Effects of hypoxemia on phrenic nerve responses to static lung inflation in anesthetized dogs

To study interactions between hypoxemia and lung stretch in modulating ventilatory activity, an experimental preparation was used that allows independent control of static airway pressure (Paw) and arterial PO2 in anesthetized dogs. Phrenic burst frequency (f) and integrated amplitude (Phr) were monitored while Paw was varied between 2 and 12 cm H2O at levels of PaO2 between 30 and 200 mm Hg. Experiments were repeated in intact (n = 8) and carotid denervated dogs (CBX; n = 7). In intact dogs, f decreased with increasing Paw through an effect on the expiratory duration (TE). Hypoxia increased f by decreasing both the inspiratory duration (TI) and TE. Hypoxia had no effect on the slope of the f vs Paw relationship, but attenuated the effect of Paw on TE. Phr was increased by hypoxia, but Paw had little effect. After CBX, f was still inhibited by Paw, but PaO2 had no consistent effect on f, TI or TE at any level of Paw. Phr was inhibited by hypoxia after CBX, but Paw had no effect. The results indicate that Paw and PaO2 exert additive effects on f in anesthetized dogs. Hypoxia attenuates the effect of Paw on TE, which alone would attenuate the slope of the f vs Paw relationship. However, the effect of hypoxia on TI enhances the slope of the f vs Paw relationship, restoring a parallel shift. These effects are abolished by carotid denervation.     

Effects of hypercapnia on phrenic and stretch receptor responses to lung inflation

To determine if hypercapnia and reflex bronchoconstriction attenuate lung inflation effects on ventilatory activity by indirect effects on intrapulmonary stretch receptors (PSR), phrenic nerve activity and single unit PSR were monitored at controlled levels of static airway pressure (Paw) and arterial PCO2 in 15 anesthetized dogs. Paw in a vascularly isolated lung was varied between 2 and 14 cm H2O at levels of PaCO2 between 35 and 85 mm Hg. PSR activity (n = 38) in fine strands dissected from an otherwise intact vagus nerve and the integrated phrenic neurogram were recorded. The response to Paw varied from one PSR to another, but was consistent in a given unit; PaCO2 had no consistent effect on individual responses. Selected PSR (n = 15) were averaged to yield a population response to Paw; the selection criteria were: phrenic activity responded briskly to Paw and measurements were made at three levels of PaCO2. Average PSR discharge increased linearly with Paw but was unaffected by PaCO2. On the other hand, phrenic burst frequency decreased as Paw increased and hypercapnia attenuated the slope of this relationship. These results suggest that effects on the relationship between PSR activity and Paw cannot account for attenuation of the relationship between phrenic frequency and Paw in hypercapnia. The effect of PaCO2 on the phrenic frequency vs Paw relationship probably arises from integrative mechanisms in the central nervous system.     

An analysis of respiratory frequency alterations in vagotomized, decerebrate cats.

Changes in inspiratory (TI), expiratory (TE) and total respiratory cycle (TTOT) durations with hypercapnia- of hypoxia-induced tidal volume (VT) elevations were evaluated in midcollicular decerebrate cats. As VT increased, TI, TE, and TTOT decreased for most animals having intact vagi. Following vagotomy, TI, TE, and TTOT increased with hypercapnia for cats which had TI, TE and TTOT values shorter than 1.6, 3.7 and 5.2 sec respectively while breathing 100% O2; values longer than these forecast hypercapnia-induced decreases in each parameter. Similar systematic changes were not evident for hypoxia-induced responses. Varying the midbrain transection level or pentobarbital administration altered TI, TE and TTOT values while breathing 100% O2; however, the predictability of hypercapnia-induced responses, based on data analysis from midcollicular decerebrate cats, was maintained. It is concluded that the vagally-independent brainstem frequency controller is sensitive to hypercapnia and hypoxia. The predictability of hypercapnia-induced TI, TE and TTOT changes in vagotomized animals is considered in the context of previous models for respiratory rhythm generation.     

Differences in respiratory patterns after acute and chronic pulmonary denervation

The role of pulmonary vagal information in the control of respiratory patterns was assessed in awake and anaesthetised rats in which pulmonary denervation was effected by bilateral cervical vagotomy or by right cervical vagotomy combined with left pneumonectomy or left intrathoracic vagotomy. Acute denervation led to increases of tidal volume (VT), inspiratory duration (TI) and expiratory duration (TE) in both awake and halothane anaesthetised animals; in awake rats the increase of TE rapidly subsided. Chronic pulmonary denervation produced markedly smaller increases of VT and TI and no change of TE from control values. In hypercapnia, awake animals with combined pneumonectomy and vagotomy consistently increased respiratory frequency by reductions in TI and TE; awake animals with combined intrathoracic and cervical vagotomy showed no increase in f because decreases in TI offset increases in TE; in anaesthetised rats with acute bilateral cervical vagotomy there was a consistent fall in respiratory frequency due to an expiratory pause. The results demonstrate that (1) the role of vagal activity in the production of respiratory patterns is unlikely to be accounted for solely in terms of influences arising from pulmonary stretch receptors; (2) vagal influences of TE are transitory; (3) under halothane anaesthesia hypercapnia induces an expiratory pause; and (4) the combination of pneumonectomy with contralateral vagotomy makes possible studies in awake rats although pulmonary denervation is less complete than with bilateral intrathoracic vagotomy.     

Influence of phasic volume feedback on abdominal expiratory nerve activity

Our purpose was to examine the influence of phasic lung volume feedback on the activities of motor nerves innervating the diaphragm and transversus abdominis muscles during hypercapnia and hypoxia. We studied seventeen decerebrate cats that were paralyzed and ventilated with a servo-respirator controlled by the integrated phrenic neurogram. The effects of phasic lung volume feedback were assessed by withholding pulmonary inflation during the central inspiratory period. Withholding lung inflation for a single respiratory cycle under hyperoxic, normocapnic conditions consistently prolonged the durations of the inspiratory and expiratory periods, and caused marked increases in the peak electrical activities of both phrenic and abdominal nerves. Hyperoxic hypercapnia (PaCO2 50-80 mmHg) and isocapnic hypoxia (PaO2 60-35 mmHg) increased peak phrenic and abdominal neural activities, and withholding pulmonary inflation under these conditions caused even greater augmentations of inspiratory and expiratory motor output. The augmentation of expiratory activity by withholding lung inflation was proportionately greater than the concomitant prolongation of the central expiratory period. All responses to non-inflation maneuvers were abolished following bilateral cervical vagotomy. The results indicate that vagally mediated volume feedback during inspiration can attenuate the output of abdominal motoneurons in the subsequent expiratory period. Moreover, hypoxia, which attenuates abdominal motor activity in vagotomized animals, enhances this activity when the vagi are intact.     

Effects of end-expired pressure on phrenic output in servo-ventilated dogs

The pattern of breathing induced by increases in end-expired lung volume (EEVL) was determined in 9 anesthetized dogs. The pulmonary and systemic circulations were separately pump-perfused and the lungs were ventilated with a servo-ventilator actuated from the phrenic neurogram. EEVL was increased as a continuous ramp by slowly raising end-expired transpulmonary pressure from 1.5 to 12 cm H2O. Tidal volume (VT), inspiratory time (TI), and expiratory time (TE) were measured at vagal temperatures of 39 degrees C and 7 degrees C and following vagotomy. At a vagal temperature of 39 degrees C, increasing EEVL produced significant reductions in VT and TI while greatly prolonging TE. Vagal cooling to 7 degrees C, substantially altered the reflex response to increased EEVL. At 7 degrees C, VT decreased as EEVL increased, but the reduction was not so pronounced as at 39 degrees C. In addition, both TI and TE shortened. Increasing EEVL following vagotomy had no consistent effects on breathing pattern. We conclude that increasing EEVL stimulates tachypneic promoting pulmonary afferent nerves, most likely pulmonary C-fibers, but at normal vagal temperature their effect is masked by the stronger reflex inhibition of slowly adapting pulmonary stretch receptors.     

Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities

In decerebrate, paralyzed cats, ventilated by a servo-respirator in accordance with phrenic nerve activity, we examined the influence of lung volume on the activities of the phrenic, hypoglossal and mylohyoid nerves. When lung inflation was briefly withheld, the durations of inspiration (TI) and expiration (TE) and the activities of all three nerves increased. The relative increase in hypoglossal activity greatly exceeded that of phrenic activity and was apparent earlier in the course of inspiration. This hypoglossal response was enhanced by hypercapnia and isocapnic hypoxia. The responses of mylohyoid activity were quite variable: withholding lung inflation augmented inspiratory activity in some cats, but expiratory discharge in others. Sustained increases in end-expiratory lung volume were induced by application of 3-4 cm H2O of positive end-expiratory pressure (PEEP). Steady-state PEEP did not influence nerve activities or the breathing pattern. Bilateral vagotomy increased TI, TE, and the activities of all three nerves. No response to withoholding lung inflation could be discerned after vagal section. The results provide further definition of the influence of vagally mediated, lung volume dependent reflexes on the control of upper airway muscles. These reflexes are well suited to relieve or prevent upper airway obstruction.     

A short-term memory in the respiratory centres: statistical analysis.

It has been observed previously that the successive values of depth and duration of respiratory cycles recorded in man are not independent random variable. The present study has been performed in order to test whether a serial dependence of the characteristics of the respiratory cycles results from an inherent property of the central respiratory oscillator. In the "isolated respiratory centre" preparation of the cat (spinalized, bivagotomized, curarized and artificially ventilated) the following respiratory data have been studied: the value of integrated phrenic discharge per breath (S), inspiratory duration (TI), expiratory duration (TE) and total cycle duration (T), at rest and during hypercapnia and hyperthermia. Each recording in a steady-state condition provided a set of four series of data; using statistical analysis of time series the following results were obtained: 1. In each series the successive values are not independent random variables. This suggests that a cycle may be considered as an event whose characteristics condition those of the following cycle. 2. TE is not independent of the preceding TI, and TI is not independent of the immediately preceding TE. However, this last relation cannot be asserted in hypercapnia and hyperthermia. 3. A positive correlation exists between S and TI. This result indicates that a simultaneous adjustment of S and TI, in terms of one another, does exist in absence of the vagal mechanism.     

Respiratory patterns in anesthetised rats before and after anemic decerebration.

Experiments were undertaken to test the comparability of changes in respiratory frequency and tidal volume during hypoxia and hypercapnia in rats with and without intact peripheral chemoreceptors and with intact vagi. Neural organisation of respiratory control was perturbed by anemic decerebration, achieved by ligation of the common carotid and basilar arteries. Ischemia of the brain was produced as far candal as the rostral pontine nuclei involved in respiratory control but left the medulla well perfused. The dominant respiratory effect in animals breathing air or oxygen was polypnea with hypocapnia (mean PaCO2 when breathing air 24.7 mmHg, when breathing oxygen 29.6 mmHg). After decerebration the increase of ventilation produced by breathing 10% O2 in N2 was reduced compared with responses in the intact state but levels of ventilation (V1) in hypoxia were similar to those before decerebration. After decerebration, the increase of ventilation produced by breathing 5% CO2 was greatly reduced and the level of V1 in animals breathing CO2 was significantly less than in the intact state. Intermediate changes were seen in animals breathing 2-3% CO2 which converted the hypocapnia (PaCO2 30.9 mmHg) to eucapnia (PaCO2 46.4 mmHg). In the intact state, hypoxia dominantly caused increased frequency (f) and hypercapnia caused increased tidal volume (VT); after decerebration, hypoxia produced reduction of VT while hypercapnia produced reduction of f. Bilateral carotid sinus nerve section in decerebrate animals eliminated the ventilatory response to hypoxia but left the responses to hypercapnia unaltered. The results point to differences in the mechanisms by which hypoxia and hypercapnia influence respiration in both intact and decerebrate animals with carotid sinus and vagus nerves functional. The differences can now be interpreted in terms of specific neural features of respiratory control.     

Inhibitory and excitatory effects on respiration by phrenic nerve afferent stimulation in cats

Respiratory effects of electrical stimulation of phrenic nerve afferents were studied in anesthetized cats, either spontaneously breathing or paralyzed and ventilated. The type of phrenic afferent fibers activated was controlled by recording the evoked action potentials from dorsal root fibers. In both preparations, stimulation at a strength sufficient to activate small diameter myelinated phrenic nerve afferents induced a biphasic response. The first phase lasted a few respiratory cycles and was inhibitory and consisted of a decrease in tidal volume (VT) or phrenic activity (NA), inspiratory time (TI), respiratory duty cycle (TI/Ttot) and instantaneous ventilation (VE) or minute phrenic activity (NMA). Expiratory time (TE) increased and breathing frequency (f) and mean inspiratory flow (VT/TI) or mean inspiratory neural activity (NA/TI) did not change. This short-term response was suppressed in animals pretreated with bicuculline. The second phase was a long-term excitation in which VT or NA, f, VE or NMA and VT/TI increased whereas both TI and TI/Ttot decreased and TE did not change. Unlike published data, our results suggest that small-diameter myelinated phrenic nerve afferents are involved in these responses. These phrenic fibers, like afferents from other muscles, affect respiratory output and may play a role in the control of breathing.     

Effects of vagotomy on ventilatory responses to CO2 in alligators.

Reptiles increase ventilation during hypercapnia at a constant temperature. In this study, the contributions of vagal vs non-vagal receptors to CO2 ventilatory responses were investigated in 16 sedated Alligator mississippiensis (25 mg/kg pentobarbital; 3 days prior to data collection). Four animals served as controls to assess the effects of time and/or anesthetic drift on ventilation and blood gases; significant ventilatory drift was not detected during the observation period. The effects of bilateral vagotomy on CO2 ventilatory responses were determined during spontaneous breathing (n = 6) and unidirectional ventilation (UDV; n = 6) at two body temperatures (Tb = 30 and 20 degrees C). Resting PaCO2, minute ventilation (VI), tidal volume (VT) and breathing frequency (f) were elevated at 30 degrees C relative to 20 degrees C in spontaneously breathing alligators. Increasing inspired CO2 to 5% increased PaCO2, f, VT and VI at both levels of Tb. Ventilatory sensitivity to CO2 (S = delta VI/delta PaCO2) was higher at 30 degrees C with a temperature coefficient (Q10) of 2.3. Vagotomy increased PaCO2 and VT, decreased f and had no effect on VI at either Tb. After vagotomy, hypercapnia had no effects on ventilation. When CO2 feedback loops were opened by UDV at a high flow rate (greater than 2 L/min), Tb had no effects on ventilatory efforts at constant PCO2, but hypercapnia significantly increased f, VT and VI. S was variable with a Q10 of 2.1. After vagotomy, a significant CO2-ventilatory response remained during UDV, but S was unaffected by Tb (Q10 = 0.8). The results indicate that non-vagal chemoreceptors contribute to CO2 ventilatory responses in alligators, although their contribution following vagotomy is evident only during unidirectional ventilation. Although tentative, the data also suggest that CO2-sensitive vagal receptors may be necessary for the temperature dependency of S.     

The effects of hypercapnia and cooling the ventral medullary surface on capsaicin induced respiratory reflexes

The effect of right atrial (RA) injection of 3 micrograms/kg capsaicin on phrenic, hypoglossal and recurrent laryngeal activities was studied in chloralose anesthetized, paralyzed and artificially ventilated cats. Within 2 sec following capsaicin injection, the phrenic and hypoglossal activities completely disappeared (apnea), while the recurrent laryngeal activity markedly increased. Similar responses were also obtained with RA injection of phenyldiguinide (PDG), suggesting that the respiratory responses of both drugs are essentially similar. Sino-aortic denervation did not affect the capsaicin induced respiratory responses. Bilateral vagotomy abolished the responses, suggesting that vagal sensory receptors are responsible for the reflex effects. Hyperoxic hypercapnia (3 and 7% CO2 in O2) reduced the apneic duration of phrenic and hypoglossal nerves. The magnitude of the recurrent laryngeal excitation was decreased during CO2 breathing. Graded focal cooling of the intermediate area (Is area) of the ventral medullary surface (to inhibit central chemoreceptor activity) significantly prolonged capsaicin induced apneic duration of hypoglossal nerves more than the phrenic. The recurrent laryngeal responses, however, were unaffected by cooling of the ventral medullary surface. The results show that capsaicin and PDG, presumably by stimulating C fibers, affect cranial nerves as well as the phrenic. The reflex responses to C fiber stimulation seem to be altered by intervention which stimulate (hypercapnia) or depress (Is cooling) 'central chemoreceptors.'     

CO2-induced prolongation of expiratory time during early development.

In these studies, we determined the contribution of central mechanisms and the role of GABA(A)-receptor signal transduction pathways in mediating hypercapnia-induced slowing of breathing frequency. Experiments were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated piglets of 3-5 days and 2-3 weeks of age (n=19). Repeated exposure to progressive hyperoxic hypercapnia induced a reproducible increase in phrenic nerve activity, accompanied by a CO2 concentration-dependent increase in expiratory duration. No differences were observed in piglets with intact or cut carotid sinus nerves. Intravenous administration of bicuculline (2 mg/kg: n=7), a gamma-aminobutyric acid (GABA(A)) receptor antagonist, significantly reduced the CO2-induced prolongation of TE. These data demonstrate for the first time that in early postnatal life, hypercapnia induced increase in phrenic activity is associated with centrally mediated prolongation of expiratory duration. Furthermore. the results suggest that brainstem GABAergic mechanisms play an important role in CO2-induced prolongation of expiratory time during early development.     

Control of expiratory duration by arterial CO2 oscillations in vagotomized dogs

The role of respiratory oscillations of PaCO2 (CO2 oscillations) in the regulation of expiratory duration (TE) was examined in eight anesthetized dogs by measuring instantaneous changes of arterial pH during the respiratory cycle with a catheter-tip ISFET (ion-sensitive field effect transistor) pH electrode. Steady-state changes in arterial pH oscillation were induced by vagotomy, which increased the amplitude of pH oscillation from 0.014 +/- 0.002 (mean +/- SEM) to 0.058 +/- 0.006 units (P less than 0.001), and prolonged TE from 5.12 +/- 0.56 to 9.99 +/- 1.11 sec (P less than 0.005) with little change in average pH (0.021 +/- 0.011 units, P = 0.12). Vagotomy also reversed the phase relationship between arterial pH oscillation at the carotid bodies and tidal ventilation, such that pH rose during early expiration, rather than falling as occurred in the intact state. When the within-breath oscillation of arterial pH was transiently reduced by having the vagotomized dogs inspire a single breath of CO2 enriched air, TE of the same breath was shortened in proportion to the reduction in amplitude of pH oscillation (r = 0.72, P less than 0.001), rather than in proportion to changes in the average pH of the test breath (r = 0.44). The results indicate that the profile of within-breath oscillation of PaCO2 (phase relationship and amplitude) can exert an important influence on TE, and may in part account for the prolongation of TE following vagotomy.     

Arterial PO2 and PCO2 stimulus threshold for carotid chemoreceptors and breathing

The PaO2 and PaCO2 stimulus thresholds for activity of carotid chemoreceptors and for ventilation were investigated in twenty anesthetized adult cats at sea level. Over the range studied PaCO2 threshold for carotid chemoreceptors decreased with increasing intensity of hypoxia showing stimulus interaction. Once begun, the carotid chemoreceptor activity increased gradually at a rate that was inversely related to initial PaO2. The greater the initial hypoxia the greater was the carotid chemoreceptor activity at which the first inspiration occurred, apnea was shorter and inspiratory PaCO2 threshold lower. Hypoxia per se depressed the central mechanism for the resumption of inspiration. We conclude that (1) carotid chemoreceptor PaO2-PaCO2 stimulus thresholds are largely interdependent; (2) these receptors are activated at a lower PaO2-PaCO2 stimulus strength than ventilation is; (3) an increased input from peripheral chemoreceptors initiates breathing at a lower PaCO2 indicating that central chemoreceptor threshold is lower than the PCO2 threshold for inspiration; (4) a finite total input from the receptors is needed to start ventilation.     

Functional characteristics of arterial chemoreceptors in an amphibian (Bufo marinus).

In order to further describe the functional characteristics of arterial chemoreceptors of anuran amphibians, multi-unit chemoreceptor discharge frequency (MCDF) was recorded from the carotid (N = 23) or aortic nerve (N = 2) of pithed, unidirectionally ventilated toads (Bufo marinus). MCDF increased with decreasing PaO2: typically, the threshold PaO2 lay between 40 and 60 mmHg. The MCDF-PaO2 relationship was right-shifted along the PaO2 axis by increasing PaCO2 (N = 5). In three toads, the MCDF-PaO2 relationship was unaffected when CaO2 was reduced 35-89% by hemorrhage. MCDF was also unaffected by occlusion of the outflow from the heart, though it increased upon release of the occlusion. MCDF was stimulated by epinephrine, and inhibited by dopamine. Our results demonstrate that the MCDF responds to the range of PaO2 and PaCO2 values encountered in vivo, suggesting that arterial chemoreceptors may participate in ventilatory control in toads. The receptors do not respond to the rate of oxygen delivery per se, and may be influenced by catecholamines known to exist in the carotid labyrinth.     

Effect of hypoxic, hyperoxic or hypercapnic ventilation on inspiratory termination in the cat

Intercostal nerve stimulation was used to examine the effects of altered concentrations of inspired oxygen or carbon dioxide on the termination of inspiration. Experiments were performed in decerebrate cats which were paralyzed, artificially ventilated and bilaterally vagotomized. The threshold current at which electrical stimulation of the T6 intercostal nerve terminated phrenic neural activity was determined at 10 different delays from the onset of phrenic nerve discharge. Ventilation with either hypercapnic normoxic gas (4% CO2) or hypoxic gas (17% O2) increased the threshold current required for inspiratory termination. Hyperoxic ventilation (45% O2), however, decreased the threshold for inspiratory termination. Bilateral section of the carotid sinus nerve abolished the response to hyperoxic ventilation, but did not alter the response to normoxic hypercapnia. These results demonstrate that an oxygen-related stimulus transduced by the peripheral chemoreceptors can influence the mechanism(s) responsible for inspiratory termination.     

Histamine and phenyldiguanide induced tachypnea in hypercapnia and hypoxia.

The rapid shallow breathing of pulmonary vagal origin following administration of histamine (H) and phenyldiguanide (PDG) was studied at different levels of hypercapnic and hypoxic stimulation. At all levels of chemical drive H and PDG caused an excitatory effect on timing of breathing and an inhibitory effect on the respiratory output. The latter was evaluated from the mean inspiratory flow rate and the mean rate of change of pressure developed in the lungs during an inspiratory effort against closed airways. The timing effect was greater at low than at high PaCO2 while the opposite was true for the output effect. At all PaCO2, H and PDG decreased the volume-threshold for termination of inspiration (leftward displacement of the VT vs TI relationship) of the VT Vs TI relationship). Hypoxia increased the respiratory output in control as much as with drug stimulation. Moreover, hypoxia did not affect the volume-threshold curve both in control and with H and PDG. We concluded that vagal afferents stimulated by H and PDG (irritant and/or J receptors) interfere with the timing and output response to central chemoreceptors stimulation (CO2 sensitivity) without affecting the response to peripheral chemoreceptors stimulation (mainly hypoxic chemosensitivity).     

Hypoxemic threshold for lung ventilation in the toad

The relationship between the activity of the buccal force pump, expressed as the time integral of positive buccal pressure, and PaO2 was investigated in conscious toads, Bufo marinus, unidirectionally ventilated at a high flow rate (240-260 ml/min). The high ventilatory flow rate meant that PaO2 was largely independent of the animal's ventilatory activity so that the relationship between pulmonary ventilation and PaO2 was effectively open-loop. The hypoxemic threshold (PaO2) for lung ventilation was 54.2 mm Hg in hypocapnia (PaCO2 = 4.7 +/- 0.3 mm Hg), 82.6 mm Hg in normocapnia (PaCO2 = 11.6 +/- 0.2 mm Hg), and 137.9 mm Hg in hypercapnia (PaCO2 = 20.1 +/- 0.1 mm Hg). Unidirectional ventilation with 20% O2 in N2, a condition in which the toads were normoxic but hypocapnic, stopped pulmonary ventilation cycles. Taken with existing evidence that hyperoxia stops pulmonary ventilation even under conditions in which PaCO2 is elevated this suggests that hypoxic and hypercapnic stimuli summate to drive lung ventilation in the toad. Bilateral denervation of the carotid labyrinths decreased pulmonary ventilation in absolute terms, but did not reduce the proportionate increase in pulmonary ventilation in response to normocapnic hypoxia, suggesting that chemoreceptors within the carotid labyrinth may contribute to, but are not solely responsible for, the hypoxemic ventilatory drive.     

Analysis of respiratory patterns in the awake and in the halothane anaesthetised rat

Respiratory patterns have been studied in awake and halothane anaesthetised rats. Tidal volume (VT) was shown to be age-sensitive over 44-200 days; failure to account for this gave the appearance of an increased ventilatory sensitivity to CO2 with age. Inspiration of CO2 (0-10.5%) produced linear responses of VT whereas frequency responses stabilised at 6% CO2. Initially expiratory duration (TE) decreased more than inspiratory duration (TI) and both decreased linearly relative to increased VT; above 6% CO2, increases in VT occurred with only minor changes in TI and TE. Halothane anaesthesia dominantly depressed the frequency response to CO2. We conclude that the rat shows a great influence of vagal control on breathing in the awake state and in halothane anaesthesia; that TE is controlled independently of TI; and that respiratory frequency is more rigorously controlled than VT.