Central chemoreceptor drive to breathing in unanesthetized toads, Bufo paracnemis.

Central chemoreceptor drive to breathing was studied in unanesthetized toads, equipped with face masks to measure pulmonary ventilation and arterial catheters to analyze blood gases. Two series of experiments were performed. Expt. 1: The fourth cerebral ventricle was perfused with solutions of mock CSF, adjusted to stepwise decreasing pH values. Concomitant perfusion-induced increases of pulmonary ventilation, pHa and PaO2 were measured. Expt. 2: Inspiration of hypercapnic gas mixtures was applied to stimulate both central and peripheral chemoreceptors. Subsequently, only peripheral chemoreceptors were stimulated. This was accomplished by repeating the hypercapnic conditions while the fourth ventricle was perfused with mock CSF at pH 7.7. This procedure reduced the slope of the ventilatory response curve by about 80%. Taken together, the experiments suggest a highly dominant role of central chemoreceptors in the ventilatory acid-base regulation of the toad.     

Central-peripheral chemoreceptor ventilatory interaction in awake goats

This study was designed to characterize the ventilatory interaction between central and carotid body (CB) chemoreceptor stimulation in awake goats undergoing selective CB perfusion. This model allowed us to expose central and CB chemoreceptors to separate blood gas conditions in an animal that is conscious and not systemically hypoxic. Systemic CO2 ventilatory response curves, performed by progressively increasing FICO2 in systemic hyperoxia, were completed in 7 goats during CB perfusion with hypercapnic-hypoxic blood and normocapnic-normoxic blood, and in 3 goats without CB perfusion. The slopes of the curves done with perfusion were not significantly different (P greater than 0.05) in CB hypercapnic hypoxia and CB normocapnic normoxia for VE, VT, f and VT/TI, and the coefficients of variation of slopes generated with and without perfusion were similar. Our data indicate there is addition of central and CB chemoreceptor input in respiratory control, and we conclude that the previously demonstrated stimulus interaction at the CB is the primary source of the hyperadditive hypercapnic-hypoxic ventilatory interaction in an animal unaffected by anesthetics or brain hypoxia.     

An assessment of central-peripheral ventilatory chemoreflex interaction in humans.

The independence of the central and peripheral chemoreflexes has been tested in humans. Acute metabolic acidosis generated by a prior bout of brief, hard exercise was used to stimulate primarily the peripheral chemoreceptors, and respiratory acidosis generated by inhaled CO2 was used to stimulate both central and peripheral chemoreceptors. Seven healthy young men were studied. Ventilation and arterial pH, PCO2 and PO2 were recorded. Peripheral chemoreflex sensitivity to hypoxia during acute metabolic acidosis was repeatedly determined by measuring ventilation in euoxia (PETO2 = 100 Torr) and hypoxia (PETO2 = 50 Torr) as the subject recovered from exercise-induced acidosis. Peripheral chemoreflex sensitivity to hypoxia during CO2 inhalation was repeatedly determined by measuring ventilation in euoxia and hypoxia at two levels of hypercapnia (PETCO2 = 45 Torr and PETCO2 = 50 Torr). The ventilatory sensitivity to hypoxia at matched arterial pH values was not significantly different between conditions of high (CO2 inhalation) and low (metabolic acidosis) central chemoreceptor activity. We therefore conclude that interaction between central and peripheral chemoreflexes was non-significant in all subjects.     

Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep

We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure (PET(CO2)) was gradually reduced during non-rapid eye movement sleep by increasing tidal volume with pressure support mechanical ventilation, causing a reduction in diaphragm electromyogram amplitude until apnea/periodic breathing occurred. We used the reduction in PET(CO2) below spontaneous breathing required to produce apnea (DeltaPET(CO2)) as an index of the susceptibility to apnea. DeltaPET(CO2) was -5 mm Hg in control animals and changed in proportion to background ventilatory drive, increasing with metabolic acidosis (-6.7 mm Hg) and nonhypoxic peripheral chemoreceptor stimulation (almitrine; -5.9 mm Hg) and decreasing with metabolic alkalosis (-3.7 mm Hg). Hypoxia was the exception; DeltaPET(CO2) narrowed (-4.1 mm Hg) despite the accompanying hyperventilation. Thus, hyperventilation and hypocapnia, per se, widened the DeltaPET(CO2) thereby protecting against apnea and hypopnea, whereas reduced ventilatory drive and hypoventilation narrowed the DeltaPET(CO2) and increased the susceptibility to apnea. Hypoxia sensitized the ventilatory responsiveness to CO2 below eupnea and narrowed the DeltaPET(CO2); this effect of hypoxia was not attributable to an imbalance between peripheral and central chemoreceptor stimulation, per se. We conclude that the DeltaPET(CO2) and the ventilatory sensitivity to CO2 between eupnea and the apneic threshold are changeable in the face of variations in the magnitude, direction, and/or type of ventilatory stimulus, thereby altering the susceptibility for apnea, hypopnea, and periodic breathing in sleep.     

Diethyl pyrocarbonate (DEPC) inhibits CO2 chemosensitivity in Helix aspersa

Central CO₂ chemoreceptors in poikilothermic vertebrates may not regulate ventilation at a particular pH setpoint; central chemoreceptor responses may more accurately reflect the relative charge state (alpha) of the imidazole of histidine. We have tested the alphastat hypothesis in the terrestrial, air breathing, pulmonate snail, Helix aspersa, by chemically modifying histidine residues in the central CO₂ chemoreceptor area of this animal using diethyl pyrocarbonate (DEPC). After focal application of 20 mM DEPC to the central CO₂ chemoreceptor region, the pneumostome, a respiratory, CO₂ responsive organ in the snail, no longer responded to hypercapnic, acidotic stimulation of the central chemoreceptor area. However, pneumostomal responses to hypoxic stimulation of the pneumostome and to focal stimulation of the central chemoreceptor area with sodium nitroprusside, a respiratory stimulant in H. aspersa, remained intact after DEPC treatment. Furthermore, DEPC treatment of the central chemoreceptor area blocked pneumostomal responses to ammonia pre-pulse treatment, which changes intracellular pH, while extracellular pH is held constant. These results resemble mammalian responses to DEPC treatment and indicate that central chemoreceptor responses in H. aspersa may originate from changes in the alpha of intracellular histidine residues.     

Ventilatory responses to respiratory and metabolic acid-base disturbances in cats

To determine the relative importance of the peripheral and central chemoreceptors in the ventilatory response to acute metabolic acid-base disturbances we measured the normoxic ventilatory response to acute respiratory and metabolic acidosis and alkalosis in 10 chloralose-urethane anesthetized cats using a technique of vertebral artery perfusion that allows one to independently manipulate the PaCO2, PaO2 and the H+ concentration of the blood in the systemic circulation (peripheral) and the blood perfusing the brain stem (central) (Berkenbosch et al., 1979). The ventilation could be satisfactorily described by a linear function of the peripheral and central arterial H+ concentration and the central PaCO2. Mean values (+/- SEM) found for the peripheral arterial H+ sensitivity and the isocapnic central arterial H+ sensitivity were 26.0 +/- 3.2 and 12.7 +/- 1.8 ml X min-1 X nM-1, respectively; the isohydric central arterial CO2 sensitivity was 545.9 +/- 96.7 ml X min-1 X kPa-1. We conclude that in the ventilatory response to an acute metabolic acid-base disturbance both the peripheral and central chemoreceptors play a role. However, the sensitivity of the peripheral chemoreceptors to isocapnic changes in the arterial H+ concentration is twice as large as the sensitivity of the central chemoreceptors. It is argued that in the adaptation of the ventilation to an acute metabolic acidosis the stimulatory effect of the peripheral chemoreceptors is counteracted by a diminished stimulation of the central chemoreceptors.     

Ventilatory responses to hypocapnic vertebral artery perfusion in intact and carotid body denervated dogs

The ventilatory responses to step changes in vertebral artery PCO2 were investigated in intact and carotid body denervated dogs. The steady-state ventilatory responses of the denervated dogs were less than those of intact dogs. However, when expressed as a ratio to the control ventilation there was no difference between the two groups. While the arterial PCO2 was held at 56 mm Hg by adding CO2 to the inspired air the perfusion of the vertebral arteries was switched from the dog's own arterial supply to hypocapnic blood. The ventilation of the denervated dogs decreased at a faster rate (half time = 130 +/- 9 sec) to a level less than the room air control ventilation. The ventilation in the intact dogs decreased at a slower rate (half time = 184 +/- 23 sec) and was maintained above the room air control level after ten minutes of hypocapnic perfusion. Increasing the medullary blood flow, as measured with radiolabeled microspheres, augmented the rate of decline of ventilation in intact dogs. We conclude, (1) the influence of the peripheral chemoreceptors appears to increase as central drive is decreasing, and (2) the remaining time course of the decrease in ventilation is related to the rate of brain stem perfusion.     

Intracisternal diethylpyrocarbonate inhibits central chemosensitivity in conscious rabbits

As a direct chemical test of the alpha-imidazole hypothesis for the function of mammalian central chemoreceptors (CCR), diethylpyrocarbonate (DEPC) a relatively specific reactant with imidazole groups in vitro has been administered in vivo via intracisterna magna (ICM) infusion in conscious rabbits using each rabbit as its own control. DEPC, in a dose-dependent fashion, induced resting hypoventilation and inhibited (1) the ventilatory response to CO2 in peripherally chemodenervated animals, and (2) both the PaCO2 and minute ventilation responses to ICM infusion of an acidic mock cerebrospinal fluid (CSF). DEPC had no effect on the hypoxic ventilatory response and had small non-dose-dependent effects on body temperature. ICM administration of hydroxylamine (HDA), a substance that reverses the DEPC-imidazole binding in vitro, prevented DEPC induced inhibition of CCR function. These data support but do not prove the alpha-imidazole hypothesis for mammalian central chemoreceptor function and demonstrate a potentially useful chemical tool for the study of central chemoreception.     

Relationship between carotid chemoreceptor activity and ventilation in the cat.

The steady-state stimulus-response relations between arterial P02 and PCO2 and the mean activity of carotid chemoreceptors (single and multi-fiber) and ventilation were simultaneously recorded in 48 anesthetized cats. The carotid chemoreceptor activity varied linearly with the increase of arterial PCO2, below and above the normal value, at any given level of arterial P02. A decrease in arterial P02 increased the activity of the carotid chemoreceptors and increased its sensitivity to changes in arterial PCO2, showing multiplicative stimulus interaction. The authors also found that the response in ventilation during hypoxia to changes in arterial PCO2 below the normal value was smaller than that to changes above it, unlike the response of carotid chemoreceptors. This arterial PCO2 quasi-threshold for ventilation was, therefore, not due to a corresponding threshold for the activity of the carotid chemoreceptors but to a central mechanism. Above the central PaCO2 threshold, the ventilatory response to changes in PaCO2 and Pa02 resembled that of chemoreceptors but the ventilation dependent on hypoxia was greater than that could be directly accounted for by the activity of peripheral chemorecepors. A multiplicative interaction between the activity of peripheral chemoreceptors and central CO2 excitation appears to play a role in the regulation of ventilation.     

Central chemoreceptor stimulus in the terrestrial,pulmonate snail,Helix aspersa

We studied the effect of hypercapnic and fixed acid central chemoreceptor stimulation on the pneumostone in the pulmonate snail, Helix aspersa. We found that focal stimulation of the central chemoreceptor area of the pulmonate snail brain with hypercapnic solutions more effectively increased the pneumostonal area than did fixed acid stimulation at the same extracellular pH. Disrupting intracellular pH regulation by inhibiting Cl⁻ transport, either pharmacologically (DIDS) or by ion substitution (Cl⁻-free perfusate), enhanced pneumostomal responses to CO₂. While maintaining a constant perfusate pH, addition of NH₄Cl to the perfusate resulted in pneumostomal closure; whereas removal of NH₄Cl from the bath resulted in pneumostomal opening. In conclusion, the ventilatory response to CO₂ in H. aspersa does not require Cl⁻ transport or conductance. Furthermore, changing pH_i alone is an adequate stimulus for the central chemoreceptors in the snail.     

A model of the chemoreflex control of breathing in humans: model parameters measurement

We reviewed the ventilatory responses obtained from rebreathing experiments on a population of 22 subjects. Our aim was to derive parameter estimates for an 'average subject' so as to model the respiratory chemoreflex control system. The rebreathing technique used was modified to include a prior hyperventilation, so that rebreathing started at a hypocapnic P(CO2) and ended at a hypercapnic P(CO2). In addition, oxygen was added to the rebreathing bag in a controlled manner to maintain iso-oxia during rebreathing, which allowed determination of the response at several iso-oxic P(O2) levels. The breath-by-breath responses were analysed in terms of tidal volume, breathing frequency and ventilation. As P(CO2) rose, ventilation was first steady at a basal value, then increased as P(CO2) exceeded a breakpoint. We interpreted this first breakpoint as the threshold of the combined central and peripheral chemoreflex responses. Above, ventilation increased linearly with P(CO2), with tidal volume usually contributing more than frequency to the increase. When breathing was driven strongly, such as in hypoxia, a second breakpoint P(CO2) was often observed. Beyond the second breakpoint, ventilation continued to increase linearly with P(CO2) at a different slope, with frequency usually contributing more than tidal volume to the increase. We defined the parameters of the variation of tidal volume, frequency and ventilation with P(O2) and P(CO2) for an average subject based on a three-segment linear fit of the individual responses. These were incorporated into a model of the respiratory chemoreflex control system based on the general scheme of the 'Oxford' model. However, instead of considering ventilatory responses alone, the model also incorporates tidal volume and frequency responses.     

Ventilatory response of the conscious or anesthetized cat to oxygen breathing

In conscious intact cats, oxygen breathing for up to 1 h does not modify ventilation, and the ventilatory response to CO2 in hyperoxia is not consistently decreased. However, oxygen breathing induces sustained hyperventilation in conscious cats after carotid body denervation. In anesthetized cats, oxygen breathing provokes a hypoventilation which is transient under light anesthesia but more sustained under deeper levels of anesthesia. At all levels of anesthesia, the ventilatory response to CO2 is decreased in hyperoxia as compared with normoxia. These results suggest that: the effects of hyperoxia include a central stimulating component, seen only in conscious animals, which offsets the decreased ventilatory drive from peripheral chemoreceptors; this central component is sensitive to anesthesia, thus allowing an explanation for the permanent decrease in ventilation and decrease in ventilatory response to CO2 observed when oxygen is given during deep anesthesia; and anesthesia may help to purposefully unmask factors involved in the control of breathing, but it markedly alters the normal functioning of the respiratory network.     

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.     

Respiratory and nonrespiratory effects of doxapram in congenital central hypoventilation syndrome.

Doxapram is a respiratory stimulating drug that affects both peripheral chemoreceptors and medullary respiratory and nonrespiratory neurons. We administered doxapram 60 2 infants with congenital central hypoventilation syndrome. In 6 separate trials at a dose range of 0.32 to 2.0 mg per kg of body weight per min, quiet-sleep tidal volume increased from 4.9 +/- 1.0 to 8.5 +/- 0.9 ml per kg of body weight, minute ventilation increased from 140 +/- 38 to 286 +/- 31 ml per kg of body weight per min, and alveolar PCO2 decreased from 60 +/- 5 to 32 +/- 2 mm Hg. In all instances, the maximal quiet-sleep ventilatory response was achieved within 10 min. The ventilatory response to steady-state CO2 breathing was not improved with doxapram. A continuous infusion of doxapram for 5.2 days in one infant successfully maintained normal quiet-sleep ventilation. In both infants, multiple nonrespiratory effects of doxapram occurred; enteral administration was associated only with generalized neuromuscular stimulation, but the 5-day intravenous infusion was also associated with acute hepatotoxicity and a perforated duodenal ulcer. The medullary respiratory neurons in central hypoventilation syndrome may be incapable of responding to doxapram, and the ventilatory responses observed may be due entirely to stimulation of peripheral chemoreceptors. Although quiet-sleep ventilation can be successfully maintained with intravenous and enteral administration of doxapram, and tachyphylaxis has not been observed, we have been unable to avoid at least the neuromuscular manifestations of nonrespiratory medullary stimulation.     

Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.     

Evidence that maturation of the peripheral chemoreceptors is not complete in childhood

We examined the hypothesis that the peripheral chemoreceptors contribute a different degree of tone to respiration during exercise in normal young children as compared to adults. To improve resolution of the peripheral chemoreceptor contribution, the studies were conducted during controlled levels of exercise. Peripheral chemoreceptor function was assessed by the hyperoxic (FIO2 = 0.80) switch technique during steady-state, sub-anaerobic threshold exercise during air (FIO2 = 0.21) and midly hypoxic gas (FIO2 = 0.15) breathing in 9 healthy children (mean +/- 1 SD age (years) = 8.2 +/- 1.4) and 10 healthy adults (28.2 +/- 6.5). Ventilation during exercise was significantly greater under hypoxic conditions in both children and adults. During air breathing exercise the mean ventilatory decrease in response to the hyperoxic switch was similar in the two groups (27.9 +/- 10.7% in children and 23.3 +/- 6.3% in adults). In contrast, during hypoxic gas breathing exercise the children demonstrated a much greater decrease in ventilation following the hyperoxic switch (57.9 +/- 3.6%) compared to adults (38.9 +/- 5.5%) (P less than 0.0001). Thus, the peripheral chemoreceptors have a greater role in the exercise hyperpnea during hypoxic exercise in young children as compared to adults, suggesting attenuation of peripheral chemoreceptor function during maturation.     

Contribution of peripheral chemoreceptors to ventilation and the effects of their suppression on exercise tolerance in chronic heart failure.

OBJECTIVES: To assess the contribution of peripheral chemoreceptors to ventilation and the effects of continuous inspired oxygen on exercise tolerance in chronic heart failure patients. The role of peripheral chemoreceptors in mediating hyperpnoea in chronic heart failure is unknown. Hyperoxia is known to suppress the peripheral chemoreceptor drive. The magnitude of decrease in ventilation with transient inhalations of oxygen thus provides a measure of the contribution of the peripheral chemoreceptors to ventilation. SETTING: Tertiary specialist hospital. SUBJECTS AND METHODS: Three breaths of 100% oxygen were given at rest and also during cycle ergometry at 25 W to 8 healthy controls (age 52.0 (4.7) (SEM) years) and 13 patients with chronic heart failure (age 60.5 (2.1) years (P = NS); radionuclide left ventricular ejection fraction 25.5 (4.3)%). The peripheral chemoreceptor sensitivity was also measured by assessing the ventilatory response to hypoxia using transient inhalations of pure nitrogen. Another group of 12 patients with chronic heart failure (age 65.5 (1.5) years; left ventricular ejection fraction 21.3 (3.0)%) underwent treadmill exercise testing on 2 occasions, breathing air or 100% oxygen in a randomised single-blind manner, to examine the effects of continuous inspired oxygen on exercise tolerance. RESULTS: The reduction in ventilation with transient hyperoxia was 18.1 (2.9)% v 17.9 (2.6)% (P = NS) at rest and 20.4 (2.8)% v 21.0 (1.6)% (P = NS) during cycle ergometry, for controls and patients respectively. The hypoxic chemosensitivity was higher in patients (0.232 (0.022) v 0.572 (0.082) 1/min/%SaO2; P = 0.002). Continuous inspired oxygen increased exercise time (517 (31) v 455 (27) seconds; P = 0.003), and a trend towards a reduction in the ventilatory response to exercise, characterised by the regression slope relating ventilation to carbon dioxide output, was evident (31.27 (2.60) v 34.19 (2.35); P = 0.08). CONCLUSIONS: Despite an increased peripheral chemoreceptor sensitivity, the proportionate contribution of peripheral chemoreceptors to ventilation remained similar in heart failure patients (about 20%). This suggests that the peripheral chemoreceptors are not the main mediator of increased ventilation and there are other non-peripheral chemoreceptor-mediated mechanisms involved. Hyperoxia reduced ventilation at rest and during cycle ergometry. The increase in exercise duration with continuous inspired oxygen that was associated with a reduction in exercise ventilatory response suggests that suppression of the peripheral chemoreceptors may improve exercise tolerance; the effects of possible reduced skeletal muscle anaerobiosis cannot be excluded, however.     

The effect of central and peripheral dopamine-agonists on ventilation in the mouse

This study was designed to investigate the role of central dopaminergic pathways in ventilatory control in unanaesthetised, chemoreceptor intact mice. Dopamine does not cross the blood-brain barrier and was used to selectively affect peripheral arterial chemoreceptors. Levodopa, the immediate precursor of dopamine, was given alone when it is converted to dopamine mainly in the periphery, and together with carbidopa, which prevents the peripheral conversion of levodopa to dopamine, and enhances central generation of dopamine from levodopa. Dopamine (60-240 mg X kg-1), levodopa (50-300 mg X kg-1), and levodopa with carbidopa in a constant ratio of 10:1 (33/3.3-100/10 mg X kg-1) were given by intraperitoneal injection. Ventilation was measured in 10% O2 and in 7.5% CO2 by a plethysmographic method. Levodopa with carbidopa stimulated ventilation in both 10% O2 and 7.5% CO2. Ventilation in 10% O2 increased from 55.1 +/- 1.43 ml X min-1 (mean +/- SE) to 93.8 +/- 4.75 ml X min-1 with levodopa 100 mg X kg-1/carbidopa 10 mg X kg-1 (P less than 0.01). Ventilation in 7.5% CO2 increased from 101.8 +/- 3.42 ml X min-1 to 138.5 +/- 4.94 ml X min-1 with levodopa 100 mg X kg-1/carbidopa 10 mg X kg-1 (P less than 0.05). In contrast, very high doses of dopamine alone (240 mg X kg-1) and levodopa alone (300 mg X kg-1) depressed hypoxic but not hypercapnic ventilation. Carbidopa alone had no effect of ventilation. It is concluded that dopaminergic transmission within the brain mediates pathways leading to increased ventilation.     

Effects of CO2 and H+ on the ventilatory response to peripheral chemoreceptor stimulation

To determine whether the stimulatory effect of CO2 on the peripheral chemoreceptors is due to molecular CO2, H+ or both we measured steady-state ventilation (Ve) during normoxia in 9 and during hypoxia in 5 chloralose-urethane anaesthetized cats using the artificial brain stem perfusion technique. This technique allows one to manipulate independently the PaCO2, PaO2 and the pHa of the blood in the systemic circulation (peripheral) and the blood perfusing the brain stem (central). Keeping the central conditions constant the H+ and CO2 concentrations in the systemic circulation were changed by i.v. infusion of 0.3 M HCl or 0.6 M NaHCO3 and by giving the animal different CO2 mixtures to inhale. The peripheral H+ concentration ([H+]p) range covered was from 27 to 103 nmol X 1(-1); the peripheral arterial CO2 tension (PaPCO2) ranged from 2.3 kPa to 8.4 kPa. Fitting the data with the function VE = a[H+]p + bPaPCO2 + c revealed that the coefficient b was not significantly different from zero at the 0.05 level during normoxia and hypoxia. The mean value (+/- SEM) found for the coefficient a was 33.0 +/- 3.6 at normoxia and 36.0 +/- 15.4 ml X min-1 X nM-1 at hypoxia. We conclude that the steady-state ventilatory response due to the stimulation of the peripheral chemoreceptors with CO2 is mediated by H+. The effects of molecular CO2 are negligible.     

Control of metabolic and ventilatory responses to cold in anesthetized cats.

Interactions between the control of thermogenesis and ventilation were studied during normoxia, hyperoxia, and ambient or CO hypoxia in adult anesthetized intact or carotid-denervated cats. Shivering, metabolic and ventilatory responses to cold stress were studied. In addition, the effects of transient pharmacological stimulation (NaCN) or inhibition (Dopamine) of arterial chemoreceptor activity were studied under different levels of oxygenation. In intact animals, cold exposure provoked increases in VO2 and ventilation which were directly proportional to the intensity of shivering. During ambient or CO hypoxia, VO2 was less than in normoxia for all values of shivering intensity, suggesting that a non-shivering thermogenesis component may also be inhibited by hypoxia. The decrease in VO2 was associated with a smaller decrease in ventilation in ambient than in CO hypoxia because of the presence of the chemoreflex drive during ambient hypoxia. Pharmacological changes in chemoreceptor activity induced transient and opposite changes in ventilation and shivering intensity, confirming their role in the control of thermogenesis. After carotid denervation, when the drug effects were inconsistent or absent, changes in levels of oxygenation were still followed by changes in shivering activity and associated changes in VO2 and ventilation. We conclude that control of thermogenesis and ventilation and their interaction may be mediated by chemoreceptors as well as by direct effects upon central, possibly diencephalic structures.