Adaptive changes in hypercapnic ventilatory response during training and detraining

Summary To confirm the effects of physical training and detraining on CO2 chemosensitivity, we followed hypercapnic ventilatory response at rest in the same five subjects during pre-, post- and detraining for 6 years. They joined our university badminton teams as freshmen and participated regularly in their team's training for about 3 h a day, three times a week, for 4 years. After that they retired from their teams and stopped training in order to study in the graduate school for 2 years. Maximum pulmonary ventilation and maximal oxygen uptake for each subject were determined during maximal treadmill exercise. The slope (S) of ventilatory response to carbon dioxide at rest was measured by Read's rebreathing method. Mean values of increased statistically during training and decreased statistically during detraining. A similar tendency was observed in . The average value ofS before training was 1.91 l·min^–1·mmHg^–1, (+) SD 0.52 and it decreased gradually with increasing training periods; the difference between theS values before (1980) and after training (1982, 1983 and 1984) were all significant. Furthermore, the mean values ofS increased significantly during detraining as compared with those obtained at the end of training (April 1984). We concluded that in normal subjects, long-term physical training increases aerobic work capacity and decreases CO₂ventilatory responsiveness, and that the ventilatory adaptations with training observed here are reversible through detraining.     

Long term modulation of the leg exercise ventilatory response is not elicited by hypercapnic arm exercise

The aim of the present investigation was to test the hypothesis that long-term modulation (LTM) of the exercise ventilatory response, evidenced as an augmentation in minute ventilation (V(I)) and tidal volume (VT) during the early phase of exercise, is only evident when the muscle groups recruited are the same during testing and during hypercapnic exercise conditioning. Measurements of cardiorespiratory variables were made at rest and during leg cycling (fH=107+/-5) exercise in eight male subjects, 1 week before and 1 h after conditioning. Conditioning involved either: (a) ten trials of arm cranking exercise (V(I)=29.0+/-4.4), or (b) ten trials of arm cranking exercise paired with external respiratory dead space (1400 ml; V(I)=57.3+/-6.5). Neither arm conditioning paradigm evoked any of the modulatory responses described in previous studies. We, therefore, conclude that the general upregulation of the spinal respiratory motoneuron pool excitability after conditioning (the "final common pathway" hypothesis), may be inadequate to fully explain the underlying mechanisms of LTM of ventilation in humans.     

Repeated experiences of air hunger and ventilatory behavior in response to hypercapnia in the standardized rebreathing test: effects of anxiety

In this study, we assessed air hunger (AH) and ventilatory responses to repeated CO(2) exposures in healthy women (N=31), scoring high or low for trait anxiety. A standardized rebreathing test, implying a gradually increasing CO(2) stimulus, was administered three times with 15-min intervals. Respiratory behavior and the intensity of AH perception were measured continuously. Across repeated exposures, maximal tolerance for AH habituated and the slope of AH (increase in AH per unit increase in CO(2)) diminished. Also the dynamics of the breathing response changed across trials. The thresholds for AH and tidal volume (V(T)) moved closer to each other, whereas the threshold for the respiratory rate (RR) was generally postponed. In addition, the association between AH and V(T) was stronger than between AH and RR, and the latter association became weaker over trials, particularly in high anxious persons. This suggests that AH perception became increasingly influenced by psychological factors, especially in high anxious persons. The results suggest that habituation of perceived air hunger is depending on a complex interplay between both changes in respiratory behavior and in perceptual-cognitive processes related to trait anxiety.     

Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO₂ sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO₂ sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7% CO₂ exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10 mg/(kg day)) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p > 0.05), although tidal volume (V_T) was reduced in BN rats (p < 0.05). There were also minimal effects of fluoxetine on CO₂ sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and V_T during hypercapnia in BN rats (p < 0.05). The augmented CO₂ response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (p < 0.05) consistent with selective and effective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO₂ sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO₂ sensitivity in the BN rat.     

Effect of exogenous dopamine on the hypercapnic ventilatory response in cats during normoxia

The effects of exogenous dopamine on the normoxic hypercapnic ventilatory response were assessed in nine chloralose-urethane anesthetized cats using the technique of dynamic end-tidal forcing. The ventilatory responses to step changes in end-tidalP _{CO 2} (PET_{CO 2}) were measured before (control), during and after intravenous infusion of dopamine (420 g·kg^–1·h^–1). Each response was separated into a slow central and a fast peripheral chemoreflex loop by fitting two exponential functions to the measured ventilation. Both loops were described by a CO₂ sensitivity, time constant, time delay and a single off-set B (extrapolated PET_{CO 2}, of the steady-state response curve at zero ventilation). Dopamine infusion only caused a significant increase of B (mean 0.3 kPa,P<0.0001) compared to control; the other model parameters were not significantly affected. After dopamine infusion B returned to significantly lower values (mean 0.2 kPa,P=0.006) than in control.In two additional cats the dopamine administered to the blood which was artificially perfusing the brainstem, did not affect ventilation.We conclude that in normoxic cats the effect of exogenous dopamine on the ventilatory response to CO₂ is due to a CO₂ independent inhibition of the ventilatory drive which originates outside the brainstem.     

CO2 responsivity in the mouse measured by rebreathing

We have modified the rebreathing method to study CO₂ responsivity in very small mammals. Tidal volume (V _T) and frequency (f) of pentobarbital-anesthetized mice were measured during rebreathing from a closed circuit, primed with 95% O₂, 5% CO₂, through which the gas was constantly circulated at 0.5 l·min^–1. The circuit consisted of T-tube from a plethysmograph, Tygon tubing with compliant element, CO₂ analyzer and pump, in series. CircuitPCO₂ (PctCO₂), which was recorded continuously during spontaneous breathing, rapidly equilibrated with end-tidalPCO₂. CO₂ response curves were constructed from extrapolated minute ventilation ( ),V _T,f and parameters of breath-to-breath timing, respectively, onPctCO₂. Analyses of slopes of the response curves, change from onset of rebreathing to peak response, andPctCO₂ at which the response peaked revealed that CO₂ stimulates by increasingf andV _T and that this is effected by facilitation of central inspiratory-expiratory phase switching and inspiratory drive mechanisms. However, the stimulatory effect of CO₂ on phase switching was not sustained, with maximal effect occurring before peak . The advantages and facility of the modified rebreathing method make it suitable for studies of other small mammals, including neonates.     

CO2-ventilatory response of the anesthetized rat by rebreathing technique

The ventilatory response to CO₂ in rats under sodium pentobarbital anesthesia has been measured using the rebreathing technique. The animal rebreathed through a tracheal cannula for a period of 4 min from an apparatus of 200–400 ml capacity, containing 5–6% CO₂ in O₂. in the rebreathing apparatus (PappCO₂), instantaneousV _T,f, and were monitored before, during, and after rebreathing. During the rebreathing run,PappCO₂ andPa _CO2 rose linearly from 35–40 to 65–70 mm Hg; there was no significant difference betweenPappCO₂ andPa _CO2 at any time during rebeathing.V _T and increased almost linearly with the rise inPappCO₂, whilef increased to a maximum within 2 min of rebreathing. In the rat,V _T regulation seemed to operate exclusively as a proportional control system in response to linearly increasing CO₂ stimulus. The slopes ofPappCO₂,V _T or response curves varied considerably during the time course of the experiment, depending upon the level of anesthesia, even though there was no large change in in the control periods which were under hyperoxic conditions. However, a significant linear relationship was seen betweenf in the respective control period and the slope ofPappCO₂-V _T response at various levels of anesthesia. We concluded that the rebreathing technique can be applied in small experimental animals and that changes in the sensitivity of the respiratory control system to a CO₂ stimulus by anesthesia can be easily monitored by repeating the rebreathing test.     

A feedback controller for ventilatory therapy

A computerized system that uses feedback of end-tidal CO₂ fraction (FET CO ₂) to adjust minute volume of a ventilator has been developed and tested. The effectiveness and robustness of the controller were evaluated in five anesthetized dogs. The controlled responded to step-changes in the set-point for FET CO ₂ by adjusting minute volume so that the FET CO ₂ settled to the new set-point in less than 60 sec with less than 20% overshoot. The system exhibited suitable dynamic response to step-changes in set-point with loop gains as large as two times and as small as one-half the optimal value. The breath-to-breath variation in FET CO ₂ values during prolonged periods of closed-loop controlled ventilation was smaller than the variation during periods of constant minute volume ventilation in three of five experiments. The controller generally maintained FET CO ₂ within ±0.1 vol% of the set-point. A disturbance to the controlled system was produced by releasing an occlusion of a branch of the pulmonary artery. The controller always responded to this disturbance in a stable manner, returning the FET CO ₂ to its desired value within 30 sec. Accurate control of arterial partial pressure of CO₂(PaCO ₂) will require modifications enabling the system to determine the relationship between FET CO ₂ and PaCO ₂.     

Carbon dioxide sensitivity of the central chemosensitive mechanisms

Summary In urethane-anaesthetised adult albino rats ventral surface of the brainstem was stimulated chemically by increasing the local CO₂ concentration and electrically. Two areas were demarcated on the ventral surface of the brainstem, one which showed an increase in pulmonary ventilation on chemical and electrical stimulation, and another which showed a decrease in pulmonary ventilation and sometimes even respiratory arrest. EEG activity recorded from the area from where increased pulmonary ventilation was obtained showed a synchronous slow wave activity during chemical stimulation and inhalation of a CO₂-air mixture. This area is situated 0.5–1 mm lateral to the mid-line extending up to the rootlets of the VIIth to IXth cranial nerves. The response increased proportionately on increasing the strength of the chemical stimulus, till it reached a plateau. In carotid body denervated and chronic hypoxic animals, the magnitude of the responses was shown to be increased, probably due to increased sensitivity of the central chemosensitive mechanisms.     

Naloxone and the ventilatory response to exercise in mana

Summary Endogenous opiate peptides are known to exert a depressant action on ventilation ( ), and their plasma levels have been shown to be elevated during a variety of exercise protocols. We investigated whether they might modulate the control of the hyperpnea of short-term constant-load (CLE) and incremental (IE) cycle-ergometer exercise. Four healthy subjects performed CLE tests at ca. 80% of the anaerobic threshold (_an) for 5 min following a period of unloaded pedaling, and IE tests (10 or 20 W min^–1) to the limit of tolerance. Normal saline (3 ml) or the opiate antagonist naloxone (1.2 mg in 3 ml) were administered intravenously prior to each test. Naloxone elicited no discernible effect on , alveolar gas tensions, or heart rate throughout the entire range of work rates; neither were _an nor the maximum work rate affected. It is concluded that, for short-term exercise ranging in intensity from moderate to severe, the role played by endogenous opiate peptides in the control of the exercise hyperpnea appears to be neglible in man.Senior Investigator of the American Heart Association (Greater Los Angeles Affiliate)     

The influence of CSF calcium and magnesium on the ventilatory response to carbon dioxide during hyperoxia

Summary Respiratory responses to inhaled carbon dioxide were measured in anaesthetized cats during perfusion of the ventriculocisternal system with artificial cerebrospinal fluid. A study was performed to evaluate the effect of changes in the magnesium and/or calcium concentration of the CSF on the CO₂ response curve which was described as .A decrease ofS was observed when the magnesium concentration of the perfusion fluid was increased; theB-value remaining the same. The reverse was true down to magnesium concentrations of 0.6 mmol · l^–1. Below this concentrationS remained the same or decreased; theB-value was lowered.When both the calcium and magnesium concentrations of the CSF were changed, the relation betweenS and these concentrations could be described as to be proportional toC _Ca ^a ·C _Mg ^b . The effect of changes in the calcium concentration was much more pronounced than comparable changes of the magnesium concentration as reflected by the magnitude of the exponentsa andb which were found to be –2.80 (S.D. 0.11) and –0.60 (S.D. 0.03) respectively.     

The involvement of expiratory termination in the vagally mediated facilitation of ventilatory CO2 responsiveness during hyperoxia

In anaesthetized rabbits the influence of differential vagal cold blockade on the ventilatory response to inhaled CO₂ during hyperoxia was investigated.Following total inactivation, the relationship between ventilation ( ) and arterialPCO₂ (P _aCO₂) was shifted to the left and steepened slightly over a range of modest hypercapnia, but was progressively flattened as hypercapnia intensified. The latter effect, suggestive of a vagally mediated facilitation of ventilatory CO₂ responsiveness, was studied further.Differential vagal cold blockade to a temperature (5–11°C) which abolished the Breuer-Hering inflation reflex (end-inspiratory tracheal occlusion no longer eliciting a prolongation of expiratory duration,T _E) had no effect on either during normocapnia or at a substantial level of hypercapnia. Only with further vagal cooling to 0°C did the ventilatory depression during hypercapnia emerge, largely becauseT _E failed to shorten in response to the hypercapnic stimulus.It is concluded that the integrity of expiratory-terminating mechanisms is crucial for the manifestation of the vagally mediated facilitation of and its CO₂ responsiveness which is evident during hyperoxic hypercapnia. A possible role is suggested for lung epithelial irritant receptors or for the tonic late-expiratory activity from pulmonary stretch receptors.Supported by the Deutsche Forschungsgemeinschaft, SFB 114Preliminary reports of this work have been presented in Pflügers Arch 355: (Suppl) R47 (1975); 377: (Suppl) R54 (1978) and in Proc. XXVIII. Int. Congr. of Physiol. Sciences, Budapest, Vol VIV, 515 (1980)     

Ventilatory response of prepubertal boys and adults to carbon dioxide at rest and during exercise

Summary The aim of this study was to determine whether the greater ventilation in children at rest and during exercise is related to a greater CO₂ ventilatory response. The CO₂ ventilatory response was measured in nine prepubertal boys [10.3 years (SD 0.1)] and in 10 adults [24.9 years (SD 0.8)] at rest and during moderate exercise ( CO₂ = 20 ml·kg^–1·min^–1) using the CO₂-rebreathing method. Three criteria were measured in all subjects to assess the ventilatory response to CO₂: the CO₂ sensitivity threshold (Th), which was defined as the value of end titalPCO₂ (P _ETCO₂) where the ventilation increased above its steady-state level; the reactivity slope expressed per unit of body mass (SBM), which was the slope of the linear relation between minute ventilation ( _E) andP _ETCO₂ above Th; and the slope of the relationship between the quotient of tidal volume (V _T) and inspiration time (t _I) andP _ETCO₂ (V _T ·t _I ^–1 ·P _ETCO₂ ^–1) values above Th. The _E,V _T, breathing frequency (f _R), oxygen uptake ( O₂), and CO₂ production ( CO₂) were also measured before the CO₂-rebreathing test. The following results were obtained. First, children had greater ventilation per unit body weight than adults at rest (P<0.001) and during exercise (P<0.01). Second, at rest, onlyV _T ·t _I ^–1 ·P _ETCO₂ ^–1 was greater in children than in adults (P<0.001). Third, during exercise, children had a higher S_BM (P < 0.02) andV _T ·t _I ^–1 ·P _ETCO₂ ^–1 (P<0.001) while Th was lower (P<0.02). Finally, no correlation was found between _E/ CO₂ and Th while a significant correlation existed between _E/ CO₂ and S_BM (adults,r=0.79,P<0.01; children,r=0.73,P<0.05). We conclude that children have, mainly during exercise, a greater sensitivity of the respiratory centres than adult. This greater CO₂ sensitivity could partly explain their higher ventilation during exercise, though greater CO₂ production probably plays a role at rest.     

Influence of changes in cardiac output on the acid-base status of arterial and mixed venous blood

While maintaining the arterial CO₂ tension constant near the normal level of the dog (4.3 kPa), we studied the influence of decreasing cardiac output on both the arterial and mixed-venous blood acid-base status in anaesthetized, artificially ventilated dogs. Cardiac output was manipulated by applying positive end-expiratory pressure (PEEP), and by -adrenergic blockade to suppress a compensatory heart rate response. The systemic vascular response was attenuated by -adrenergic blockade. Metabolic rate remained virtually unchanged when cardiac output decreased. Under these conditions a fall in cardiac output led to a shift of the arterial acid-base status in the direction of a metabolic acidosis. The changes occurring in the mixed-venous blood resembled those of an in-vivo CO₂ bufferline, with the shift being such as if a respiratory acidosis was developing.     

Do gender differences exist in the ventilatory response to progressive exercise in males and females of average fitness?

Gender differences in lung volumes and flow rates, and in respiratory control have been documented previously. How these gender differences affect exercise responses in normal subjects is less clear, particularly as many studies involved highly fit subjects. This study aimed to investigate potential gender differences occurring during progressive exercise in healthy males and females of average fitness. Fourteen males and ten females of mean (SD) age 23 (0.35) years completed a progressive exercise test to exhaustion on a cycle ergometer, with a ramp increase of 15 W min⁻¹ (female) or 20 W min⁻¹ (male). All females were studied during the follicular phase of their menstrual cycle. Cardiorespiratory variables were measured, breath by breath, and values were compared at rest, at 40 W, at physiologically equivalent workloads below, at and above the gas exchange threshold and at peak oxygen uptake (V̇O_2peak). Mean V̇O_2peak (SEM) was 32.4 (2.01) ml kg⁻¹ min⁻¹ for the females and 41.9 (1.80) ml kg⁻¹ min⁻¹ for the males. Females had a significantly lower end-tidal partial CO₂ pressure at rest and throughout exercise. Increases in exercise minute ventilation were achieved by a significantly greater tidal volume in males, whereas females adopted a significantly greater breathing frequency. Ratings of respiratory discomfort were significantly greater in the male group at physiologically equivalent workloads compared to the female group. This study shows gender differences exist in the ventilatory and sensory response to progressive exercise in untrained subjects. Further work is required to ascertain if these effects are altered during the luteal phase of the menstrual cycle.     

Mechanisms of ventilatory periodicities

The study of ventilatory periodicities is relevant to the problem of obstructive sleep apnea. Apneas occur at the nadirs of periodicities during sleep. Periodicities can be caused by chemical instability, related to unstable action of the closed loop feedback system for the chemical regulation of breathing. Such instability occurs when overall loop gain is greater than or equal to unity and the phase lag around the loop is 180°. Periodic breathing during hypoxia and in patients with congestive heart failure is likely to be explained by this mechanism. Periodic breathing can also be the result of state instability. Here ventilation declines at sleep onset and the resultant changes in blood gases trigger an arousal, i.e., sudden transition to a lighter stage of sleep. With arousal, ventilation increases. Thus, periodic breathing is secondary to these changes in sleep state. These processes, chemical instability and state instability, can interact and produce complex patterns of oscillation in ventilation.     

Hyperpnoea and CO2 sensitivity of the respiratory centres during exercise

Summary The aim of this study was to specify whether exercise hyperpnoea was related to the CO₂ sensitivity of the respiratory centres measured during steady-state exercise of mild intensity. Thus, ventilation , breathing pattern [tidal volume (V _T), respiratory frequency (f), inspiratory time (T _I), total time of the respiratory cycle (T _TOT),V _T/T _I,T _I/T _TOT] and CO₂ sensitivity of the respiratory centres determined by the rebreathing method were measured at rest (SCO_{2 re}) and during steady-state exercise (SCO_{2 ex}) of mild intensity [CO₂ output =20 ml·kg⁻¹·min⁻¹] in 11 sedentary male subjects (aged 20–34 years). The results showed that SCO_{2 re} and SCO_{2 ex} were not significantly different. During exercise, there was no correlation between and SCO_{2 ex} and, for the same , all subjects had very close values normalized for body mass (bm), regardless of their SCO_{2 ex} ( =1.44 l·min⁻¹·kg⁻¹ SD 0.10). A highly significant positive correlation between SCO_{2 ex} andV _T (normalised for bm) (r=0.80,P<0.01),T _I (r=0.77,P<0.01) andT _TOT (r=0.77,P<0.01) existed, as well as a highly significant negative correlation between SCO_{2 ex} and (normalised for bm^−0.25) (r=−0.73,P<0.01). We conclude that the hyperpnoea during steady-state exercise of mild intensity is not related to the SCO_{2 ex}. The relationship between breathing pattern and SCO_{2 ex} suggests that the breathing pattern could influence the determination of the SCO_{2 ex}. This finding needs further investigation.     

Ventilatory response to oscillating and non-oscillatingPa CO 2 in the anesthetized cat

Summary In 11 adult cats, lightly anesthetized with chloralose-urethane, blood from both common carotid arteries was led into a plastic chamber of 15–20 ml and returned to the carotids at a point 1.5 cm more cranial. By doing so arterial blood was assumed to pool within the chamber and lose itsP _{CO 2} oscillations which are normally known to exist as a result of the respiratory cycle. In control periods blood bypassed the chamber, thus maintaining respiratoryP _{CO 2} oscillations. Spontaneous ventilation was measured spirometrically. The animals were breathing pure O₂.Results. 1. When the sinus (carotid) nerves were intact or sectioned there was no significant difference in ventilation before or after switching from non-oscillating to oscillatingPa _{CO 2}. 2. When the vertebral arteries were ligated a drop in ventilation occurred after turning to oscillatingPa _{CO 2} which was followed by a slight rise above control values after 30–50 sec. This phenomenon was independent of sinus nerve integrity. Thus in hyperoxie condition the smallPa _{CO 2} oscillations known to occur in phase with respiration do not seem to provide a respiratory stimulus to resting ventilation above that generated by the mean level ofPa _{CO 2}. The ventilatory depression after vertebral artery ligation must at this time remain unexplained.     

Ventilatory CO2 response in endurance-trained rats

Summary A CO₂ rebreathing technique was used to assess possible changes in the ventilatory response to CO₂ in rats following a 14-week swim training program. Over the final 9 weeks, the rats swam 1 h per day with a weight of 2.5% of the body weight attached to the tail. Ventilation was measured by a barometric method in awake, restrained rats in a total body plethysmograph at CO₂ concentrations of 0, 2, 4, 6, and 8%, with an initial O₂ concentration of approximately 100%. Ventilation increased in the trained rats with increasing CO₂ from 775 ml·min^–1·kg^–1 at 0% CO₂ to 1,387 ml·min^–1·kg^–1 at 8% CO₂. This increase was a consequence of a 34% increase in tidal volume and a 32% increase in breathing frequency. In comparison with a group of sedentary control rats, there was a significantly higher ventilation and tidal volume at 0% CO₂; however, this difference disappeared with increasing levels of CO₂. A significantly lower resting heart rate was observed in the exercised (296±44 beats·min^–1, mean±SD) compared to the sedentary control rats (380±42). It was concluded that, while the normal training response of resting bradycardia was observed following this duration and intensity of training, endurance swimming had no significant effect on the ventilatory response to CO₂ in the rat.This research was funded in part by grants from the University of Waterloo Research Foundation, the Ontario Heart Foundation, and the Medical Research Council of Canada     

CO2 control of the respiratory system: Plant dynamics and stability analysis

A stability analysis of respiratory chemical control is developed using a mathematical model of CO₂ mass transport dynamics. Starting with a 3-compartment model of CO₂ stores that distinguishes alveolar, muscle, and other tissue, model reduction techniques are applied to obtain a first-order representation of the respiratory plant. This model contains an effective tissue volume for CO₂, whose derived value is much smaller than previously predicted. To investigate oscillatory instabilities, a controller which incorporates only peripheral chemoreceptor responses was added to the first-order plant model. An explicit stability index (SI) is obtained analytically from a linearized version of this model. SI varies directly with the controller gain and circulation delay time and inversely with the effective tissue volume and inspired CO₂ concentration. Numerical simulations using the first-order nonlinear model show that SI is a good predictor of system stability. According to the linearized model, the system is stable for SI<1; from the nonlinear model, the system is stable for SI<1.1. For typical normal adults, the SI value is well within the stable region. Ahmed ElHefnawy is supported in part by a fellowship from the Egyptian Ministry of Higher Education; he is currently on leave of absence from Cairo University.