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)     

Control of breathing at elevated lung volumes in anesthetized cats

We monitored the steady-state ventilatory responses of anesthetized cats to increases in lung volume produced by expiratory threshold loads (ETL) to study the roles of peripheral and central neural mechanisms in controlling respiration at elevated lung volumes. Application of an ETL of 5 cmH2O produced a significant decrease in respiratory frequency (-18%) but no change in minute ventilation (VE) due to a significant increase in tidal volume (VT) (19.3%). The drop in frequency was due solely to an increase in expiratory duration. ETL of 10 cmH2O significantly reduced VE (-17.5%) for the same reason. VT was maintained or increased at elevated lung volumes due to both an increase in the rate of rise of phrenic activity and a maintenance of inspiratory duration (TI) despite increases in both chemical drive and pulmonary stretch receptor (PSR) activity. No PSR adapted completely to the maintained change in lung volume. The sensitivity of the inspiratory off-switch mechanism to increases in lung volume, given by the reciprocal of the VT-TI relationship, decreased significantly during breathing on ETL. The results are consistent with the hypothesis that central habituation, not just peripheral adaptation of PSR, determines breathing pattern at elevated lung volumes.     

Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading.

Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.     

Endothelin involvement in respiratory centre activity.

To evaluate the role of endothelin (ET) in respiratory homeostasis we studied the effects of the ET(A) and ET(B) receptor blocking agent bosentan on respiratory mechanics and control in seven anaesthetised spontaneously breathing pigs, for 180 min after single bolus administration (20 mg/kg i.v.). The results show that the block of ET receptors induced a significant increase in compliance and decrease in resistance of the respiratory system, entailing a significant reduction of diaphragmatic electromyographic activity, without affecting the centroid frequency of the power spectrum. Bosentan administration induced a significant increase in tidal volume (V(T)), accompanied by a significant decrease in respiratory frequency, without any significant change in pulmonary ventilation, CO(2) arterial blood gas pressure or pH. Since the relationship between V(T) and inspiratory time remained substantially constant after bosentan administration, the changes in respiratory pattern appear to be the result of an upward shift in inspiratory off-switch threshold. Both inspiratory and expiratory times during occluded breathing were increased by block of ET receptors, suggesting also a central respiratory neuromodulator effect of ET. In conclusion the present results suggest that the block of ET receptors in spontaneously breathing pigs exerts a role on mechanical properties of the respiratory system as well as on peripheral and central mechanisms of breathing control.     

Effects of upper or lower airway anesthesia on hypercapnic ventilation in humans

To evaluate the contribution of vagal airway receptors to ventilatory control during hypercapnia, we studied 11 normal humans. Airway receptor block was induced by inhaling an aerosol of lidocaine; a preferential upper oropharyngeal block was also induced in a subgroup by gargling a solution of the anesthetic. Inhalation of lidocaine aerosol adequate to increase cough threshold, as measured by citric acid, did not change the ventilatory response to CO2, ratio of the change in minute ventilation to change in alveolar PCO2 (delta VI/delta PACO2), compared with saline control. Breathing pattern at mean CO2-stimulated ventilation of 25 l/min showed significantly decreased respiratory frequency, increased tidal volume, and prolonged inspiratory time compared with saline. Resting breathing pattern also showed significantly increased tidal volume and inspiratory time. In nine of the same subjects gargling a lidocaine solution adequate to extinguish gag response without altering cough threshold did not change delta VI/delta PACO2 or ventilatory pattern during CO2-stimulated or resting ventilation compared with saline. These results suggest that lower but not upper oropharyngeal vagal airway receptors modulate breathing pattern during hypercapnic as well as resting ventilation but do not affect delta VI/delta PACO2.     

Regulation of ventilation in the caiman (Caiman latirostris): effects of inspired CO2 on pulmonary and upper airway chemoreceptors

In order to study the relative roles of receptors in the upper airways, lungs and systemic circulation in modulating the ventilatory response of caiman (Caiman latirostris) to inhaled CO₂, gas mixtures of varying concentrations of CO₂ were administered to animals breathing through an intact respiratory system, via a tracheal cannula by-passing the upper airways (before and after vagotomy), or via a cannula delivering gas to the upper airways alone. While increasing levels of hypercarbia led to a progressive increase in tidal volume in animals with intact respiratory systems (Series I), breathing frequency did not change until the CO₂ level reached 7%, at which time it decreased. Despite this, at the higher levels of hypercarbia, the net effect was a large and progressive increase in total ventilation. There were no associated changes in heart rate or arterial blood pressure. On return to air, there was an immediate change in breathing pattern; breathing frequency increased above air-breathing values, roughly to the same maximum level regardless of the level of CO₂ the animal had been previously breathing, and tidal volume returned rapidly toward resting (baseline) values. Total ventilation slowly returned to air breathing values. Administration of CO₂ via different routes indicated that inhaled CO₂ acted at both upper airway and pulmonary CO₂-sensitive receptors to modify breathing pattern without inhibiting breathing overall. Our data suggest that in caiman, high levels of inspired CO₂ promote slow, deep breathing. This will decrease dead-space ventilation and may reduce stratification in the saccular portions of the lung.     

Respiratory responses in reversible diaphragm paralysis

The effects of diaphragm paralysis on respiratory activity were assessed in 13 anesthetized, spontaneously breathing dogs studied in the supine position. Transient diaphragmatic paralysis was induced by bilateral phrenic nerve cooling. Respiratory activity was assessed from measurements of ventilation and from the moving time averages of electrical activity recorded from the intercostal muscles and the central end of the fifth cervical root of the phrenic nerve. The degree of diaphragm paralysis was evaluated from changes in transdiaphragmatic pressure and reflected in rib cage and abdominal displacements. Animals were studied both before and after vagotomy breathing O2, 3.5% CO2 in O2, or 7% CO2 in O2. In dogs with intact vagi, both peak and rate of rise of phrenic and inspiratory intercostal electrical activity increased progressively as transdiaphragmatic pressure fell. Tidal volume decreased and breathing frequency increased as a result of a shortening in expiratory time. Inspiratory time and ventilation were unchanged by diaphragm paralysis. These findings were the same whether O2 or CO2 in O2 was breathed. After vagotomy, no significant change in phrenic or inspiratory intercostal activity occurred with diaphragm paralysis in spite of increased arterial CO2 partial pressure. Ventilation and tidal volume decreased significantly, and respiratory timing was unchanged. These results suggest that mechanisms mediated by the vagus nerves account for the compensatory increase in respiratory electrical activity during transient diaphragm paralysis. That inspiratory time is unchanged by diaphragm paralysis whereas the rate or rise of phrenic nerve activity increases suggest that reflexes other than the Hering-Breuer reflex contribute to the increased respiratory response.     

Control of respiratory pattern in conscious dog: effects of heat and CO2

We measured tidal volume (VT) and inspiratory (TI) and expiratory (TE) durations in five conscious tracheostomized dogs breathing air or 5% CO2 in air either at normal (20 degrees C) or elevated (30 degrees C) ambient temperatures. Respiratory frequency ranged between 16 and 333/min due to changes in both TI and TE. During panting TI exceeded TE. During air inhalation instantaneous ventilation (V) spontaneously ranged from 100 to 1,600 ml . kg-1 . min-1. Hypercapnia, heat stress, or both, increased this range of V by increasing maximum V, primarily due to increases in mean inspiratory flow. Under these conditions, changes in TI accounted for more of the spontaneous changes in breath duration. During inhalation of air and 5% CO2, a positive correlation between VT and TI was obtained for TI between 0.13 and 1.05 s; above 1.05 s VT decreased. Heat stress increased VT at a given TI. We suggest that either the decay rate or position of the inspiratory off-switch threshold curve (Clark and von Euler, J. Physiol. London 222: 267, 1972) varies in conscious dogs. Shifts in either the reset (onset) value or decay rate of the curve yield a positive correlation between VT and TI. This modification to the Clark-von Euler model implies that the primary effect of anesthesia on respiratory control is fixation of the inspiratory off-switch threshold curve.     

A Closed-Loop Model of the Respiratory System: Focus on Hypercapnia and Active Expiration

Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal “expiratory” muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O₂ and CO₂) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO₂ level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model can be used for simulation of closed-loop control of breathing under different conditions including respiratory disorders.     

Significance of airway resistance for the pattern of breathing and lung volumes in exercising humans

The effects of increased airway resistance on lung volumes and pattern of breathing were studied in eight subjects performing leg exercise on a cycle ergometer. Airway resistance was changed 1) by increasing the density (D) of the respired gas by a factor of 4.2 and changing the inspired gas from O2 at 1.3 bar to air at 6 bar and 2) by increasing airway flow rates by exposing the subjects to incremental work loads of 0-200 W. Increased gas D caused a slower and deeper respiration at rest and during exercise and, at work loads greater than 120 W, depressed the responses of ventilation and mean inspiratory flow. Raised airway resistance induced by increases in D and/or airway flow rates altered respiratory timing by increasing the ratio of inspiratory time (TI) to total breath duration. Furthermore, analyses of the relationships between tidal volume and TI and between end-inspiratory volume and TI revealed elevation of Hering-Breuer inspiratory volume thresholds. We propose that this elevation, and hence exercise-induced increases of tidal volume, can largely be explained by previous observations that the threshold of the inspiratory off-switch mechanisms depends on central inspiratory activity (cf. C. von Euler, J. Appl. Physiol. 55: 1647-1659, 1983), which in turn increases with airway resistance (Acta Physiol. Scand. 120: 557-565, 1984).     

Effect of venous (gut) CO2 loading on intrapulmonary gas fractions and ventilation in the tegu lizard

Summary Studies were conducted to determine regional pulmonary gas concentrations in the tegu lizard lung. Additionally, changes in pulmonary gas concentrations and ventilatory patterns caused by elevating venous levels of CO₂ by gut infusion were measured.It was found that significant stratification of lung gases was present in the tegu and that dynamic fluctuations of CO₂ concentration varied throughout the length of the lung. Mean was greater and less in the posterior regions of the lung. In the posterior regions gas concentrations remained nearly constant, whereas in the anterior regions large swings were observed with each breath. In the most anterior sections of the lung near the bronchi, CO₂ and O₂ concentrations approached atmospheric levels during inspiration and posterior lung levels during expiration.During gut loading of CO₂, the rate of rise of CO₂ during the breathing pause increased. The mean level of CO₂ also increased. Breathing rate and tidal volume increased to produce a doubling ofV _E.These results indicate that the method of introduction of CO₂ into the tegu respiratory system determines the ventilatory response. If the CO₂ is introduced into the venous blood a dramatic increase in ventilation is observed. If the CO₂ is introduced into the inspired air a significant decrease in ventilation is produced. The changes in pulmonary CO₂ environment caused by inspiratory CO₂ loading are different from those caused by venous CO₂ loading. We hypothesize that the differences in pulmonary CO₂ environment caused by either inspiratory CO₂ loading or fluctuations in venous CO₂ concentration act differently on the IPC. The differing response of the IPC to the two methods of CO₂ loading is the cause of the opposite ventilatory response seen during either venous or inspiratory loading.Abbreviations IPC intrapulmonary chemoreceptors - UAC upper airway chemoreceptors - V _T inspiratory tidal volume - CO₂ gas fraction - O₂ gas fraction - V _E minute ventilation     

Blood flow in respiratory muscles during maximal exertion in ponies with laryngeal hemiplegia

The interactive effects of upper airway negative pressure and hypercapnia on the pattern of breathing were assessed in pentobarbital-anesthetized cats. At any given level of pressure in the upper airway, hypercapnia increased respiratory rate, reduced inspiratory time, and augmented tidal volume, inspiratory airflow, and the peak and rate of rise of diaphragm electrical activity. Conversely, at any given level of CO2, upper airway negative pressure decreased respiratory rate, prolonged inspiratory time, and depressed inspiratory airflow and diaphragm electromyogram (EMG) rate of rise. Application of negative pressure to the upper airway shifted the relationship between tidal volume and inspiratory time upward and rightward. The relationship between inspiratory and expiratory times, however, was linearly correlated over a wide range of chemical drives and levels of upper airway pressure. These results suggest that in the anesthetized cat upper airway negative pressure afferent inputs 1) interact in an additive fashion with hypercapnia to alter the pattern of breathing, 2) interact multiplicatively with CO2 to influence mean inspiratory airflow and diaphragm EMG rate of rise, 3) depress the generation of central inspiratory activity, 4) increase the time-dependent volume threshold for inspiratory termination, and 5) affect the ratio between inspiratory and expiratory times in a similar manner as alterations in PCO2.     

Changes in respiratory activity induced by mastication in humans.

We studied the influence of mastication on respiratory activity in nine healthy volunteers who were requested to masticate a 5-g chewing gum bolus at a spontaneous rate (SR) for 5 min and "at the maximum possible rate" (MPR) for 1 min. Significant increases in respiratory frequency were induced by SR mastication due to a decrease in both the inspiratory and expiratory time. Tidal volume displayed slight nonsignificant decreases, but minute ventilation and mean inspiratory flow significantly increased. The duty cycle (TI/TT) did not change significantly. Total airway resistance significantly increased. Both peak and rate of rise of the integrated electromyographic activity of inspiratory muscles presented marked increases, accompanied by the appearance of a low level of tonic muscular activity. Similar but more intense effects on respiratory activity were induced by MPR mastication; in addition, a significant decrease in tidal volume and a significant increase in TI/TT were observed. Rhythmic handgrip exercise performed at metabolic rates comparable to those attained during SR or MPR mastication induced similar changes in the drive and time components of the breathing pattern, although accompanied respectively by nonsignificant or significant increases in tidal volume. Furthermore, the frequency of SR mastication significantly entrained the respiratory rhythm. The results suggest that mastication-induced hyperpnea does not merely represent a ventilatory response to exercise but also reflects complex interactions between respiratory and nonrespiratory functions of the upper airway and chest wall muscles.     

Role of vagal stimuli in exercise ventilation in dogs with experimental pneumonitis.

We have investigated the possibility that afferent vagal stimuli may be responsible for the excessive ventilatory drive during exercise characteristic of many diffuse pulmonary parenchymal diseases. Studies were performed on four conscious dogs with cervical vagal loops, in whom experimental pneumonitis was induced by the intravenous administration of complete Freund's adjuvant. Control measurements were made over a 3-mo interval prior to induction of disease which then ran a course of 6 wk. The disease was characterized histologically by a diffuse interstitial pneumonitis during the first week, and by a proliferative granulomatosis during the subsequent 4-5 wk. Physiologic disturbances at rest included decreased total lung and functional residual capacities; increased lung elastic recoil; and decreased carbon monoxide diffusing capacity. During mild-to-moderate steady-state exercise, the minute volume of ventilation (VE) and respiratory frequency (f) were increased significantly compared to control values; tidal volume (VT) was decreased significantly; and exercise tolerance (ET) was impaired. Complete cervical vagal blockade abolished the abnormally high VE, decreased f, and increased VT in all dogs, and improved ET in at least two dogs. The results indicate that afferent vagal stimuli were responsible for the excessive ventilation during exercise and contributed to the abnormal pattern of breathing.     

Effects of tonic vagal input on breathing pattern in newborn rabbits

Respiratory effects of positive and negative pressure breathing were studied in 1- and 4-day-old rabbit pups anesthetized with ketamine (50 mg/kg, im) and acepromazine (3 mg/kg, im). We recorded tidal volume (VT), tracheal pressure (Ptr), and integrated diaphragmatic EMG (DiEMG). Inspiratory (TI) and expiratory time (TE) were measured from the records of DiEMG. During breathing with increased Ptr by 1 or 2 cmH2O, VT, minute ventilation (VE), and respiratory rate (f) decreased. Changes in f relied on a TE prolongation. Neither DiEMG nor its rate of rise (DiEMGt) were affected. Except for VT decrease during positive Ptr, all other effects disappeared after vagotomy. Our results indicate that an increase in tonic vagal activity interacts with the mechanisms controlling TE and has no effect on depth and duration of inspiration. When Ptr decreased by 1 and 2 cmH2O, VE increased due to an increase in f. Increase in f relied on shortening of both TI and TE; the TE effect being more pronounced. DiEMG and DiEMGt also increased. Adverse effects of lung deflation and vagotomy strongly suggest that the respiratory reflex stimulation due to decrease in Ptr does not rely on inhibition of the slowly adapting stretch receptor activity. Therefore other excitatory vagal inputs must be responsible for this response. We propose two vagally mediated inputs: the irritant and/or the cardiac receptors.     

The ventilatory response to environmental hypercarbia in the South American rattlesnake,<Emphasis Type="Italic"> Crotalus durissus</Emphasis>

To study the effects of environmental hypercarbia on ventilation in snakes, particularly the anomalous hyperpnea that is seen when CO₂ is removed from inspired gas mixtures (post-hypercapnic hyperpnea), gas mixtures of varying concentrations of CO₂ were administered to South American rattlesnakes, Crotalus durissus, breathing through an intact respiratory system or via a tracheal cannula by-passing the upper airways. Exposure to environmental hypercarbia at increasing levels, up to 7% CO₂, produced a progressive decrease in breathing frequency and increase in tidal volume. The net result was that total ventilation increased modestly, up to 5% CO₂ and then declined slightly on 7% CO₂. On return to breathing air there was an immediate but transient increase in breathing frequency and a further increase in tidal volume that produced a marked overshoot in ventilation. The magnitude of this post-hypercapnic hyperpnea was proportional to the level of previously inspired CO₂. Administration of CO₂ to the lungs alone produced effects that were identical to administration to both lungs and upper airways and this effect was removed by vagotomy. Administration of CO₂ to the upper airways alone was without effect. Systemic injection of boluses of CO₂-rich blood produced an immediate increase in both breathing frequency and tidal volume. These data indicate that the post-hypercapnic hyperpnea resulted from the removal of inhibitory inputs from pulmonary receptors and suggest that while the ventilatory response to environmental hypercarbia in this species is a result of conflicting inputs from different receptor groups, this does not include input from upper airway receptors.Communicated by G. Heldmaier     

Relationship between the control of the duration of inspiration and the resting ventilation pattern in conscious man]

The relationship between tidal volume (V1) and inspiratory duration (T1) was studied in 5 subjects by a rebreathing procedure in pure O2. The range of this relationship marked by a decrease of T1 with increasing V1, related by Clark and Von Euler to the inhibitory vagal feed-back loop Breuer Hering or B.H. reflex, was only found in 3 subjects possessing the B.H. reflex. In the others, whose pattern of breathing was very slow, nor this range nor the B.H. reflex were found. These findings confirm previous owner data (2). Indeed in our subjects having a slow pattern of breathing, the control of T1 seems to be unrelated to vagal afferences coming from lung stretch receptors.     

Cyclic model of respiration applied to asymmetrical ventilation and periodic breathing

A model taking into account the cyclic character of respiration in humans is developed using two classical simplifications: CO₂ is the only respiratory gas involved; and respiration is regulated only by a CO₂ linear controller. The model is used to investigate two important clinical aspects of respiratory disease: asymmetrical ventilation and periodic breathing. We show that asymmetry in ventilation significantly influences the time course of the CO₂ partial pressure in the expired alveolar air at the mouth and the elimination of CO₂ through the lungs. Furthermore, the CO₂ controller delay plays a major role in periodic breathing.     

Vagal feedback with expiratory threshold load under extracorporeal circulation

In 11 anesthetized dogs placed under extracorporeal circulation, the vagal feedback was tested by electrical stimulation of the vagus nerves with cold block of their caudal part and by passive lung hyperinflation. The apneic response to such vagal stimulation progressively disappeared during expiratory threshold load breathing but then returned to control values some minutes after the load was removed. This suppression of the inhibitory response to stimulation of the vagus nerves was usually observed when vagal afferents were intact or blocked by cold. However, it was not observed whether no evoked activity continued in expiratory muscles after the cold block, or after suppression of all proprioceptive muscular afferents after transection of the spinal cord at C6 level. These results strongly suggest that enhancement of proprioceptive inputs to the respiratory centers counteracts the vagally mediated inspiratory "off-switch" mechanisms.     

Effects of thromboxane on respiration and pulmonary circulation in the cat: role of vagus nerve

Infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat elicits pulmonary hypertension and rapid shallow breathing (J. Appl. Physiol. 62: 2362-2370, 1987), and thromboxane A2 (TxA2), released from platelets, is responsible for these effects (Respir. Physiol. 71: 169-183, 1988). To investigate the involvement of vagal afferent fibers in these responses, we reversibly blocked signal conduction in the vagus of the cat by bilaterally cooling the vagus nerves to 1 degree C and measured the cardiorespiratory parameters in response to neutral acid-base infusion and infusion of the TxA2 mimetic U-46619. Vagal cooling before infusion caused tidal volume (VT) to increase and respiratory frequency (fresp) to decrease, whereby total ventilation (VE) was slightly enhanced, but did not affect right ventricular blood pressure (Prv). Infusion of neutral acid-base after vagal cooling prompted Prv to rise, on average from 35 Torr to a peak of 60 Torr, and a similar rise was elicited by infusion of U-46619. However, vagal cooling abolished any effect on VT or fresp of both acid-base and U-46619 infusion. After rewarming the vagus nerves, infusion of U-46619 caused fresp to increase and VT to decrease (rapid shallow breathing) with a concomitant rise in Prv, similar to what had been observed in the earlier studies. Our data suggest that the effects of TxA2 and of its mimetic U-46619 on respiration are mediated by the stimulation of vagal afferent fibers, whereas pulmonary hypertension is unrelated to vagal activity.