Chronic fluoxetine microdialysis into the medullary raphe nuclei of the rat, but not systemic administration, increases the ventilatory response to CO2.

In conscious rats, focal CO2 stimulation of the medullary raphe increases ventilation, whereas interference with serotonergic function here decreases the ventilatory response to systemic hypercapnia. We sought to determine whether repeated administration of a selective serotonin reuptake inhibitor in this region would increase the ventilatory response to hypercapnia in unanesthetized rats. In rats instrumented with electroencephalogram-electromyogram electrodes, 250 or 500 microM fluoxetine or artificial cerebrospinal fluid (aCSF) was microdialyzed into the medullary raphe for 30 min daily over 15 days. To compare focal and systemic treatment, two additional groups of rats received 10 mg x kg(-1) x day(-1) fluoxetine or vehicle systemically. Ventilation was measured in normocapnia and in 7% CO2 before treatment (day 0), acutely (days 1 or 3), on day 7, and on day 15. There was no change in normocapnic ventilation in any treatment group. Rats that received 250 microM fluoxetine microdialysis showed a significant 13% increase in ventilation in wakefulness during hypercapnia on day 7, due to an increase in tidal volume. In rats microdialyzed with 500 microM fluoxetine, there were 16 and 32% increases in minute ventilation during hypercapnia in wakefulness and sleep on day 7, and 20 and 28% increases on day 15, respectively, again due to increased tidal volume. There was no change in the ventilatory response to CO2 in rats microdialyzed with aCSF or in systemically treated rats. Chronic fluoxetine treatment in the medullary raphe increases the ventilatory response to hypercapnia in an unanesthetized rat model, an effect that may be due to facilitation of chemosensitive serotonergic neurons.     

In vivo evaluation of 5-hydroxytryptamine stimulation of the testes in the fiddler crab,Uca pugilator: A presumed action on the neuroendocrine system

1. Male fiddler crabs, Uca pugilator, received injections of 5-hydroxytryptamine (5-HT, serotonin). The crabs showed dose-dependent testicular development.2. Like 5-HT, the 5-HT releaser fenfluramine and the 5-HT potentiator fluoxetine induced testicular maturation also, but the 5-HT receptor blocker LY-53857 did not.3. The data support the hypothesis that 5-HT exerts this stimulatory effect on the testes indirectly, by triggering release of gonad-stimulating hormone.     

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.     

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.     

Alterations of central hypercapnic respiratory response induced by acute central administration of serotonin re-uptake inhibitor, fluoxetine

Long-term neurochemical changes are responsible for therapeutic actions of fluoxetine. The role of increased central concentration of serotonin by inhibiting its re-uptake via fluoxetine on the central hypercapnic ventilatory response is complex and little is known. We aimed to research the effect of acute intracerebroventricular (ICV) injection of fluoxetine on hypercapnic ventilatory response in the absence of peripheral chemoreceptor impulses and the role of 5-HT2 receptors on responses. Eighteen anesthetized albino rabbits were divided as Fluoxetine and Ketanserin groups. For ICV administration of fluoxetine and ketanserin, a cannula was placed in the left lateral ventricle by the stereotaxic method. Respiratory frequency (fR), tidal volume (V(T)) and ventilation minute volume (V(E)) were recorded in both groups. ICV fluoxetine (10.12 mmol/kg) injection during normoxia caused significant increases in V(T) and V(E) (both P < 0.01) in the fluoxetine group. When the animals were switched to hypercapnia f/min, V(T) and V(E) increased significantly. The increases in percentage values in V(T) and V(E) in Fluoxetine + Hypercapnia phase were higher than those during hypercapnia alone (P < 0.01 and P < 0.05, respectively). On blocking of 5-HT2 receptors by ketanserin (0.25 mmol/kg), the ventilatory response to Fluoxetine was abolished and the degree of increases in V(T) and V(E) in the Ketanserin + Hypercapnia phase were lower than those during hypercapnia alone (P < 0.01 and P < 0.001, respectively). We concluded that acute central fluoxetine increases normoxic ventilation and also augments the stimulatory effect of hypercapnia on respiratory neuronal network by 5-HT2 receptors in the absence of peripheral chemoreceptor impulses.     

Raphe magnus nucleus is involved in ventilatory but not hypothermic response to CO2.

There is evidence that serotonin [5-hydroxytryptamine (5-HT)] is involved in the physiological responses to hypercapnia. Serotonergic neurons represent the major cell type (comprising 15-20% of the neurons) in raphe magnus nucleus (RMg), which is a medullary raphe nucleus. In the present study, we tested the hypothesis 1) that RMg plays a role in the ventilatory and thermal responses to hypercapnia, and 2) that RMg serotonergic neurons are involved in these responses. To this end, we microinjected 1) ibotenic acid to promote nonspecific lesioning of neurons in the RMg, or 2) anti-SERT-SAP (an immunotoxin that utilizes a monoclonal antibody to the third extracellular domain of the serotonin reuptake transporter) to specifically kill the serotonergic neurons in the RMg. Hypercapnia caused hyperventilation and hypothermia in all groups. RMg nonspecific lesions elicited a significant reduction of the ventilatory response to hypercapnia due to lower tidal volume (Vt) and respiratory frequency. Rats submitted to specific killing of RMg serotonergic neurons showed no consistent difference in ventilation during air breathing but had a decreased ventilatory response to CO(2) due to lower Vt. The hypercapnia-induced hypothermia was not affected by specific or nonspecific lesions of RMg serotonergic neurons. These data suggest that RMg serotonergic neurons do not participate in the tonic maintenance of ventilation during air breathing but contribute to the ventilatory response to CO(2). Ultimately, this nucleus may not be involved in the thermal responses to CO(2).     

Airway anesthesia effects on hypercapnic breathing pattern in humans

Minute ventilation (VE) and breathing pattern during an abrupt increase in fractional CO2 were compared in 10 normal subjects before and after airway anesthesia. Subjects breathed 7% CO2-93% O2 for 5 min before and after inhaling aerosolized lidocaine. As a result of airway anesthesia, VE and tidal volume (VT) were greater during hypercapnia, but there was no effect on inspiratory time (TI). Therefore, airway anesthesia produced an increase in mean inspiratory flow (VT/TI) during hypercapnia. The increase in VT/TI was compatible with an increase in neuromuscular output. There was no effect of airway anesthesia on the inspiratory timing ratio or the shape and position of the curve relating VT and TI. We also compared airway resistance (Raw), thoracic gas volume, forced vital capacity, forced expired volume at 1s, and maximum midexpiratory flow rate before and after airway anesthesia. A small (0.18 cmH2O X l-1 X s) decrease in Raw occurred after airway anesthesia that did not correlate with the effect of airway anesthesia on VT/TI. We conclude that airway receptors accessible to airway anesthesia play a role in hypercapnic VE.     

Role of serotonergic input to the ventrolateral medulla in expression of the 10-Hz sympathetic nerve rhythm

We studied the changes in inferior cardiac sympathetic nerve discharge (SND) produced by unilateral microinjections of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists into the ventrolateral medulla (VLM) of urethane-anesthetized, baroreceptor-denervated cats. Microinjection of the 5-HT2 receptor antagonist LY-53857 (10 mM) into either the rostral or caudal VLM significantly reduced (P < or = 0.05) the 10-Hz rhythmic component of basal SND without affecting its lower-frequency, aperiodic component. The selective depression of 10-Hz power was accompanied by a statistically significant decrease in mean arterial pressure (MAP). Microinjection of LY-53857 into the VLM also attenuated the increase in 10-Hz power that followed tetanic stimulation of depressor sites in the caudal medullary raphé nuclei. Microinjection of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane (DOI; 10 microM) into the VLM selectively enhanced 10-Hz SND, and intravenous DOI (1 mg/kg) partially reversed the reduction in 10-Hz SND produced by 5-HT2 receptor blockade in the VLM. Microinjection of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT; 10 mM), into either the rostral or caudal VLM also selectively attenuated 10-Hz SND and significantly reduced MAP. The reduction in 10-Hz SND produced by 8-OHDPAT was partially reversed by intravenous WAY-100635 (1 mg/kg), which selectively blocks 5-HT1A receptors. These results support the view that serotonergic inputs to the VLM play an important role in expression of the 10-Hz rhythm in SND.     

Comparison of volume changes in the upper airway and thorax

To describe the mechanical cycles of the upper and lower portions of the respiratory system, we measured volume change in and out of the isolated upper airway in 13 anesthetized dogs and compared volume changes in the upper airway with tidal volume change during spontaneous respiratory efforts. During inspiration the onset and peak increase in volume into the upper airway preceded the onset and peak of inspiratory tidal volume by 84 +/- 8 and 638 +/- 47 ms, respectively. The volume cycle of the upper airway was nearly complete by the end of inspiratory airflow into the thorax. With progressive hypercapnia there was an increase in the change in both upper airway volume and tidal volume but the temporal sequence was preserved. End-expiratory tracheal occlusion increased the volume change in the isolated upper airway at any level of CO2; however, the effect was disproportionately greater at low rather than at high levels of CO2. Following hyperventilation-induced apnea, a change in volume in the upper airway and thorax occurred on the first inspiratory effort. In most animals at lower levels of CO2, the percent change in upper airway volume with inspiration was relatively less than tidal volume, but the reverse was true at higher levels of CO2. These differences represent dissimilarities in the mechanical forces occurring as the result of upper airway and chest wall muscle contraction during inspiration.     

Respiratory-related recruitment of the masseter: response to hypercapnia and loading

To test the hypothesis that a muscle that closes the jaw, the masseter, can be recruited by ventilatory stimuli, we studied the electromyographic activation of the masseter and genioglossus in seven normal awake males who were exposed in random order to progressive hyperoxic hypercapnia, inspiratory threshold loading (-40 cmH2O), and combined hypercapnia and loading. With hypercapnia, the masseter was generally recruited after the genioglossus had been activated. Once recruited, activation of both muscles increased linearly with increasing CO2. Combined hypercapnia and loading produced more activation than either stimulus alone. These data indicate that the masseter is activated by ventilatory stimuli that activate the genioglossus. Earlier recruitment of the genioglossus suggests that activation of the masseter serves to stabilize the mandible and allow the genioglossus to function as a more efficient dilator of the upper airway.     

Interaction of hypercapnia and phasic volume feedback on motor control of the upper airway

The effect of hypercapnia on the suppression of efferent hypoglossal and recurrent laryngeal nerve activity by phasic volume feedback was studied in decerebrate paralyzed intubated cats ventilated with a phrenic-driven servo-respirator. The gain of the respirator was altered for single inspirations, and the resulting changes in neural activities were quantified by comparison with respective neural activities without phasic volume feedback. This maneuver was performed when the end-tidal CO2 concentration was 5, 7, and 9%. Changes in the level of CO2 did not alter the slope or position of the volume thresholds for suppression of hypoglossal and recurrent laryngeal activities. The slope of the volume-time isopleths for specific levels of graded suppression also remained constant for each nerve at the different levels of CO2. Under hypercapnic conditions, greater volumes were required at a given time into inspiration to achieve any particular level of suppression, but these differences generally did not reach statistical significance. These data demonstrate a lack of effect of the CO2 stimulus on the suppression of upper airway motoneuron activity by phasic volume feedback. Despite the absence of this interaction, a CO2-induced increase in central inspiratory activation of upper airway motoneurons, in the presence of a very sensitive volume feedback system, would help maintain airway patency in the face of upper airway narrowing or closure.     

Effect of inspiratory resistive loading on control of ventilation during progressive exercise

Eight healthy volunteers performed gradational tests to exhaustion on a mechanically braked cycle ergometer, with and without the addition of an inspiratory resistive load. Mean slopes for linear ventilatory responses during loaded and unloaded exercise [change in minute ventilation per change in CO2 output (delta VE/delta VCO2)] measured below the anaerobic threshold were 24.1 +/- 1.3 (SE) = l/l of CO2 and 26.2 +/- 1.0 l/l of CO2, respectively (P greater than 0.10). During loaded exercise, decrements in VE, tidal volume, respiratory frequency, arterial O2 saturation, and increases in end-tidal CO2 tension were observed only when work loads exceeded 65% of the unloaded maximum. There was a significant correlation between the resting ventilatory response to hypercapnia delta VE/delta PCO2 and the ventilatory response to VCO2 during exercise (delta VE/delta VCO2; r = 0.88; P less than 0.05). The maximal inspiratory pressure generated during loading correlated with CO2 sensitivity at rest (r = 0.91; P less than 0.05) and with exercise ventilation (delta VE/delta VCO2; r = 0.83; P less than 0.05). Although resistive loading did not alter O2 uptake (VO2) or heart rate (HR) as a function of work load, maximal VO2, HR, and exercise tolerance were decreased to 90% of control values. We conclude that a modest inspiratory resistive load reduces maximum exercise capacity and that CO2 responsiveness may play a role in the control of breathing during exercise when airway resistance is artificially increased.     

Effect of sleep-induced increases in upper airway resistance on respiratory muscle activity

To investigate the response of inspiratory and expiratory muscles to naturally occurring inspiratory resistive loads in the absence of conscious control, five male "snorers" were studied during non-rapid-eye-movement (NREM) sleep with and without continuous positive airway pressure (CPAP). Diaphragm (EMGdi) and scalene (EMGsc) electromyographic activity were monitored with surface electrodes and abdominal EMG activity (EMGab) with wire electrodes. Subjects were studied in the following conditions: 1) awake, 2) stage 2 sleep, 3) stage 3/4 sleep, 4) CPAP during stage 3/4 sleep, 5) CPAP plus end-tidal CO2 pressure (PETCO2) isocapnic to stage 2 sleep, and 6) CPAP plus PETCO2 isocapnic to stage 3/4 sleep. Inspired pulmonary resistance (RL) at peak flow rate and PETCO2 increased in all stages of sleep. Activity of EMGdi, EMGsc, and EMGab increased significantly in stage 3/4 sleep. CPAP reduced RL at peak flow, increased tidal volume and expired ventilation, and reduced PETCO2. EMGdi and EMGsc were reduced, and EMGab was silenced. During CPAP, with CO2 added to make PETCO2 isocapnic to stage 3/4 sleep, EMGsc and EMGab increased, but EMGdi was augmented in only one-half of the trials. EMG activity in this condition, however, was only 75% (EMGsc) and 43% (EMGab) of the activity observed during eupneic breathing in stage 3/4 sleep when PETCO2 was equal but RL was much higher. We conclude that during NREM sleep 1) inspiratory and expiratory muscles respond to internal inspiratory resistive loads and the associated dynamic airway narrowing and turbulent flow developed throughout inspiration, 2) some of the augmentation of respiratory muscle activity is also due to the hypercapnia that accompanies loading, and 3) the abdominal muscles are the most sensitive to load and CO2 and the diaphragm is the least sensitive.     

Effects of airway anesthesia on ventilatory responses to graded dead spaces and CO2

Ventilatory response to graded external dead space (0.5, 1.0, 2.0, and 2.5 liters) with hyperoxia and CO2 steady-state inhalation (3, 5, 7, and 8% CO2 in O2) was studied before and after 4% lidocaine aerosol inhalation in nine healthy males. The mean ventilatory response (delta VE/delta PETCO2, where VE is minute ventilation and PETCO2 is end-tidal PCO2) to graded dead space before airway anesthesia was 10.2 +/- 4.6 (SD) l.min-1.Torr-1, which was significantly greater than the steady-state CO2 response (1.4 +/- 0.6 l.min-1.Torr-1, P less than 0.001). Dead-space loading produced greater oscillation in airway PCO2 than did CO2 gas loading. After airway anesthesia, ventilatory response to graded dead space decreased significantly, to 2.1 +/- 0.6 l.min-1.Torr-1 (P less than 0.01) but was still greater than that to CO2. The response to CO2 did not significantly differ (1.3 +/- 0.5 l.min-1.Torr-1). Tidal volume, mean inspiratory flow, respiratory frequency, inspiratory time, and expiratory time during dead-space breathing were also depressed after airway anesthesia, particularly during large dead-space loading. On the other hand, during CO2 inhalation, these respiratory variables did not significantly differ before and after airway anesthesia. These results suggest that in conscious humans vagal airway receptors play a role in the ventilatory response to graded dead space and control of the breathing pattern during dead-space loading by detecting the oscillation in airway PCO2. These receptors do not appear to contribute to the ventilatory response to inhaled CO2.     

Electrical and mechanical activity of respiratory muscles during hypercapnia

In nine anesthetized supine spontaneously breathing dogs, we compared moving average electromyograms (EMGs) of the costal diaphragm and the third parasternal intercostal muscles with their respective respiratory changes in length (measured by sonomicrometry). During resting O2 breathing the pattern of diaphragm and intercostal muscle inspiratory shortening paralleled the gradually incrementing pattern of their moving average EMGs. Progressive hypercapnia caused progressive increases in the amount and velocity of respiratory muscle inspiratory shortening. For both muscles there were linear relationships during the course of CO2 rebreathing between their peak moving average EMGs and total inspiratory shortening and between tidal volume and total inspiratory shortening. During single-breath airway occlusions, the electrical activity of both the diaphragm and intercostal muscles increased, but there were decreases in their tidal shortening. The extent of muscle shortening during occluded breaths was increased by hypercapnia, so that both muscles shortened more during occluded breaths under hypercapnic conditions (PCO2 up to 90 Torr) than during unoccluded breaths under normocapnic conditions. These results suggest that for the costal diaphragm and parasternal intercostal muscles there is a close relationship between their electrical and mechanical behavior during CO2 rebreathing, this relationship is substantially altered by occluding the airway for a single breath, and thoracic respiratory muscles do not contract quasi-isometrically during occluded breaths.     

The role of the 5-HT2 receptor in the regulation of sexual performance of male rats

The present studies have attempted to evaluate the role of 5-HT2 receptors in the regulation of sexual behavior of male rats by determining the effects of 5-HT2 receptor antagonists, pirenperone, LY53857 and LY281067, and a 5-HT2 receptor agonist, DOI. The administration of 1 mg/kg s.c. pirenperone produced a total suppression of ejaculatory response and lower doses had no effect. However, the administration 0.1 mg/kg s.c. of either LY53857 or LY281067 restored ejaculatory capacity to rats that were unable to ejaculate and produced significant decreases in ejaculatory latency in rats with full sexual capacity. Although all of these agents are 5-HT2 antagonists, LY53857 and LY281067 lack the additional monoaminergic activity of pirenperone. Since the effects of pirenperone were opposite from the effects of the selective 5-HT2 antagonists, the suppressive effects of this agent were probably related to its other monoaminergic activity e.g. alpha 1 antagonist activity. This proposal was supported by the observation that the administration of prazosin, an alpha 1 antagonist, significantly increased ejaculatory latency and suppressed the stimulatory effects of LY53857. In contrast to the stimulatory effects of the selective 5-HT2 antagonists, the administration of DOI, resulted in a suppression of sexual performance, which was blocked by pretreatment with LY53857.     

Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat

We aimed to investigate whether newborn rats respond to acute hypoxia with a biphasic pattern as other newborn species, the characteristics of their ventilatory response to hypercapnia, and the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that newborn unanesthetized rats (2-4 days old) exposed to 10% O2 respond as other species. Their ventilation (VE), measured by flow plethysmography, immediately increased by 30%, then dropped and remained around normoxic values within 5 min. The drop was due to a decrease in tidal volume, while frequency remained elevated. Hence, alveolar ventilation was about 10% below normoxic value. At the same time O2 consumption, measured manometrically, dropped (-23%), possibly indicating a mechanism to protect vital organs. Ten percent CO2 in O2 breathing determined a substantial increase in VE (+47%), indicating that the respiratory pump is capable of a marked sustained hyperventilation. When CO2 was added to the hypoxic mixture, VE increased by about 85%, significantly more than without the concurrent hypoxic stimulus. Thus, even during the drop in VE of the biphasic response to hypoxia, the respiratory control system can respond with excitation to a further increase in chemical drive. Analysis of the breathing patterns suggests that in the newborn rat in hypoxia the inspiratory drive is decreased but the inspiratory on-switch mechanism is stimulated, hypercapnia increases ventilation mainly through an increase in respiratory drive, and moderate asphyxia induces the most powerful ventilatory response by combining the stimulatory action of hypercapnia and hypoxia.     

Flesinoxan Dose-Dependently Reduces Extracellular 5-Hydroxytryptamine (5-HT) in Rat Median Raphe and Dorsal Hippocampus Through Activation of 5-HT1A Receptors

Abstract: The effects of systemic administration of the serotonin (5-hydroxytryptamine) 5-HT_1A receptor agonists flesinoxan and 8-hydroxy-2-(di- n -propylamino)tetralin on extracellular 5-HT were measured using microdialysis probes in both median raphe nucleus and dorsal hippocampus. Both 5-HT_1A agonists dose-dependently decreased dialysate 5-HT levels from both brain regions. The effects of flesinoxan in the median raphe (0.3 mg/kg) and dorsal hippocampus (1.0 mg/kg) could be blocked by the 5-HT_1A receptor antagonist N -[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N -(2-pyridyl)cyclohexane carboxamide trihydrochloride (WAY 100,635) at a dose of 0.05 mg/kg s.c. The antagonist itself had no effect at this dosage. Local perfusion of flesinoxan for 30 min through the dialysis probe into the median raphe region at concentrations of 20, 100, and 1,000 n M resulted in a significant decrease in dialysate 5-HT content from both regions. The effect of 100 n M flesinoxan could be blocked by coperfusion of 1,000 n M WAY 100,635. The data indicate that flesinoxan is a potent 5-HT_1A receptor agonist and also support the notion that somatodendritic 5-HT_1A autoreceptors regulate both terminal and somatodendritic 5-HT release.     

Interaction between vagal and chemoreceptors afferents in ventilatory response to transient hypercapnia (awake rabbits).

The ventilatory response to a transient hypercapnia was studied in four awake rabbits maintained in a volume displacement plethysmograph : the increase in inspiratory volume (VI) was associated or not with an increase in inspiratory and expiratory durations (TI and TE). These ventilatory variations were consistent with the activation of the peripheral chemoreceptors by carbon dioxide (short latency of the initial response). After vagal blockade by local anaesthesia, relative ventilatory variations were not significantly different from those previously measured. Central activity seems an important factor reducing inhibitory vagal input and favouring peripheral chemoreceptor afferents.     

Stress-induced attenuation of the hypercapnic ventilatory response in awake rats.

To test the hypothesis that stress alters the performance of the respiratory control system, we compared the acute (20 min) responses to moderate hypoxia and hypercapnia of rats previously subjected to immobilization stress (90 min/day) with responses of control animals. Ventilatory measurements were performed on awake rats using whole body plethysmography. Under baseline conditions, there were no differences in minute ventilation between stressed and unstressed groups. Rats previously exposed to immobilization stress had a 45% lower ventilatory response to hypercapnia (inspiratory CO(2) fraction = 0.05) than controls. In contrast, stress exposure had no statistically significant effect on the ventilatory response to hypoxia (inspiratory O(2) fraction = 0.12). Stress-induced attenuation of the hypercapnic response was associated with reduced tidal volume and inspiratory flow increases; the frequency and timing components of the response were not different between groups. We conclude that previous exposure to a stressful condition that does not constitute a direct challenge to respiratory homeostasis can elicit persistent (> or =24 h) functional plasticity in the ventilatory control system.