Cardiopulmonary control during exercise in the duck

To determine the importance of nonhumoral drives to exercise hyperpnea in birds, we exercised adult White Pekin ducks on a treadmill (3 degrees incline) at 1.44 km X h-1 for 15 min during unidirectional artificial ventilation. Intrapulmonary gas concentrations and arterial blood gases could be regulated with this ventilation procedure while allowing ventilatory effort to be measured during both rest and exercise. Ducks were ventilated with gases containing either 4.0 or 5.0% CO2 in 19% O2 (balance N2) at a flow rate of 12 l X min-1. At that flow rate, arterial CO2 partial pressure (PaCO2) could be maintained within +/- 2 Torr of resting values throughout exercise. Arterial O2 partial pressure did not change significantly with exercise. Heart rate, mean arterial blood pressure, and mean right ventricular pressure increased significantly during exercise. On the average, minute ventilation (used as an indicator of the output from the central nervous system) increased approximately 400% over resting levels because of an increase in both tidal volume and respiratory frequency. CO2-sensitivity curves were obtained for each bird during rest. If the CO2 sensitivity remained unchanged during exercise, then the observed 1.5 Torr increase in PaCO2 during exercise would account for only about 6% of the total increase in ventilation over resting levels. During exercise, arterial [H+] increased approximately 4 nmol X l-1; this increase could account for about 18% of the total rise in ventilation. We conclude that only a minor component of the exercise hyperpnea in birds can be accounted for by a humoral mechanism; other factors, possibly from muscle afferents, appear responsible for most of the hyperpnea observed in the running duck.     

Role of VCO2 in control of breathing of awake exercising dogs

Steady-state ventilatory responses to CO2 inhalation, intravenous CO2 loading (loading), and intravenous CO2 unloading (unloading) were measured in chronic awake dogs while they exercised on an air-conditioned treadmill at 3 mph and 0% grade. End-tidal PO2 was maintained at control levels by manipulation of inspired gas. Responses obtained in three dogs demonstrated that the response to CO2 loading [average increase in CO2 output (Vco2) of 216 ml/min or 35%] was a hypercapnic hyperpnea in every instance. Also, the response to CO2 unloading [average decrease in Vco2 of 90 ml/min or 15% decrease] was a hypocapnic hypopnea in every case. Also, the analysis of the data by directional statistics indicates that there was no difference in the slopes of the responses (change in expiratory ventilation divided by change in arterial Pco2) for loading, unloading, and inhalation. These results indicate that the increased CO2 flow to the lung that occurs in exercise does not provide a direct signal to the respiratory controller that accounts for the exercise hyperpnea. Therefore, other mechanisms must be important in the regulation of ventilation during exercise.     

Comparison of hyperthermic hyperpnea elicited during rest and submaximal, moderate-intensity exercise.

We tested the hypothesis that, in humans, hyperthermic hyperpnea elicited in resting subjects differs from that elicited during submaximal, moderate-intensity exercise. In the rest trial, hot-water legs-only immersion and a water-perfused suit were used to increase esophageal temperature (T(es)) in 19 healthy male subjects; in the exercise trial, T(es) was increased by prolonged submaximal cycling [50% peak O(2) uptake (Vo(2))] in the heat (35 degrees C). Minute ventilation (Ve), ventilatory equivalent for Vo(2) (Ve/Vo(2)) and CO(2) output (Ve/Vco(2)), tidal volume (Vt), and respiratory frequency (f) were plotted as functions of T(es). In the exercise trial, Ve increased linearly with increases (from 37.0 to 38.7 degrees C) in T(es) in all subjects; in the rest trial, 14 of the 19 subjects showed a T(es) threshold for hyperpnea (37.8 +/- 0.5 degrees C). Above the threshold for hyperpnea, the slope of the regression line relating Ve and T(es) was significantly greater for the rest than the exercise trial. Moreover, the slopes of the regression lines relating Ve/Vo(2), Ve/Vco(2), and T(es) were significantly greater for the rest than the exercise trial. The increase in Ve reflected increases in Vt and f in the rest trial, but only f in the exercise trial, after an initial increase in ventilation due to Vt. Finally, the slope of the regression line relating T(es) and Vt or f was significantly greater for the rest than the exercise trial. These findings indicate that hyperthermic hyperpnea does indeed differ, depending on whether one is at rest or exercising at submaximal, moderate intensity.     

Long-lasting ventilatory response of humans to a single breath of hypercapnia in hyperoxia.

It has often been assumed that under normoxia, closed-loop ventilatory responses to transient CO2 stimulation (i.e., lasting for 1-3 breaths) are less likely to be mediated by the slow-responding central (medullary) chemoreflex. This assumption, however, has not been quantitatively examined in humans. We hypothesized that in the closed-loop respiratory chemical feedback system [in which the centrally mediated ventilatory response to transient changes in the arterial PCO2 levels (PaCO2) will in turn affect the pulmonary CO2 and hence PaCO2], the contribution of the central chemoreflex pathways to brief disturbances in blood gases may be more important than considered previously. Using the technique of pseudorandom binary CO2 stimulation, we quantified the ventilatory response of normal humans to brief disturbances in arterial CO2 during hyperoxia. Tidal volume (VI), inspiratory ventilation (VI), inspiratory time (TI), expiratory time (TE), and end-tidal CO2 fraction (FETCO2) were measured in subjects who inhaled a mixture that was pseudorandomly switched between 95% O2-5% CO2 and 100% O2 (63 breath sequences). From these data, we calculated the responses of VI, VI, TI, TE, and FETCO2 to a single-breath inhalation of 1% CO2 in O2. Our results showed that in response to a brief increase of 0.75 Torr in alveolar CO2, VI showed a transient increase (average peak response of 0.12 1/min) that persisted for greater than or equal to 80 s in every subject. The response of VI was similar to that of VI, whereas TI and TE showed no consistent changes. Using these results we calculated that central chemoreflex pathways may contribute significantly to typical transient CO2 stimulation tests in hyperoxic and normoxic humans.     

Chemoreflex modulation of ventilatory dynamics during exercise in humans

The precision of arterial blood gas homeostasis following a change of work rate depends on the response kinetics of ventilation. The carotid bodies (CB's) have been proposed as modulators of these kinetics. The present investigation was undertaken to determine whether the effect is specific to CB activation or whether other factors that augment the exercise hyperpnea would produce a similar response. We therefore established the effects of increased CB and central (C) chemoreflex activation on the inspired ventilatory (VI) dynamics for moderate-intensity cycling. Work tests were separately performed with air, 12% O2 to increase CB activity, 100% O2 to "abolish" CB activity, and CO2 in O2 to increase C activity. The time constant of the VI response was substantially shortened by hypoxia (40 s) compared with air breathing (58 s) and increased by 100% O2 (92 s) and, even more so, by CO2 in O2 (101 s). We conclude that increased carotid (but not central) chemoreflex responsiveness speeds the kinetics of the exercise hyperpnea by a process that is not merely the consequence of increased ventilatory drive.     

Regulation of breathing during exercise

This paper reviewed in short neural and humoral factors which might be responsible for inducing exercise hyperpnea. As one of the neural factors afferent signals which arise in the exercising limbs and are transmitted via group III or IV high threshold sensory fibres were involved. The other neural factor is command signals originating in the central nervous system and being fed onto the respiratory center. Hypothalamic locomotor region is assumed to be a possible locus to integrate these peripheral and central neural signals. There are enough evidences to believe that humoral factors mediated via cardiac output is also essential for the hyperpnea. Changes in VCO2 is well correlated with those of VE in dynamic as well as in steady-state response. Oscillations in PaCO2 can be assumed to play a role to link metabolic CO2 changes to those in ventilation. Thus, no single factor can explain the whole process of exercise hyperpnea. Poon's optimization model may give a key to integrate complicated and coflicting experimental results in a unique concept.     

Ventilatory control during exercise with increased respiratory dead space in goats

Our objectives were to determine 1) the effects of increased respiratory dead space (VD) on the ventilatory response to exercise and 2) whether changes in the ventilatory response are due to changes in chemoreceptor feedback (rest to exercise) vs. changes in the feedforward exercise stimulus. Steady-state ventilation (VI) and arterial blood gas responses to mild or moderate hyperoxic exercise in goats were compared with and without increased VD. Responses were compared using a simple mathematical model with the following assumptions: 1) steady state, 2) linear CO2 chemoreceptor feedback, 3) linear feedforward exercise stimulus proportional to CO2 production (VCO2) and characterized by an exercise gain (Gex), and 4) additive exercise stimulus and CO2 feedback producing the system gain (Gsys = delta VI/delta VCO2). Model predictions at constant Gex [assuming VD-to-tidal volume (VT) ratio independent of VCO2] are that increased VD/VT will 1) increase arterial PCO2 (PaCO2) and VI at rest and 2) increase Gsys via changes in chemoreceptor feedback due to a small increase in the PaCO2 vs. VCO2 slope. Experimental results indicate that increased VD increased VD/VT, PaCO2, and VI at rest and increased Gsys during exercise. However, measurable changes in the PaCO2 vs. VCO2 slope occurred only at high VD/VT or running speeds. Gex was estimated at each VD for each goat by using the model in conjunction with experimental measurements. With 0.2 liter VD, Gex increased 40% (P less than 0.01); with 0.6 liter VD, Gex increased 110% between 0 and 2.4 km/h and 5% grade (P less than 0.01) but not between 2.4 and 4.8 km/h. Thus, Gex is increased by VD through a limited range. In goats, increases in Gsys with increased VD result from increases in both Gex and CO2 chemoreceptor feedback. These results are consistent with other experimental treatments that increase the exercise ventilatory response, maintaining constant relative PaCO2 regulation, and suggest that a common mechanism linked to resting ventilatory drive modulates Gex.     

Anatomy of diaphragmatic circulation

During progressive exercise ventilation (VI) initially increases through increases in both tidal volume (VT) and respiratory frequency (f) but at high levels of exercise further increases in VI are almost completely due to increases in f and a VT plateau is seen. We wished to determine whether the presence of the VT plateau is due to a tachypneic influence related to very high levels of exercise or whether it represents a stereotypic response of the respiratory system at high levels of VI. We therefore compared breathing pattern in six subjects during maximal incremental exercise (ME) with that in the same subjects when similar levels of VI were obtained by a combination of submaximal exercise and hypercapnia (E/CO2). A VT plateau was seen in all ME and E/CO2 tests. There was no significant difference in the level of the VT plateau between the ME (2.93 +/- 0.17 liters) and E/CO2 (2.97 +/- 0.12 liters) tests. We conclude that the presence and level of the VT plateau during ME is not due to a tachypneic stimulus related to very high levels of exercise but is a function of the level of VI.     

Transient ventilatory and heart rate responses to moderate nonabrupt pseudorandom exercise

Dynamic responses of inspired minute ventilation, CO2 and O2 end-tidal gas fractions, and heart rate were obtained from six normal human volunteers in response to a complex dynamic exercise challenge. Subjects pedalled a chair ergometer at constant frequency. The retarding torque applied to the ergometer pedals was controlled by a low-pass-filtered pseudorandom binary sequence (fPRBS), which provided a complex, nonanticipatory exercise stimulus containing sufficient high- and low-frequency energy to excite the small signal, broadband ventilatory response. The exercise range was chosen to produce a mean level of O2 consumption at or below 50% maximum O2 consumption. Cross-covariant analysis of the fPRBS exercise with breath-by-breath ventilation provided an estimate of the dynamic (impulse) response to exercise, which contained both fast phase 1 and slow phase 2 components. The initial, phase one, hyperpnea occurred within the same breath as the exercise transition and preceded a hypocapnic response. The phase one hyperpnea represented 26% of the total ventilatory response. The secondary, phase 2, hyperpnea was delayed several breaths from the onset of phase 1. It contained slower dynamics and followed a hypercapnic response. Heart rate increased abruptly during phase 1, peaked near the phase 1-to-2 boundary, and then decreased rapidly. The experimental protocol was designed to minimize the subjective response and provide an adequate stimulus for the faster time constants. Results obtained from these experiments were consistent with a nonhumoral induced phase 1 exercise hyperpnea.     

Effect of aging on ventilatory response to exercise and CO2

Studies were performed to determine the effects of aging on the ventilatory responsiveness to two known respiratory stimulants, inhaled CO2 and exercise. Although explanation of the physiological mechanisms underlying development of exercise hyperpnea remains elusive, there is much circumstantial evidence that during exercise, however mediated, ventilation is coupled to CO2 production. Thus matched groups of young and elderly subjects were studied to determine the relationship between increasing ventilation and increasing CO2 production (VCO2) during steady-state exercise and the change in their minute ventilation in response to progressive hypercapnia during CO2 rebreathing. We found that the slope of the ventilatory response to hypercapnia was depressed in elderly subjects when compared with the younger control group (delta VE/delta PCO2 = 1.64 +/- 0.21 vs. 2.44 +/- 0.40 l X min-1 X mmHg-1, means +/- SE, respectively). In contrast, the slope of the relationship between ventilation and CO2 production during exercise in the elderly was greater than that of younger subjects (delta VE/delta VCO2 = 29.7 +/- 1.19 vs. 25.3 +/- 1.54, means +/- SE, respectively), as was minute ventilation at a single work load (50 W) (32.4 +/- 2.3 vs. 25.7 +/- 1.54 l/min, means +/- SE, respectively). This increased ventilation during exercise in the elderly was not produced by arterial O2 desaturation, and increased anaerobiasis did not play a role. Instead, the increased ventilation during exercise seems to compensate for increased inefficiency of gas exchange such that exercise remains essentially isocapnic. In conclusion, in the elderly the ventilatory response to hypercapnia is less than in young subjects, whereas the ventilatory response to exercise is greater.     

Pulmonary control systems in exercise

We reviewed the response and regulation of alveolar ventilation, chest wall mechanics, and alveolar-to-arterial gas exchange to the demands imposed by increases in tissue metabolic rate. The primary mediator of iso-capnic exercise hyperpnea remains a dilemma--with conflicting evidence presented on both sides of a "CO2 flow" humoral hypothesis versus a "neurogenic" non-humoral hypothesis. The increased expiratory flows and tidal volumes at any given level of hyperpnea are achieved at a "minimum" of increased mechanical work exerted on the lung and chest wall, owing to a control system that has multiple levels of nervous integration (from cortex to spinal motor neuron) readily accessible to a wide variety of sensory information concerning the mechanical status of the lung and respiratory muscles. The maintenance of arterial PO2 in the face of a falling CVO2 during exercise was attributed to a precise regulation over factors that limit diffusion equilibrium and intra- and interregional ventilation: perfusion distributions in the lung. Finally, we noted that the near-optimal nature of these responses and their control during exercise had many exceptions in the real world of physical exercise outside of the laboratory.     

Bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

We demonstrated spontaneous self-limited bronchoconstriction after eucapnic dry gas hyperpnea in 22 anesthetized, mechanically ventilated guinea pigs pretreated with propranolol (1 mg/kg iv). Eucapnic hyperpnea "challenges" of room temperature dry or humidified gas (5% CO2-95% O2) were performed by mechanically ventilating animals (150 breaths/min, 3-6 ml tidal volume) for 5 min. During a "recovery" period after hyperpnea, animals were returned to standard ventilation conditions (6 ml/kg, 60 breaths/min, 50% O2 in air, fully saturated at room temperature). After dry gas hyperpnea (5 ml, 150 breaths/min), respiratory system resistance (Rrs) increased in the recovery period by 7.7-fold and dynamic compliance (Cdyn) decreased by 79.7%; changes were maximal at approximately 3 min posthyperpnea and spontaneously returned to base line in 10-40 min. This response was markedly attenuated by humidification of inspired air. Four consecutive identical dry air challenges resulted in similar posthyperpnea responses in four animals. Increasing the minute ventilation during hyperpnea (by varying tidal volume from 3 to 6 ml) caused increased bronchoconstriction in a dose-dependent fashion in six animals. Neither vagotomy nor atropine altered the airway response to dry gas hyperpnea. We conclude that dry gas hyperpnea in anesthetized guinea pigs results in a bronchoconstrictor response that shares five similar features with hyperpnea-induced bronchoconstriction in human asthma: 1) time course of onset and spontaneous resolution, 2) diminution with humidification of inspired gas, 3) reproducibility on consecutive identical challenges, 4) stimulus-response relationship with minute ventilation during hyperpnea, and 5) independence of parasympathetic neurotransmission.     

Respiration during recovery from exercise: effects of trapping and release of femoral blood flow

To investigate the contribution of vascular and metabolic stimuli to the sustained hyperpnea after exercise, the respiratory effects of obstructing and then releasing the femoral blood flow were recorded in 15 normal volunteers during recovery from steady-state cycle exercise (80 W). Obstruction was achieved using cuffs around the upper thighs, inflated for the first 2 min of recovery to a pressure of 200 mmHg. Cuff inflation significantly reduced ventilation during recovery compared with control (P less than 0.001); the subsequent release of pressure was accompanied by an increase in ventilation (averaging 3.2 l/min), which began on the first breath after release. This preceded a rise in end-tidal CO2 (maximum 8.3 Torr increase), which first became significant on the fourth breath after release and led to a further rise in ventilation. The first-breath increase in ventilation after cuff release persisted, although slightly attenuated (averaging 2.5 l/min), in additional experiments with inspired O2 fraction of 1.0. The pattern of ventilatory response was also similar when the experiments were performed with 5% CO2 in air as the inspirate. The immediate rise in ventilation on cuff release, together with the persistent response on 100% O2, suggests that the vascular changes resulting from cuff release exert an influence on ventilation independent of the effects of released metabolites on the known chemoreceptors. The persistence of the response on 5% CO2 indicates that CO2-sensitive lung afferents do not have a major role in these responses.     

Activation of upper airway muscles before onset of inspiration in normal humans

Animal studies have shown activation of upper airway muscles prior to inspiratory efforts of the diaphragm. To investigate this sequence of activation in humans, we measured the electromyogram (EMG) of the alae nasi (AN) and compared the time of onset of EMG to the onset of inspiratory airflow, during wakefulness, stage II or III sleep (3 subj), and CO2-induced hyperpnea (6 subj). During wakefulness, the interval between AN EMG and airflow was 92 +/- 34 ms (mean +/- SE). At a CO2 level of greater than or equal to 43 Torr, the AN EMG to airflow was 316 +/- 38 ms (P < 0.001). During CO2-induced hyperpnea, the AN EMG to airflow interval and AN EMG magnitude increased in direct proportion to CO2 levels and minute ventilation. During stages II and III of sleep, the interval between AN EMG and airflow increased when compared to wakefulness (P < 0.005). We conclude that a sequence of inspiratory muscle activation is present in humans and is more apparent during sleep and during CO2-induced hyperpnea than during wakefulness.     

Exercise hyperpnea in birds: evidence against a primary role for pCO2

Ventilatory responses of domestic fowl to graded intensities of treadmill exercise were compared when the birds breathed air, 3% CO2 in air or 4.2% CO2 in air. During exercise in air, increased minute ventilation resulted mainly from increased respiratory rate with little change in tidal volume. This pattern of ventilatory response was not altered when the birds respired CO2. In contrast, the pattern of ventilatory response to CO2, at given work loads, consisted of a primary increase in tidal volume with little change in respiratory rate. It is concluded that intrapulmonary pCO2 does not affect the ventilatory response to exercise.     

Influence of body CO2 stores on ventilatory dynamics during exercise

Pulmonary CO2 flow (the product of cardiac output and mixed venous CO2 content) is purported to be an important determinant of ventilatory dynamics in moderate exercise. Depletion of body CO2 stores prior to exercise should thus slow these dynamics. We investigated, therefore, the effects of reducing the CO2 stores by controlled volitional hyperventilation on cardiorespiratory and gas exchange response dynamics to 100 W cycling in six healthy adults. The control responses of ventilation (VE), CO2 output (VCO2), O2 uptake (VO2), and heart rate were comprised of an abrupt increase at exercise onset, followed by a slower rise to the new steady state (t1/2 = 48, 43, 31, and 33 s, respectively). Following volitional hyperventilation (9 min, PETCO2 = 25 Torr), the steady-state exercise responses were unchanged. However, VE and VCO2 dynamics were slowed considerably (t1/2 = 76, 71 s) as PETCO2 rose to achieve the control exercise value. VO2 dynamics were slowed only slightly (t1/2 = 39 s), and heart rate dynamics were unaffected. We conclude that pulmonary CO2 flow provides a significant stimulus to the dynamics of the exercise hyperpnea in man.     

Temporal delay of venous blood correlates with onset of exercise hyperpnea

We tested the hypothesis that humoral factors contribute to the onset of exercise hyperpnea in an electrically induced model of isocapnic exercise in alpha-chloralose-anesthetized dogs. A cannula placed in the inferior vena cava (IVC) permitted hindlimb venous blood to flow either directly to the lungs or through a variable-length extracorporeal circuit. Mean transit times (MTT) of blood from exercising hindlimbs were measured from the arrival at the pulmonary artery of green dye injected into the saphenous vein. Onset of hyperpnea was determined by the half time of the ventilatory response (T 1/2), the time required to reach 50% of the steady-state ventilation. In seven dogs, T 1/2 was directly related to MTT (P less than 0.001), suggesting that blood-borne substances released at the onset of exercise contribute to the hyperpneic response. The T 1/2-MTT relation persisted following L2 cord transection (n = 4), suggesting that intraspinal afferents are not required for this response. Chemoreceptor denervation (n = 4) slowed the onset of exercise hyperpnea but did not alter the T 1/2-MTT relation. In this model of electrically induced "exercise" in which neurogenic influences have been minimized, humoral factors alone may stimulate ventilation sufficiently to produce arterial isocapnia.     

Respiratory adaptations to dead space loading during maximal incremental exercise

We examined the effects of dead space (VD) loading on breathing pattern during maximal incremental exercise in eight normal subjects. Addition of external VD was associated with a significant increase in tidal volume (VT) and decrease in respiratory frequency (f) at moderate and high levels of ventilation (VI); at a VI of 120 l/min, VT and f with added VD were 3.31 +/- 0.33 liters and 36.7 +/- 6.7 breaths/min, respectively, compared with 2.90 +/- 0.29 liters and 41.8 +/- 7.3 breaths/min without added VD. Because breathing pattern does not change with CO2 inhalation during heavy exercise (Gallagher et al. J. Appl. Physiol. 63: 238-244, 1987), the breathing pattern response to added VD is probably a consequence of alteration in the PCO2 time profile, possibly sensed by the carotid body and/or airway-pulmonary chemoreceptors. The increase in VT during heavy exercise with VD loading indicates that the tachypneic breathing pattern of heavy exercise is not due to mechanical limitation of maximum ventilatory capacity at high levels of VT.     

Effect of ruminal CO2 on gas exchange and ventilation in the Hereford calf

The contribution of ruminal CO2 to gas exchange measurements and ventilation was determined in four rumen-fistulated Hereford steers at rest and during exercise. The calves were exercised at 1.4 and 2.2m X s-1 under three treatments: 1)full rumen with fistula sealed, 2) full rumen with fistula open, and 3) empty rumen. Measurements also were made at rest while flushing the empty rumen with either 100% N2 or a mixture of 50% CO2-50% N2. O2 consumption, CO2 production (Mco2), and ventilation were measured by collecting the expired gas. Absorption across the ruminal epithelium during rest increased Mco2 by 3%, whereas absorption and eructation together increased Mco2 by 15%. The respiratory exchange ratio (R) was significantly different among the three treatments at rest, but no differences were observed in R among the treatments during exercise. No changes were observed in minute ventilation among the three conditions, but a decrease in respiratory frequency and an increase in tidal volume occurred when the rumen was empty. These changes in ventilatory pattern may have been due to a decrease in body temperature when the rumen was empty. When the empty rumen was flushed with 50% CO2, Mco2 was increased 21% over the value observed when flushing with 100% N2. CO2 of fermentation origin is added to the expired gas by both eructation and absorption and has a significant effect on R in the resting animal, but no effect on R during exercise.