The role of pulmonary CO2 flow in the control of the phase i ventilatory response to exercise in humans

To gain an insight into the origin of the phase I ventilatory response to exercise (ph I) in humans, pulmonary ventilation WE) and end-tidal partial pressures of oxygen and carbon dioxide (P _ETO₂ and P _ETCO₂, respectively) were measured breath-by-breath in six male subjects during constant-intensity exercise on the cycle ergometer at 50, 100 and 150 W, with eupnoeic normocapnia (N) or hyperpnoeic hypocapnia (H) established prior to the exercise test. Cardiac output (Q₂) was also determined beat-by-beat by impedance cardiography on eight subjects during moderate exercise (50 W), and the C0₂ flow to the lungs (Q₂·C_vCO₂ where C_vCO₂ is concentration of CO₂ in mixed veneous blood) was estimated with a time resolution of one breathing cycle. In N, the initial abrupt increase of PE during ph I (V_E approximately 18 l · min^–1 above rest) was followed by a transient fall. When P _ETCO₂ started to increase (and P _ETO₂ decreased) V_E increased again (phase II ventilatory response, ph II). In H, during ph I V_E was similar to that of N. By contrast, during ph II V_E kept gradually decreasing and started to increase only when P _ETCO₂ had returned to approximately 40 mmHg (5.3 kPa). Thus, as a result of the prevailing initial conditions (N or H) a temporal shift of the time-course of V_E during ph II became apparent. No correlation was found between C0₂ flow to the lungs and V_E during ph I. These results are interpreted as suggesting that an increased C0₂ flow to the lungs does not constitute an important factor for the initial hyperventilatory response to exercise. They are rather compatible with a neural origin of ph I, and would support the neurohumoral theory of ventilatory control during exercise.     

Ventilatory responses to exercise performed below and above the first ventilatory threshold

These experiments examined the changes in ventilation at the start and end of exercise. Six subjects walked on a treadmill at two work rates above and two below that corresponding to their first ventilatory thresholds, for three durations. The subjects also exercised at the lowest and highest work rates while inspiring oxygen-enriched air. The group mean results showed that the abrupt increases in ventilation at the start of exercises at work rates above that of the first ventilatory threshold were greater than those below, but did not vary with duration or work rate either above or below. The abrupt falls in ventilation at the end of the exercises were less than the increases at the start. At work rates above that of the first ventilatory threshold, increases in work rate and duration were found to reduce the abrupt falls. The time constants of exponential curves fitted to the post-exercise declines in ventilation increased with work rate, and also with duration for work rates above that of the first ventilatory threshold. Finally, breathing oxygen enriched air did not alter any of these variables. These findings were interpreted as showing that the fast neural exercise drive is enhanced at work rates above that of the first ventilatory threshold, and becomes progressively less as exercise continues, a process exaggerated at higher work rates. In addition, the time course of the decline in ventilation following exercise, although altered by work rate and duration, was independent of the level of oxygenation.     

Spinal serotonin receptor activation modulates the exercise ventilatory response with increased dead space in goats

Small increases in respiratory dead space (VD) augment the exercise ventilatory response by a serotonin-dependent mechanism known as short-term modulation (STM). We tested the hypotheses that the relevant serotonin receptors for STM are in the spinal cord, and are of the 5-HT2-receptor subtype. After preparing adult female goats with a mid-thoracic (T6-T8) subarachnoid catheter, ventilation and arterial blood gases were measured at rest and during treadmill exercise (4.8 km/h; 5% grade) with and without an increased VD (0.2-0.3 L). Measurements were made before and after spinal or intravenous administration of a broad-spectrum serotonin receptor antagonist (methysergide, 1-2mg total) and a selective 5-HT2-receptor antagonist (ketanserin, 5-12 mg total). Although spinal methysergide had no effect on the exercise ventilatory response in control conditions, the augmented response with increased VD was impaired, allowing [Formula: see text] to increase from rest to exercise. Spinal methysergide diminished both mean inspiratory flow and frequency responses to exercise with increased VD. Spinal ketanserin impaired [Formula: see text] regulation with increased VD, although its ventilatory effects were less clear. Intrathecal dye injections indicated CSF drug distribution was caudal to the upper cervical spinal cord and intravenous drugs at the same total dose did not affect STM. We conclude that spinal 5-HT2 receptors modulate the exercise ventilatory response with increased VD in goats.     

Increase in reaction time for the peripheral visual field during exercise above the ventilatory threshold

The purpose of the present study was to determine whether reaction time (RT) for the peripheral visual field increases at exercise intensity above the ventilatory threshold (VT) during incremental exercise and to examine the relationship between aerobic capacity and the extent of increase in the RT. Nine healthy subjects performed a simple manual RT task for the peripheral visual field at rest, during exercise on a cycle ergometer, and immediately after exercise. After warm-up exercise, the subjects cycled at 40 W for 3 min, increasing by 40 W every 3 min until 240 W in a step-wise manner. During incremental exercise, RT measurements were performed 1 min and 30 s after the start of every increase in workload. The RT for the peripheral visual field significantly increased at exercise intensity above VT, as compared with at rest. The increase in the RT, which was calculated by subtracting the RT at rest from the RT at 240 W, negatively correlated with maximal oxygen uptake for each subject (r=–0.73, P<0.05). It is likely that high aerobic capacity attenuates the increase in the RT for the peripheral visual field during exhaustive exercise.     

Chronic hypoxia suppresses the CO2 response of solitary complex (SC) neurons from rats

We studied the effect of chronic hypobaric hypoxia (CHx; 10–11% O₂) on the response to hypercapnia (15% CO₂) of individual solitary complex (SC) neurons from adult rats. We simultaneously measured the intracellular pH and firing rate responses to hypercapnia of SC neurons in superfused medullary slices from control and CHx-adapted adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. We found that CHx caused the percentage of SC neurons inhibited by hypercapnia to significantly increase from about 10% up to about 30%, but did not significantly alter the percentage of SC neurons activated by hypercapnia (50% in control vs. 35% in CHx). Further, the magnitudes of the responses of SC neurons from control rats (chemosensitivity index for activated neurons of 166 ± 11% and for inhibited neurons of 45 ± 15%) were the same in SC neurons from CHx-adapted rats. This plasticity induced in chemosensitive SC neurons by CHx appears to involve intrinsic changes in neuronal properties since they were the same in synaptic blockade medium.     

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.     

CO2 fixation in the nervous tissue IV. CO2 fixation and citrate metabolism in lobster nerve

Summary The specific activity of citric acid of the lobster nerve which was incubated in Ringer-bicarbonate solution containing ¹⁴C-bicarbonate was determined. The specific activity of citric acid was higher than that of malic acid by a factor of 2.5. The citric acid obtained from the lobster nerve was degraded with an improved method which is described in this paper. The ratio of the radio-activity of C-6 to C-1 of citric acid was 11. Aspartic acid obtained from the lobster nerve was also degraded, and the ratio of the radioactivity of C₄ to C₁ was almost 101.From these results, it is assumed that CO₂ fixation in the lobster nerves occurs at the oxalosuccinate level and at the oxaloacetate level and that the rates of these fixations were almost the same. Thus the active backwards reaction from -ketoglutaric acid to citric acid in lobster nerve was confirmed. It was also possible that both the activity of the citrate cleavage enxyme and the mixing of the dicarboxylic acid carboxyl groups were minimal.The concentration of oxaloacetic acid was estimated to be 2 mmole/mg protein, or 4 mmoles for a 50 mg nerve.Fellow of the Rockefeller Foundation     

CO2 fixation in the nervous system V. CO2 fixation and citrate metabolism in rabbit nerve

Summary The extent of CO₂ fixation in the sciatic nerve of the rabbit was determined. The specific activitiy of citric acid was higher than that of glutamic, aspartic, and malic acids, and the specific activity of citric acid obtained from the 2 hour incubation nerve was close to 1/3 of that of the CO₂ in the medium. The ratio of the radioactivity of the C-6 to C-1 of citrate was about 21 in intact nerves and about 11 in damaged nerves, and the ratio of the radioactivitiy of C-4 to C-1 of aspartate was approximately 11 in both cases. These results suggest that in the sciatic nerve of the rabbit: 1) the dicarboxylic acid shuttle was active, 2) the extent of the carboxylation at the oxalosuccinic acid level was 1/2 or more of that at the oxaloacetic acid level, and 3) the CO₂ fixation by the carboxylation of a-ketoglutaric acid might have some relationship to nerve function. The significance of CO₂ fixation, and the possible relationship between the carboxylation of -ketoglutaric acid and the concentrations of citric acid, acetyl-CoA and acetylcholine, and the control of the rate of tricarboxylic acid cycle were discussed.Fellow of the Rockefeller Foundation     

CO2 retention in lung disease; could there be a pre-existing difference in respiratory physiology

Some patients with lung disease retain CO₂, while others with similar lung function do not. This could be explained if CO₂ retainers had a pre-existing low hypercapnic ventilatory response (HCVR) and, from this, a tendency to retain CO₂. To test if such a phenomenon exists in healthy people, we determined the change in end-tidal P_CO2 (ΔPET_CO2) produced by the addition of a dead-space (DS), during wakefulness and sleep, and related this to the HCVR measured awake. The group mean (n=14) HCVR slope was 2.2±1.1 (S.D.) L min⁻¹ mmHg⁻¹. The ΔPET_CO2 with the application of DS was 1.6±1.6 mmHg awake and 2.6±2.2 mmHg asleep. During wakefulness the ?PET_CO2 with DS did not correlate with the HCVR slope. However, during sleep, four subjects had a marked increase in the ΔPET_CO2 (3.7, 4.3, 6.2, 8.0 mmHg) and a relatively low HCVR (slope 1.5, 1.7, 1.5, 1.7 L min⁻¹ mmHg⁻¹, respectively). We speculate that such individuals, should they develop lung disease, may be predisposed to retain CO₂.     

Adenosine triphosphate content in the cat carotid body under different arterial O2 and CO2 conditions

The adenosine triphosphate (ATP) level in the carotid body has often been discussed as the crucial step in the chemoreceptive process. Therefore, the ATP level of the cat carotid body was investigated with the aid of the bioluminescence method under different stimulation conditions. Under normoxic conditions an ATP level of about 0.087 nmol/glomus was measured, which is very low in comparison to other organs. The level did not change significantly, neither under hypoxic nor hypercapnic conditions. From these results we conclude that the primary effect of the chemoreceptive process in the carotid body cannot be explained by changes of the ATP level under different stimulation conditions.     

The intent to exercise influences the cerebral O2/carbohydrate uptake ratio in humans

During and after maximal exercise there is a 15–30 % decrease in the metabolic uptake ratio (O₂/[glucose + 1/2 lactate]) and a net lactate uptake by the human brain. This study evaluated if this cerebral metabolic uptake ratio is influenced by the intent to exercise, and whether a change could be explained by substrates other than glucose and lactate. The arterial-internal jugular venous differences (a-v difference) for O₂, glucose and lactate as well as for glutamate, glutamine, alanine, glycerol and free fatty acids were evaluated in 10 healthy human subjects in response to cycling. However, the a-v difference for the amino acids and glycerol did not change significantly, and there was only a minimal increase in the a-v difference for free fatty acids after maximal exercise. After maximal exercise the metabolic uptake ratio of the brain decreased from 6.1 ± 0.5 (mean ± s.e.m. ) at rest to 3.7 ± 0.2 in the first minutes of the recovery (   P < 0.01  ). Submaximal exercise did not change the uptake ratio significantly. Yet, in a second experiment, when submaximal exercise required a maximal effort due to partial neuromuscular blockade, the ratio decreased and remained low (4.9 ± 0.2) in the early recovery (   n = 10  ;   P < 0.05  ). The results indicate that glucose and lactate uptake by the brain are increased out of proportion to O₂ when the brain is activated by exhaustive exercise, and that such metabolic changes are influenced by the will to exercise. We speculate that the uptake ratio for the brain may serve as a metabolic indicator of 'central fatigue'.     

The effect of endurance training on the ventilatory response to exercise in elite cyclists

The purpose of this study was to investigate the effects of endurance training on the ventilatory response to acute incremental exercise in elite cyclists. Fifteen male elite cyclists [mean (SD) age 24.3 (3.3) years, height 179 (6) cm, body mass 71.1 (7.6) kg, maximal oxygen consumption (V˙O_2max) 69 (7) ml · min⁻¹ · kg⁻¹] underwent two exercise tests on a cycle ergometer. The first test was assessed in December, 6 weeks before the beginning of the cycling season. The second test was performed in June, in the middle of the season. During this period the subjects were expected to be in a highly endurance-trained state. The ventilatory response was assessed during an incremental exercise test (20 W · min⁻¹). Oxygen consumption (V˙O₂), carbon dioxide production (V˙CO₂), minute ventilation (V˙ _E), and heart rate (HR) were assessed at the following points during the test: at workloads of 200 W, 250 W, 300 W, 350 W, 400 W and at the subject's maximal workload, at a respiratory exchange ratio (R) of 1, and at the ventilatory threshold (Th_vent) determined using the V-slope-method. Post-training, the mean (SD) V˙O_2max was increased from the pre-training level of 69 (7) ml · min⁻¹ · kg⁻¹ (range 61.4–78.6) to 78 (6) ml · min⁻¹ · kg⁻¹ (range 70.5–86.3). The mean post-training V˙O₂ was significantly higher than the pre training value (P < 0.01) at all work rates, at Th_vent and at R=1. V˙O₂ was also higher at all work rates except for 200 W and 250 W. V˙ _E was significantly higher at Th_vent and R=1. Training had no effect on HR at all workloads examined. An explanation for the higher V˙O₂ cost for the same work rate may be that in the endurance-trained state, the adaptation to an exercise stimulus with higher intensity is faster than for the less-trained state. Another explanation may be that at the same work rate, in the less-endurance-trained state power is generated using a significantly higher anaerobic input. The results of this study suggest the following practical recommendations for training management in elite cyclists: (1) the V˙O₂ for a subject at the same work rate may be an indicator of the endurance-trained state (i.e., the higher the V˙O₂, the higher the endurance-trained capacity), and (2) the need for multiple exercise tests for determining the HR at Th_vent during a cycling season is doubtful since at Th_vent this parameter does not differ much following endurance training. Accepted: 19 October 1999     

Integration of CO2 and odorant signals in the mouse olfactory bulb

Carbon dioxide (CO₂) is an important environmental cue for many animal species. In both vertebrates and invertebrates, CO₂ is detected by a specialized subset of olfactory sensory neurons (OSNs) and mediates several stereotypical behaviors. It remains unknown how CO₂ cues are integrated with other olfactory signals in the mammalian olfactory bulb, the first stage of central olfactory processing. By recording from the mouse olfactory bulb in vivo, we found that CO₂-activating neurons also respond selectively to odorants, many of which are putative mouse pheromones and natural odorants. In addition, many odorant-responsive bulbar neurons are inhibited by CO₂. For a substantial number of CO₂-activating neurons, binary mixtures of CO₂ and a specific odorant produce responses that are distinct from those evoked by either CO₂ or the odorant alone. In addition, for a substantial number of CO₂-inhibiting neurons, CO₂ addition can completely block the action potential firing of the cells to the odorants. These results indicate strong interaction between CO₂ signals and odorant signals in the olfactory bulb, suggesting important roles for the integration of these two signals in CO₂-mediated behavioral responses.     

CO2 homeostasis is maintained in conscious humans by regulation of tidal volume,but not of respiratory rhythm

Automatic regulation of tidal volume (V_T) maintains CO₂ homeostasis when spontaneous respiratory rhythm is replaced with a cortically triggered rhythm. We examined whether automatic regulation of respiratory frequency (f_R) could maintain CO₂ homeostasis at rest if the V_T is cortically designated in experiments performed in 21 conscious humans. First, volitionally controlled f_R at levels lower than baseline resulted in a larger V_T, maintaining end-tidal CO₂ fraction constant at eupneic levels. However, when f_R was volitionally controlled at levels higher than baseline, end-tidal CO₂ fraction decreased unexpectedly. Next, when the V_T was volitionally constrained but f_r was freely chosen, end-tidal CO₂ fraction decreased. The present study revealed some limitations in the control of CO₂ homeostasis by automatic regulation of f_R, probably because respiratory rhythm is susceptible to non-metabolic factors. This study also showed the importance of automatic regulation of V_T in maintaining CO₂ homeostasis at rest. Nevertheless, automatic regulation of V_T was incomplete when f_R was volitionally imposed at high levels.     

Comparison of the metabolic and ventilatory response to hypoxia and H2S in unsedated mice and rats

Hypoxia alters the control of breathing and metabolism by increasing ventilation through the arterial chemoreflex, an effect which, in small-sized animals, is offset by a centrally mediated reduction in metabolism and respiration. We tested the hypothesis that hydrogen sulfide (H₂S) is involved in transducing these effects in mammals. The rationale for this hypothesis is twofold. Firstly, inhalation of a 20–80 ppm H₂S reduces metabolism in small mammals and this effect is analogous to that of hypoxia. Secondly, endogenous H₂S appears to mediate some of the cardio-vascular effects of hypoxia in non-mammalian species. We, therefore, compared the ventilatory and metabolic effects of exposure to 60 ppm H₂S and to 10% O₂ in small and large rodents (20 g mice and 700 g rats) wherein the metabolic response to hypoxia has been shown to differ according to body mass. H₂S and hypoxia produced profound depression in metabolic rate in the mice, but not in the large rats. The depression was much faster with H₂S than with hypoxia. The relative hyperventilation produced by hypoxia in the mice was replaced by a depression with H₂S, which paralleled the drop in metabolic rate. In the larger rats, ventilation was stimulated in hypoxia, with no change in metabolism, while H₂S affected neither breathing nor metabolism. When mice were simultaneously exposed to H₂S and hypoxia, the stimulatory effects of hypoxia on breathing were abolished, and a much larger respiratory and metabolic depression was observed than with H₂S alone. H₂S had, therefore, no stimulatory effect on the arterial chemoreflex. The ventilatory depression during hypoxia and H₂S in small mammals appears to be dependent upon the ability to decrease metabolism.