateral tegmental field of the medulla comprise a pattern generator for neurogenesis of gasping. Stimulations in this area produced changes characteristic of pattern generators in other systems. These included shifts in gasping rhythm and refractory periods for eliciting gasps; the latter varied inversely with spontaneous gasping frequency. These responses were recorded from activities of phrenic and hypoglossal nerves of decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats. Gasping followed freezing the brain stem between pons and medulla. In addition to lateral tegmental loci, gasps were elicited by stimulating areas extending lateral to the nucleus ambiguus and medial to the contralateral medulla. These areas are envisaged to contain axons to or from the pattern generator of lateral tegmental field. Finally, stimulations in sites approximating nucleus tractus solitarius and nucleus ambiguus delayed spontaneous gasps and terminated ongoing gasps. Current required to terminate gasps fell during neural inspiration. Our data are consistent with the lateral tegmental field of medulla comprising a central pattern generator for gasping and pacemaker elements being a component of this pattern generator.     

Differing activities of medullary respiratory neurons in eupnea and gasping

Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate, paralyzed, and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal, laryngeal, or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea, activities of inspiratory neurons commenced at various times during inspiration, and for most the discharge frequency gradually increased. In gasping, the peak discharge frequency of inspiratory neurons was unaltered. However, all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping, with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.     

Recovery of breathing pattern after 15 min of cerebral ischemia in rabbits

The study was undertaken to ascertain the neural control of breathing and vagal reflexes during and after cerebral ischemia. The experiments were performed on anesthetized, paralyzed, and artificially ventilated rabbits. Cerebral ischemia was induced by reversible intrathoracic occlusion of the brachiocephalic trunk and the left subclavian and both internal thoracic arteries for 15 min. The effect of cerebral ischemia on breathing pattern was assessed by monitoring the integrated activities of phrenic and recurrent laryngeal nerves. Ischemia produced enhancement of breathing followed by apnea and gasping. During enhanced breathing as well as during gasping, the inspiratory-inhibiting effect of lung inflation (Breuer-Hering reflex) was abolished. When brain circulation was restored, respiratory activity started with gasps, which later were intermingled with eupneic type of inspirations. During the onset of a eupneic breath, lung inflation produced inspiratory facilitation but never an inhibition. However, after 30 min of recovery from cerebral ischemia, the Breuer-Hering reflex was restored. Results show that precise analysis of vagal reflexes and respiratory pattern during ischemia and resuscitation may be used as an indicator of resumption of autonomic activity in the brain stem.     

Neurogenesis, control, and functional significance of gasping

Gasps are frequently the first and last breaths of life. Gasping, which is generated by intrinsic medullary mechanisms, differs fundamentally from other automatic ventilatory patterns. A region of the lateral tegmental field of the medulla is critical for the neurogenesis of the gasp but has no role in eupnea. Neuronal mechanisms in separate brain stem regions may be responsible for the neurogenesis of different ventilatory patterns. This hypothesis is supported by the recording of independent respiratory rhythms simultaneously from isolated brain stem segments. Data from fetal and neonatal animals also support gasping and eupnea being generated by separate mechanisms. Gasping may represent the output of a simple but rugged pattern generator that functions as a backup system until the control system for eupnea is developed. Pacemaker elements are hypothesized as underlying the onset of inspiratory activity in gasping. Similar elements, in a different brain stem region, may be responsible for the onset of the eupneic inspiration with neural circuits involving the pons, the medulla, and the spinal cord serving to shape efferent respiratory-modulated neural discharges.     

Identification of medullary loci critical for neurogenesis of gasping

We hypothesized that a discrete medullary locus, critical for gasping neurogenesis, could be identified. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, activities of phrenic, hypoglossal, and recurrent laryngeal nerves were monitored. Gasping was induced by freezing the brain stem, via a fork thermode, at the pontomedullary junction. By reversible cooling of the medulla, chemical lesions with kainic acid, and radio-frequency lesions, a critical area for gasping neurogenesis was localized bilaterally 2-3 mm rostral to obex, 2.0-2.5 mm lateral to midline, and 3-4 mm ventral to medullary surface. Electrical stimulation in this area elicited premature gasps, whereas unilateral lesions or lidocaine injections eliminated gasping activities in all nerves. These procedures did not cause similar changes during eupnea. In apneusis, however, lidocaine injections markedly altered the pattern or caused apnea. We conclude that discharge of neurons in a discrete portion of the lateral tegmental field of medulla is required for gasping neurogenesis. Our results are consistent with these neurons comprising the central pattern generator for gasping.     

Potential switch from eupnea to fictive gasping after blockade of glycine transmission and potassium channels

This study evaluated possible neuronal mechanisms responsible for the transition from normal breathing (eupnea) to gasping. We hypothesized that a blockade of both inhibitory glycinergic synaptic transmission and potassium channels, combined with an increase in extracellular concentration of potassium, would induce a switch from an eupneic respiratory pattern to gasping. Efferent activities of the phrenic, vagal, and hypoglossal nerves were recorded during eupnea and ischemia-induced gasping in a perfused in situ preparation of the juvenile rat (4-6 wk of age). To block potassium channels, 4-aminopyridine (4-AP, 1-10 microM) was administered. Strychnine (0.2-0.6 microM) was used to block glycinergic neurotransmission. After administrations of 4-AP, excess extracellular potassium (10.25-17.25 mM), and strychnine, the incrementing pattern of eupneic phrenic activity was altered to a decrementing discharge. Hypoglossal and vagal activities became concentrated to the period of the phrenic burst with expiratory activity being reduced or eliminated. These changes in neural activities were similar to those in ischemia-induced gasping. Results are consistent with the concept that the elicitation of gasping represents a switch from a network-based rhythmogenesis for eupnea to a pacemaker-driven mechanism.     

Selective loss of high-frequency oscillations in phrenic and hypoglossal activity in the decerebrate rat during gasping

Respiratory motor outputs contain medium-(MFO) and high-frequency oscillations (HFO) that are much faster than the fundamental breathing rhythm. However, the associated changes in power spectral characteristics of the major respiratory outputs in unanesthetized animals during the transition from normal eupneic breathing to hypoxic gasping have not been well characterized. Experiments were performed on nine unanesthetized, chemo- and barodenervated, decerebrate adult rats, in which asphyxia elicited hyperpnea, followed by apnea and gasping. A gated fast Fourier transform (FFT) analysis and a novel time-frequency representation (TFR) analysis were developed and applied to whole phrenic and to medial branch hypoglossal nerve recordings. Our results revealed one MFO and one HFO peak in the phrenic output during eupnea, where HFO was prominent in the first two-thirds of the burst and MFO was prominent in the latter two-thirds of the burst. The hypoglossal activity contained broadband power distribution with several distinct peaks. During gasping, two high-amplitude MFO peaks were present in phrenic activity, and this state was characterized by a conspicuous loss in HFO power. Hypoglossal activity showed a significant reduction in power and a shift in its distribution toward lower frequencies during gasping. TFR analysis of phrenic activity revealed the increasing importance of an initial low-frequency "start-up" burst that grew in relative intensity as hypoxic conditions persisted. Significant changes in MFO and HFO rhythm generation during the transition from eupnea to gasping presumably reflect a reconfiguration of the respiratory network and/or alterations in signal processing by the circuitry associated with the two motor pools.     

CO(2)/H(+) chemoreception in the cat pre-B?tzinger complex in vivo.

We examined the effects of focal tissue acidosis in the pre-B?tzinger complex (pre-B?tC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10-20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 microM) or methazolamide (MZ; 50 microM). Microinjection of AZ and MZ into 14 sites in the pre-B?tC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5-15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO(2)/H(+) brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-B?tC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-B?tC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO(2)/H(+) and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.     

Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces patterns of phrenic discharge comparable to eupnea and gasping in vivo. These ventilatory patterns differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Although we have recently demonstrated that both eupnea and gasping are similarly modulated by a Hering-Breuer expiratory-promoting reflex to tonic pulmonary stretch, it has generally been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, we recorded eupneic and gasplike efferent activity of the phrenic nerve in the in situ juvenile rat perfused brain stem preparation, with and without phrenic-triggered phasic pulmonary inflation. We tested the hypothesis that phasic pulmonary inflation produces reflex responses in situ akin to those in vivo and that both eupnea and gasping are similarly modulated by phasic pulmonary stretch. In eupnea, we found that phasic pulmonary inflation decreases inspiratory burst duration and the period of expiration, thus increasing burst frequency of the phrenic neurogram. Phasic pulmonary inflation also decreases the duration of expiration and increases the burst frequency during gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns respond to phasic activation of pulmonary stretch receptors in both eupnea and gasping. These findings support the homology of eupneic phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Autoresuscitation: a survival mechanism in piglets.

Piglets were studied to determine 1) the cardiovascular and neurophysiological effects of prolonged laryngeal-induced respiratory inhibition (n = 7) and 2) whether these effects were modulated by autonomic blockade (n = 6). Respiration, electrocardiogram, electroencephalogram (EEG), and blood pressure were recorded, and blood gases were measured. During continuous laryngeal stimulation in the presence of light anesthesia, apnea was interrupted every 1-2.5 min by clusters of two to six breaths. Compared with control, these breaths had a significantly greater tidal volume (430 +/- 30% of control), shorter inspiratory time (87 +/- 5%), and longer expiratory time (124 +/- 15%) and, thus, were of a gasping nature. With each cluster of gasps, arterial PO2 increased from 15 +/- 2 to 56 +/- 5 Torr, heart rate from 84 +/- 7 to 161 +/- 5 beats/min, and mean blood pressure from 48 +/- 4 to 106 +/- 6 mmHg. The EEG became flat by 1 min after the onset of apnea and remained isoelectric throughout the stimulus period. Cyclical gasps were not affected by sympathetic or parasympathetic blockade. These data show that, despite EEG silence, piglets can autoresuscitate by initiating gasps that are not dependent on autonomic integrity. These gasps markedly improve cardiovascular status and may sustain animals for a prolonged period of time.     

Expiratory neural activities in gasping

The purpose was to characterize expiratory-related neural activities in eupnea and gasping. In decerebrate and vagotomized cats, activities were recorded from the phrenic nerve, spinal intercostal and abdominal nerves, and recurrent laryngeal nerve and its branches. Neural inspiration was defined by phrenic discharge. The spinal and laryngeal nerves discharged in inspiration, expiration, or during both phases. Gasping was induced by freezing the brain stem at the pontomedullary junction, exposure to asphyxia or anoxia, or ligation of the basilar artery and its branches. In gasping, peak phrenic activity typically increased as did inspiratory-related activities of laryngeal and spinal nerves. Expiratory activities were greatly reduced in gasping, with some activities being completely eliminated. Reductions of expiratory activity were more prominent for spinal than laryngeal nerves. Similar results were obtained in cats having intact vagi that were ventilated with a servo-respirator so that lung inflation paralleled phrenic activity. The concept that gasping differs fundamentally form other ventilatory patterns is discussed.     

Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of alpha1-adrenergic receptors and serotonin 5-HT2 receptors.

In severe hypoxia or ischemia, normal eupneic breathing fails and is replaced by gasping. Gasping serves as part of a process of autoresuscitation by which eupnea is reestablished. Medullary neurons, having a burster, pacemaker discharge, underlie gasping. Conductance through persistent sodium channels is essential for the burster discharge. This conductance is modulated by norepinephrine, acting on alpha 1-adrenergic receptors, and serotonin, acting on 5-HT2 receptors. We hypothesized that blockers of 5-HT2 receptors and alpha 1-adrenergic receptors would alter autoresuscitation. The in situ perfused preparation of the juvenile rat was used. Integrated phrenic discharge was switched from an incrementing pattern, akin to eupnea, to the decrementing pattern comparable to gasping in hypoxic hypercapnia. With a restoration of hyperoxic normocapnia, rhythmic, incrementing phrenic discharge returned within 10 s in most preparations. Following addition of blockers of alpha 1-adrenergic receptors (WB-4101, 0.0625-0.500 microM) and/or blockers of 5-HT2 (ketanserin, 1.25-10 microM) or multiple 5-HT receptors (methysergide, 3.0-10 microM) to the perfusate, incrementing phrenic discharge continued. Fictive gasping was still induced, although it ceased after significantly fewer decrementing bursts than in preparations than received no blockers. Moreover, the time for recovery of rhythmic activity was significantly prolonged. This prolongation was in excess of 100 s in all preparations that received both WB-4101 (above 0.125 microM) and methysergide (above 2.5 microM). We conclude that activation of adrenergic and 5-HT2 receptors is important to sustain gasping and to restore rhythmic respiratory activity after hypoxia-induced depression.     

Medullary lateral tegmental field: control of respiratory rate and vagal lung inflation afferent influences on sympathetic nerve discharge

We used spectral analysis and event-triggered averaging to determine the effects of chemical inactivation of the medullary lateral tegmental field (LTF) on 1) the relationship of intratracheal pressure (ITP, an index of vagal lung inflation afferent activity) to sympathetic nerve discharge (SND) and phrenic nerve activity (PNA) and 2) central respiratory rate in paralyzed, artificially ventilated dial-urethane-anesthetized cats. ITP-SND coherence value at the frequency of artificial ventilation was significantly (P<0.05; n=18) reduced from 0.73+/-0.04 (mean+/-SE) to 0.24+/-0.04 after bilateral microinjection of muscimol into the LTF. Central respiratory rate was unexpectedly increased in 12 of these experiments (0.28+/-0.03 vs. 0.95+/-0.25 Hz). The ITP-PNA coherence value was variably affected by chemical inactivation of the LTF. It was unchanged when central respiratory rate was also not altered, decreased when respiratory rate was increased above the rate of artificial ventilation, and increased when respiratory rate was raised from a value below the rate of artificial ventilation to the same frequency as the ventilator. Chemical inactivation of the LTF increased central respiratory rate in four of six vagotomized cats but did not significantly affect the PNA-SND coherence value. These data demonstrate that the LTF 1) plays a critical role in mediating the effects of vagal lung inflation afferents on SND but not PNA, 2) helps maintain central respiratory rate in the physiological range, but 3) is not involved in the coupling of central respiratory and sympathetic circuits.     

Biphasic ventilatory response of adult cats to sustained hypoxia has central origin

Hypoxia stimulates ventilation, but when it is sustained, a decrease in the response is often seen. The mechanism of this depression or "roll off" is unclear. In this study we attempted to localize the responsible mechanism at one of three possible sites: the carotid bodies, the central nervous system (CNS), or the ventilatory apparatus. The ventilatory response to sustained hypoxia (PETO2, 40-50 Torr) was tested in 5 awake and 14 anesthetized adult cats. The roll off was found in both anesthetized and awake cats. Isocapnic hypoxia initially increased ventilation as well as phrenic and carotid sinus nerve activity in anesthetized cats (288 +/- 31, 269 +/- 31, 273 +/- 29% of control value, respectively). During the roll off, ventilation and phrenic nerve activity decreased similarly (to 230 +/- 26 and 222 +/- 28%, respectively after the roll off), but in contrast carotid sinus nerve activity remained unchanged (270 +/- 26%). Thus the ventilatory roll off was reflected in phrenic but not in carotid sinus nerve activity. We conclude that the cat represents a useful animal model of the roll off phenomenon and that the mechanism responsible for the secondary decrease in ventilation lays within the CNS.     

Large lesions in the pre-B?tzinger complex area eliminate eupneic respiratory rhythm in awake goats.

In awake goats, 29% bilateral destruction of neurokinin-1 receptor-expressing neurons in the pre-B?tzinger complex (pre-B?tzC) area with saporin conjugated to substance P results in transient disruptions of the normal pattern of eupneic respiratory muscle activation (Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, Feroah T, Davis S, and Forster HV. J Appl Physiol 97: 1620-1628, 2004). Therefore, the purpose of these studies was to determine whether large or total lesioning in the pre-B?tzC area of goats would eliminate phasic diaphragm activity and the eupneic breathing pattern. In awake goats that already had 29% bilateral destruction of neurokinin-1 receptor-expressing neurons in the pre-B?tzC area, bilateral ibotenic acid (10 microl, 50 mM) injection into the pre-B?tzC area resulted in a tachypneic hyperpnea that reached a maximum (132 +/- 10.1 breaths/min) approximately 30-90 min after bilateral injection. Thereafter, breathing frequency declined, central apneas resulted in arterial hypoxemia (arterial Po2 approximately 40 Torr) and hypercapnia (arterial Pco2 approximately 60 Torr), and, 11 +/- 3 min after the peak tachypnea, respiratory failure was followed by cardiac arrest in three airway-intact goats. However, after the peak tachypnea in four tracheostomized goats, mechanical ventilation was initiated to maintain arterial blood gases at control levels, during which there was no phasic diaphragm or abdominal muscle activity. When briefly removed from the ventilator (approximately 90 s), these goats became hypoxemic and hypercapnic. During this time, minimal, passive inspiratory flow resulted from phasic abdominal muscle activity. We estimate that 70% of the neurons within the pre-B?tzC area were lesioned in these goats. We conclude that, in the awake state, the pre-B?tzC is critical for generating a diaphragm, eupneic respiratory rhythm, and that, in the absence of the pre-B?tzC, spontaneous breathing reflects the activity of an expiratory rhythm generator.     

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.     

Cervical sympathetic and phrenic nerve responses to progressive brain hypoxia

To determine if depression of central respiratory output during progressive brain hypoxia (PBH) can be generalized to other brain stem outputs, we examined the effect of PBH on the tonic (tSCS) and inspiratory-synchronous (iSCS) components of preganglionic superior cervical sympathetic (SCS) nerve activity. Peak phrenic and SCS activity were measured in nine anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats. PBH was produced by inhalation of 0.5% CO in 40% O2 while blood pressure and end-tidal CO2 were maintained constant. A progressive reduction in arterial O2 content from 14.3 +/- 0.6 to 4.5 +/- 0.3 vol% caused a 79 +/- 7% depression of peak phrenic activity and an 84 +/- 10% reduction of iSCS activity, but tSCS activity increased 42 +/- 21%. During CO2 rebreathing, iSCS activity increased in parallel with peak phrenic activity while tSCS activity was unchanged. The slopes of the CO2 responses of both phrenic (6.3 +/- 1.2%max/mmHg) and iSCS (4.6 +/- 0.8%max/mmHg) activity were unaffected by PBH. In four of nine hypocapnic and three of nine hypoxic studies, inspiratory activity in the SCS nerve was observed even after completely silencing the phrenic neurogram.(ABSTRACT TRUNCATED AT 250 WORDS)