Phrenic neural output during hypoxia in dogs: constant-flow ventilation vs. spontaneous breathing.

We studied the effects of removing cyclic pulmonary afferent neural information on respiratory pattern generation in anesthetized dogs. Phrenic neural output during spontaneous breathing (SB) was compared with that occurring during constant-flow ventilation (CFV) at several levels of eucapnic hypoxemia. Hypoxia caused an increase in both the frequency and the amplitude of the moving time average (MTA) phrenic neurogram during both SB and CFV. The change in frequency as arterial saturation was reduced from 90 to 60% during SB was significantly higher than that during CFV [SB, 32.3 +/- 10.9 (SD) breaths/min; CFV, 10.3 +/- 5.8 breaths/min; P = 0.001]. By contrast, the increase in the amplitude of the MTA phrenic neurogram was smaller (SB, 0.62 +/- 0.68 units; CFV, 1.35 +/- 0.81 units; P = 0.01). The changes in frequency with hypoxia during both modes of ventilation resulted primarily from a shortening of expiratory time. Both inspiratory time and expiratory time were greater during CFV than during SB, but their change in response to hypoxia was not significantly different. We conclude that the amplitude response of the MTA phrenic neurogram to hypoxia is similar to that seen during hypercapnia; in the presence of phasic afferent feedback the MTA amplitude response is decreased and the frequency response is increased relative to the response observed in the absence of phasic afferents.     

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.     

Effects of hypercapnia and hypoxia on abdominal expiratory nerve activity

We examined the effects of progressive hypercapnia and hypoxia on the efferent neural activity in a whole abdominal expiratory nerve (medial branch of the cranial iliohypogastric nerve (L1) in anesthetized, paralyzed dogs. To eliminate effects of phasic lung and chest-wall movements on expiratory activity, studies were performed in the absence of breathing movements. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in the paralyzed animals by allowing 3-5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer at a predetermined rate. To quantify abdominal expiratory activity, mean abdominal nerve activity in a nerve burst was computed by integrating the abdominal neurogram and dividing by the duration of the nerve burst. Hypercapnia and hypoxia both increased mean abdominal nerve activity and decreased expiratory duration. In contrast to the ramplike phrenic neurogram, the abdominal neurogram consisted of three phases: an initial rising phase, a plateau phase in which abdominal nerve activity was approximately constant, and a terminal declining phase in which the activity returned to the base-line level. The height of this plateau phase and the rates of rise and decline of abdominal nerve activity all increased with increasing hypercapnia and hypoxia. We conclude that, with proprioceptive inputs constant, both hypercapnia and hypoxia are excitatory to abdominal expiratory neural activity.     

Influence of respiratory network drive on phrenic motor output evoked by activation of cat pre-Botzinger complex

We have previously demonstrated that microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre-B?tzinger complex (pre-B?tC) can produce either phasic or tonic excitation of phrenic nerve discharge during hyperoxic normocapnia. Breathing, however, is influenced by input from both central and peripheral chemoreceptor activation. This influence of increased respiratory network drive on pre-B?tC-induced modulation of phrenic motor output is unclear. Therefore, these experiments were designed to examine the effects of chemical stimulation of neurons (DLH; 10 mM; 10-20 nl) in the pre-B?tC during hyperoxic modulation of CO2 (i.e., hypercapnia and hypocapnia) and during normocapnic hypoxia in chloralose-anesthetized, vagotomized, mechanically ventilated cats. For these experiments, sites were selected in which unilateral microinjection of DLH into the pre-B?tC during baseline conditions of hyperoxic normocapnia [arterial PCO2 (PaCO2) = 37-43 mmHg; n = 22] produced a tonic (nonphasic) excitation of phrenic nerve discharge. During hypercapnia (PaCO2 = 59.7 +/- 2.8 mmHg; n = 17), similar microinjection produced excitation in which phasic respiratory bursts were superimposed on varying levels of tonic discharge. These DLH-induced phasic respiratory bursts had an increased frequency compared with the preinjection baseline frequency (P < 0.01). In contrast, during hypocapnia (PaCO2 = 29.4 +/- 1.5 mmHg; n = 11), microinjection of DLH produced nonphasic tonic excitation of phrenic nerve discharge that was less robust than the initial (normocapnic) response (i.e., decreased amplitude). During normocapnic hypoxia (PaCO2 = 38.5 +/- 3.7; arterial Po2 = 38.4 +/- 4.4; n = 8) microinjection of DLH produced phrenic excitation similar to that seen during hypercapnia (i.e., increased frequency of phasic respiratory bursts superimposed on tonic discharge). These findings demonstrate that phrenic motor activity evoked by chemical stimulation of the pre-B?tC is influenced by and integrates with modulation of respiratory network drive mediated by input from central and peripheral chemoreceptors.     

Entrainment of respiratory rhythm to respiratory oscillations of arterial PCO2 in vagotomized dogs.

The aim of this study was to demonstrate that the medullary respiratory rhythm generator is capable of entraining to respiratory oscillations of arterial PCO2 (CO2 oscillations). We used 10 anesthetized, paralyzed, vagotomized, and mechanically ventilated dogs. First, rate of mechanical ventilation was manually adjusted so that it matched the dog's spontaneous respiratory rate, which established a constant phase relationship between the mechanical ventilation and the burst of phrenic neurogram (initial phase). Then this phase relationship was temporally disturbed by a brief electrical stimulation of the superior laryngeal nerve (SLN). In the control group, the initial phase and the steady-state phase relationship after SLN stimulation were randomly distributed within the phase plane, implying no interaction between the respiratory center and mechanical ventilation. In contrast, when CO2 output from the lung was increased 2.6-fold above the control level by venous CO2 loading, the initial phase and the steady-state phase after SLN stimulation were locked in such a way that the onset of the burst of phrenic neurogram coincided with the peak of CO2 oscillations. This was not demonstrated when the dog was made hyperoxic. We therefore conclude that the respiratory center could entrain to phasic chemical afferent inputs originating from CO2 oscillations, provided they are considerably amplified.     

Respiratory response to partial paralysis in anesthetized dogs

The ability to maintain alveolar ventilation is compromised by respiratory muscle weakness. To examine the independent role of reflexly mediated neural mechanisms to decreases in the strength of contraction of respiratory muscles, we studied the effects of partial paralysis on the level and pattern of phrenic motor activity in 22 anesthetized spontaneously breathing dogs. Graded weakness induced with succinylcholine decreased tidal volume and prolonged both inspiratory and expiratory time causing hypoventilation and hypercapnia. Phrenic peak activity as well as the rate of rise of the integrated phrenic neurogram increased. However, when studied under isocapnic conditions, increases in the severity of paralysis, as assessed from the ratio of peak diaphragm electromyogram to peak phrenic activity, produced progressive increases in inspiratory time and phrenic peak activity but did not affect its rate of rise. After vagotomy, partial paralysis induced in 11 dogs with succinylcholine also prolonged the inspiratory burst of phrenic activity, indicating that vagal reflexes were not solely responsible for the alterations in respiratory timing. Muscle paresis was also induced with gallamine or dantrolene, causing similar responses of phrenic activity and respiratory timing. Thus, at constant levels of arterial CO2 in anesthetized dogs, respiratory muscle partial paralysis results in a decrease in breathing rate without changing the rate of rise of respiratory motor activity. This is not dependent solely on vagally mediated reflexes and occurs regardless of the pharmacological agent used. These observations in the anesthetized state are qualitatively different from the response to respiratory muscle paralysis or weakness observed in awake subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Posterior cricoarytenoid activity in normal adults during involuntary and voluntary hyperventilation

The effect of isocapnic hypoxia and hyperoxic hypercapnia on the electrical activity of the posterior cricoarytenoid (PCA) muscle was determined in eight normal adult humans by use of standard rebreathing techniques and was compared with PCA activity during voluntary hyperventilation performed under isocapnic and hypocapnic conditions. PCA activity was recorded with intramuscular hooked-wire electrodes implanted through a fiberoptic nasopharyngoscope. During quiet breathing in all subjects, the PCA was phasically active on inspiration and tonically active throughout the respiratory cycle. At comparable increments in respiratory output, hypercapnia, hypoxia, and voluntary hyperventilation appeared to be associated with similar increases in phasic or tonic PCA activity. During quiet breathing, the onset of phasic PCA activity usually occurred before inspiratory airflow and extended beyond the start of expiratory airflow. The duration of phasic PCA preactivation and postinspiratory phasic PCA activity remained unchanged during progressive hypercapnia and progressive hypoxia. The results, in combination with recent findings for vocal cord adductors, suggest that vocal cord position throughout the respiratory cycle during hyperpnea is actively controlled by simultaneously acting and antagonistic intrinsic laryngeal muscles.     

CO2 sensitivity of cat phrenic neurogram during hypoxic respiratory depression

The CO2 response of the phrenic neurogram before and during CO-induced isocapnic brain hypoxia was studied in peripherally chemodenervated, vagotomized, paralyzed, ventilated cats with blood pressure held constant. During inhalation of 0.5% CO in 40% O2, arterial O2 content (CaO2) was reduced to 40% and minute phrenic activity to 38.4 +/- 9.4% (SE; n = 9) of prehypoxic levels, primarily due to depression of peak phrenic amplitude (PP). CO2 response, defined as the slope of the plot of PP vs. end-tidal PCO2 during CO2 rebreathing, was unaffected by phrenic depression even to the point of total suppression of phrenic activity in two cats. The effect of the tissue metabolic acidosis associated with hypoxia on phrenic CO2 sensitivity was assessed in a separate group of cats by blocking lactate formation during hypoxia with dichloroacetate (DCA). Preventing lactic acidosis during hypoxia did not affect the CO2 response of the phrenic activity during hypoxia. We conclude that 1) hypoxic depression does not limit the ability of central respiratory neurons to respond to CO2, and 2) the failure of DCA to affect the CO2 response of the phrenic neurogram suggests that brain intracellular lactic acidosis does not modify the phrenic response to hypercapnia.     

Possible mechanisms of periodic breathing during sleep

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.     

Branchial mechanoreceptor activity during spontaneous ventilation in channel catfish

Extracellular afferent neural activity was recorded in vivo from cranial nerve IX (glossopharyngeal) from mechanoreceptors in the first gill arch of anesthetized, spontaneously breathing channel catfish (Ictalurus punctatus). Single unit and paucifiber recordings show that both phasic and tonic receptors were active during normal ventilation. Phasic receptors were characterized as having a burst of activity during some phase of the ventilatory cycle. Most of these occurred during peak adduction or peak abduction. Phasic receptors were not active during spontaneous apnic periods. Tonic receptors were always active, even during apneas, firing frequency was modulated by breathing movements with peak activity occurring during adduction. Flow-sensitive mechanoreceptors were identified in anesthetized, paralyzed catfish. These receptors decreased activity when the ventilatory water flow was stopped. Hypercapnia (5% CO(2) in air) stimulated ventilatory rate and amplitude but had no effect on mechanoreceptor activity. The discharge characteristics of branchial mechanoreceptors indicate that they could be involved in the timing and coordination of ventilatory movements and maintenance of the 'gill curtain' to minimize ventilatory dead space. Unlike ventilatory mechanoreceptors in the air breathing organs of gar and lungs of lungfish and tetrapods, branchial mechanoreceptors were insensitive to hypercapnia.     

GABA antagonism reverses hypoxic respiratory depression in the cat

We assessed the role of gamma-aminobutyric acid (GABA) as a potential causative agent of hypoxic respiratory depression by monitoring the response of the phrenic neurogram to systemic infusion of the GABA antagonist bicuculline (0.01 mg.kg-1.min-1) under control conditions and during isocapnic brain hypoxia produced by CO inhalation in separate groups of anesthetized, glomectomized, vagotomized, paralyzed, and ventilated cats with blood pressure held constant. The maximum effect of bicuculline in subseizure doses in control cats was to increase minute phrenic activity to 151 +/- 14% of preinfusion values. Infusion was continued until seizure activity was seen in the electroencephalogram. A 53% decrease of arterial O2 content resulted in a marked reduction of both peak phrenic amplitude and phrenic firing frequency to 16 and 64% of control values, respectively. Infusion of bicuculline while the level of hypoxia was maintained constant restored both peak phrenic amplitude and phrenic firing frequency to prehypoxic levels. The maximum effect of bicuculline was to increase minute phrenic activity to 123 +/- 13% of the prehypoxic value. These results suggest that although GABA has only a modest role in determining the output of the control phrenic neurogram, a significant portion of the phrenic depression that occurs during hypoxia can be attributed to inhibition of respiratory neurons by GABA.     

Responses to chemical stimulation of upper airway muscles diaphragm in awake cats

The steady-state and transient effects of hyperoxic hypercapnia on the electromyographic activities of the genioglossus (GG), posterior cricoarytenoid (PCA), and diaphragm (D) were studied in conscious unsedated cats with chronically implanted electrodes. Hypercapnia (inhalation of 3.4 and 7.4% CO2 in O2) increased the phasic electrical activity occurring during inspiration in all three muscles and also increased tonic activity of the GG. The GG responded to steady-state CO2 inhalation alinearly and with larger increases in activity than the PCA and D. Phasic GG activity was present in only 4 of 10 cats breathing 100% O2, whereas phasic PCA and D activity could be observed in all animals studied. When gas mixtures containing CO2 were given, the GG reached its new steady-state level more slowly than the D or PCA, and when CO2 was rapidly removed from the inspired gas mixture, the GG attained its steady state sooner than either the PCA or D. These results suggest that in awake unsedated animals, chemical stimuli do not affect either transient or steady-state responses of the GG in the same way as the D. These differences seem to be explained mainly by different threshold characteristics of hypoglossal and phrenic neurons but also in part by dissimilarities in their steady-state responses.     

Thyroarytenoid muscle activity during hypoxia, hypercapnia, and voluntary hyperventilation in humans

Intramuscular electromyographic activity of the thyroarytenoid (TA) muscle, a vocal cord adductor, was recorded in nine normal adult humans during progressive isocapnic hypoxia and hyperoxic hypercapnia. Four of the nine subjects also performed voluntary isocapnic hyperventilation. During quiet breathing of room air, the TA exhibited phasic activity in expiration and often tonic activity throughout the respiratory cycle. Both phasic and tonic TA activity progressively decreased with either increasing hypoxia or hypercapnia. Tonic activity appeared to decrease more rapidly than phasic activity with increasing chemical stimulation. At comparable tidal volume increments, the relative decrease in phasic TA activity appeared to be greater under hypoxic than under hypercapnic conditions. During voluntary isocapnic hyperventilation, phasic TA activity decreased without significant change in tonic activity. At tidal volumes approximately double those of base line, the relative decrease in TA activity was similar during both hypercapnia and voluntary hyperventilation, although differences appeared at higher tidal volumes. The results, in combination with recent findings in humans regarding the posterior cricoarytenoid muscle, a vocal cord abductor, suggest that vocal cord position is dependent on the net balance of counteracting forces not only during quiet breathing but also during involuntary and voluntary hyperpnea.     

Effects of temperature and hypercapnia on ventilation and breathing pattern in the lizard Uromastyx aegyptius microlepis

In most reptiles, the ventilatory response to hypercapnia consists of large increases in tidal volume (V(T)), whereas the effects on breathing frequency (f(R)) are more variable. The increased V(T) seems to arise from direct inhibition of pulmonary stretch receptors. Most reptiles also exhibit a transitory increase in ventilation upon removal of CO(2) and this post-hypercapnic hyperpnea may consist of changes in both V(T) and f(R). While it is well established that increased body temperature augments the ventilatory response to hypercapnia, the effects of temperature on the post-hypercapnic hyperpnea is less described. In the present study, we characterise the ventilatory response of the agamid lizard Uromastyx aegyptius to hypercapnia and upon the return to air at 25 and 35 degrees C. At both temperatures, hypercapnia caused large increases in V(T) and small reductions in f(R), that were most pronounced at the higher temperature. The post-hypercapnic hyperpnea, which mainly consisted of increased f(R), was numerically larger at 35 compared to 25 degrees C. However, when expressed as a proportion of the levels of ventilation reached during steady-state hypercapnia, the post-hypercapnic hyperpnea was largest at 25 degrees C. Some individuals exhibited buccal pumping where each expiratory thoracic breath was followed by numerous small forced inhalations caused by contractions of the buccal cavity. This breathing pattern was most pronounced during severe hypercapnia and particularly evident during the post-hypercapnic hyperpnea.     

Chronic hypoxia and chronic hypercapnia differentially regulate an NMDA-sensitive component of the acute hypercapnic ventilatory response in the cane toad (<Emphasis Type="Italic">Rhinella marina</Emphasis>)

This study addressed the hypotheses that exposure to chronic hypoxia (CH) and chronic hypercapnia (CHC) would modify the acute hypercapnic ventilatory response in the cane toad (Rhinella marina; formerly Bufo marinus or Chaunus marinus) and its regulation by NMDA-mediated processes. Cane toads were exposed to 10 days of CH (10% O₂) or CHC (3.5% CO₂) followed by acute in vivo hypercapnic breathing trials, conducted before and after an injection of the NMDA-receptor channel blocker, MK801 into the dorsal lymph sac. CH, CHC and MK801 did not alter ventilation under acute normoxic normocapnic conditions. CH blunted the increase in breathing frequency during acute hypercapnia while CHC had no effect. The effect of CH on breathing frequency was mediated by a decrease in the number of breaths per breathing episode. Neither CH nor CHC altered breath area (volume). MK801 augmented breathing frequency (via an increase in breaths per episode) and total ventilation during acute hypercapnia in control toads and toads exposed to CH; there was no effect of MK801 on the increase in breathing frequency or total ventilation, during acute hypercapnia in toads exposed to CHC. The results indicate that CH and CHC differentially alter breathing pattern. Furthermore, they indicate an absence of NMDA-mediated glutamatergic tone during normoxic normocapnia but that NMDA-mediated processes attenuate the increase in breathing frequency during acute hypercapnia under control conditions and following CH but not following CHC. Given that MK801 was administered systemically, the effects could be acting anywhere in the reflex pathway from CO₂-sensing to respiratory motor output.     

Ventilation in conscious dogs during acute and chronic hypercapnia.

Minute ventilation was measured in conscious dogs, at rest and during exercise (1 mph), over 60 min immediately following the acute inhalation of 5% carbon dioxide in air and at 2, 4, 7, and 14 days while breathing the same gas mixture in a chamber. The dogs were also studied in the immediate period of air recovery from chronic hypercapnia and 1 day later. Control studies were carried out with the dogs breathing air in the chamber under comparable conditions. A triphasic ventilation change was ovserved in dogs at rest over the 14 days of hypercapnia. After an initial marked increase in ventilation during acute hypercapnia, ventilation returned to control levels by 2 days and then appeared to be elevated above control studies from 4 to 14 days at a time when blood acid-base balance became compensated. When the same dogs were studied during exercise, ventilation was also not different from air control at 2 days of hypercapnia; however during exercise, unlike the resting studies, there was only a tendency for a secondary increase in ventilation at 7 and 14 days of hypercapnia. During the immediate recovery from chronic hypercapnia when the dogs breathed air there was no evidence of hypoventilation either at rest or exercise despite arterial alkalosis. At 24 h of recovery it appeared that dogs while at rest had a slightly reduced ventilatory response to 5% carbon dioxide relative to control studies. The findings provide suggestive evidence that other factors, in addition to acid-base balance, might contribute to the regulation of ventilation during chronic hypercapnia and the recovery from chronic hypercapnia.     

Effects of changes in level and pattern of breathing on the sensation of dyspnea

Breathing during hypercapnia is determined by reflex mechanisms but may also be influenced by respiratory sensations. The present study examined the effects of voluntary changes in level and pattern of breathing on the sensation of dyspnea at a constant level of chemical drive. Studies were carried out in 15 normal male subjects during steady-state hypercapnia at an end-tidal PCO2 of 50 Torr. The intensity of dyspnea was rated on a Borg category scale. In one experiment (n = 8), the level of ventilation was increased or decreased from the spontaneously adopted level (Vspont). In another experiment (n = 9), the minute ventilation was maintained at the level spontaneously adopted at PCO2 of 50 Torr and breathing frequency was increased or decreased from the spontaneously adopted level (fspont) with reciprocal changes in tidal volume. The intensity of dyspnea (expressed as percentage of the spontaneous breathing level) correlated with ventilation (% Vspont) negatively at levels below Vspont (r = -0.70, P less than 0.001) and positively above Vspont (r = 0.80, P less than 0.001). At a constant level of ventilation, the intensity of dyspnea correlated with breathing frequency (% fspont) negatively at levels below fspont (r = -0.69, P less than 0.001) and positively at levels above fspont (r = 0.75, P less than 0.001). These results indicate that dyspnea intensifies when the level or pattern of breathing is voluntarily changed from the spontaneously adopted level. This is consistent with the possibility that ventilatory responses to changes in chemical drive may be regulated in part to minimize the sensations of respiratory effort and discomfort.     

Fetal oxygen consumption and PO2 during hypercapnia in pregnant sheep

In 12 experiments on 9 chronically-cathetized pregnant sheep (116-143 days of gestation), fetal oxygen consumption, umbilical blood flow and blood gas values were measured before, during and after a 30-min period of hypercapnia, induced by having the ewes breathe 5% CO2 and 18% O2 in N2. During the large amplitude breathing stimulated by hypercapnia, O2 consumption increased by 21%, solely via a rise in O2 extraction. During apnoeic periods and low amplitude breathing in the hypercapnia period, oxygen consumption was not different from the control value, but fetal arterial and umbilical venous PO2 was significantly raised, by 3 and 6 mm Hg respectively. These changes were probably due to a Bohr shift in the maternal oxygen dissociation curve. During large amplitude breathing, PO2 fell to control levels, probably due in part to the increase in O2 extraction. It is concluded that vigorous breathing movements in the fetal sheep, such as those stimulated by hypercapnia, result to an increase in fetal O2 demands. Further, the work of such breathing is large, and probably equivalent to that performed in adults during vigorous hyperventilation against an inspiratory resistance.     

Effects of diaphragmatic ischemia on the inspiratory motor drive.

To assess the effect of diaphragmatic ischemia on the inspiratory motor drive, we studied the in situ isolated and innervated left diaphragm in anesthetized, vagotomized, and mechanically ventilated dogs. The arterial and venous vessels of the left diaphragm were catheterized and isolated from the systemic circulation. Inspiratory muscle activation was assessed by recording the integrated electromyographic (EMG) activity of the left and right costal diaphragms and parasternal intercostal and alae nasi muscles. Tension generated by the left diaphragm during spontaneous breathing attempts was also measured. In eight animals, left diaphragmatic ischemia was induced by occluding the phrenic artery for 20 min, followed by 10 min of reperfusion. This elicited a progressive increase in EMG activity of the left and right diaphragms and parasternal and alae nasi muscles to 170, 157, 152, and 128% of baseline values, respectively, an increase in the frequency of breathing efforts, and no change in left diaphragmatic spontaneous tension. Thus the ratio of left diaphragmatic EMG to tension rose progressively during ischemia. During reperfusion, only the frequency of breathing efforts and alae nasi EMG recovered completely. In four additional animals, left diaphragmatic ischemia was induced after the left phrenic nerve was sectioned. Neither EMG activity of inspiratory muscles nor respiratory timing changed significantly during ischemia. In conclusion, diaphragmatic ischemia increases inspiratory motor drive through activation of phrenic afferents. The changes in alae nasi activity and respiratory timing indicate that this influence is achieved through supraspinal pathways.     

Maturation of spontaneous fetal diaphragmatic activity and fetal response to hypercapnia and hypoxemia

The electromyogram (EMG) of the diaphragm, lateral rectus, and nuchal and hindlimb muscles were studied during spontaneous activity and during hypercapnia or hypoxemia in eight fetal sheep from 0.5 to 0.8 gestation (73-128 days). At the earliest gestational age, diaphragmatic EMG activity was mainly tonic and associated with tonic activity of somatic muscles. The stimulus for the diaphragmatic activity originated centrally. Brief periods of a rapid-eye-movement (REM) state characterized by phasic lateral rectus and diaphragmatic activity and absence of nuchal activity were recognized. Furthermore, from 0.5 to 0.7 gestation onward, activity of all muscles increased. Thereafter increased specificity of activity in relation to the apparent REM and non-rapid-eye-movement (NREM) state occurred. With maturation, phasic diaphragmatic activity increased at the expense of tonic activity. The most striking effect of maturation on apnea was a greater proportion of apnea lasting greater than 1 min, but the total duration of apnea as a percent of a total recording remained unchanged. The quantitative response to hypercapnia during maturation was independent of the pattern of spontaneous diaphragmatic activity. Hypercapnia at 0.5 gestation changed the pattern of diaphragmatic EMG activity from mainly tonic to phasic. Thus the central chemoreceptors and appropriate neuronal pathways are present and functional as early as 0.5 gestation. Hypercapnia at 0.5 gestation caused a shift in diaphragmatic EMG power to lower frequencies similar to that found during control conditions in the older fetus. This might suggest that during maturation there is increased recruitment of phrenic motoneurons. Hypoxemia abolished tonic somatic activity at 0.5 gestation and decreased phasic diaphragmatic activity at more advanced gestational ages. Therefore the central inhibitory mechanisms of hypoxemia are developed by 0.5 gestation.