Possible role of dopamine in ventilatory acclimatization to high altitude

Ventilatory acclimatization to high altitude is accompanied by increased hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses which may reflect increased carotid body chemosensitivity. Dopamine is an inhibitory neuromodulator of the carotid body and its activity may be reduced by hypoxic exposure. To determine whether decreased dopaminergic activity could account for the increased chemosensitivity of acclimatization, we examined the response to peripheral dopamine receptor (D₂) blockade with domperidone on HVR and HCVR in awake cats before and after exposure to simulated altitude of 14000 ft for 2 days. During anesthesia, we also examined the effects of domperidone on carotid body responses to hypoxia and hypercapnia in acclimatized and low altitude cats. Two days' exposure to hypobaric hypoxia produced an increase in HVR and HCVR. Before acclimatization, domperidone augmented HVR and HCVR, but there was no effect after acclimatization. In anesthetized low altitude cats, domperidone increased carotid body responses to hypoxia and hypercapnia, but had no effect in acclimatized cats. These results indicate that decreased endogenous dopaminergic activity may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia and hypercapnia during hypoxic ventilatory acclimatization.     

Respiratory patterns in anesthetised rats before and after anemic decerebration.

Experiments were undertaken to test the comparability of changes in respiratory frequency and tidal volume during hypoxia and hypercapnia in rats with and without intact peripheral chemoreceptors and with intact vagi. Neural organisation of respiratory control was perturbed by anemic decerebration, achieved by ligation of the common carotid and basilar arteries. Ischemia of the brain was produced as far candal as the rostral pontine nuclei involved in respiratory control but left the medulla well perfused. The dominant respiratory effect in animals breathing air or oxygen was polypnea with hypocapnia (mean PaCO2 when breathing air 24.7 mmHg, when breathing oxygen 29.6 mmHg). After decerebration the increase of ventilation produced by breathing 10% O2 in N2 was reduced compared with responses in the intact state but levels of ventilation (V1) in hypoxia were similar to those before decerebration. After decerebration, the increase of ventilation produced by breathing 5% CO2 was greatly reduced and the level of V1 in animals breathing CO2 was significantly less than in the intact state. Intermediate changes were seen in animals breathing 2-3% CO2 which converted the hypocapnia (PaCO2 30.9 mmHg) to eucapnia (PaCO2 46.4 mmHg). In the intact state, hypoxia dominantly caused increased frequency (f) and hypercapnia caused increased tidal volume (VT); after decerebration, hypoxia produced reduction of VT while hypercapnia produced reduction of f. Bilateral carotid sinus nerve section in decerebrate animals eliminated the ventilatory response to hypoxia but left the responses to hypercapnia unaltered. The results point to differences in the mechanisms by which hypoxia and hypercapnia influence respiration in both intact and decerebrate animals with carotid sinus and vagus nerves functional. The differences can now be interpreted in terms of specific neural features of respiratory control.     

Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude.

Individuals susceptible to high-altitude pulmonary oedema (HAPE) are characterised by an abnormal increase of pulmonary artery systolic pressure (PASP) in hypoxia and during normoxic exercise, reduced hypoxic ventilatory response, and smaller lung volume. In 37 mountaineers with well-documented altitude tolerance, it was investigated whether any combination of these noninvasive measurements, including exercise in hypoxia, could improve the identification of HAPE-susceptible subjects at low altitude. HAPE-susceptible subjects showed a significant higher increase of PASP during hypoxia at rest (48+/-10 mmHg) compared with controls (38+/-3 mmHg), as well as during normoxic exercise (57+/-14 versus 38+/-7 mmHg) and hypoxic exercise (69+/-13 versus 49+/-8 mmHg). PASP could not be assessed in three and eight subjects during normoxic or hypoxic exercise, respectively, due to insufficient Doppler profiles or systemic arterial hypertension. Sensitivity (77-94%) and specificity (76-93%) were not significantly different between the various testing conditions. Additional assessment of hypoxic ventilatory response and lung function parameters did not improve identification of HAPE-susceptible subjects in a multivariate analysis. Due to the greater number of missing values in pulmonary artery systolic pressure measurements during hypoxic exercise, it was concluded that pulmonary artery systolic pressure measurements at rest during hypoxia or exercise in normoxia are most feasible for the identification of high-altitude pulmonary oedema-susceptible subjects.     

Endogenous opiates and ventilatory acclimatization to chronic hypoxia in the cat

The effects of the opiate antagonist naloxone (0.4 mg.kg-1, i.v.) on carotid chemoreceptor and ventilatory responses to graded steady-state levels of hypoxia and hypercapnia were investigated in two groups of cats: chronically normoxic and chronically hypoxic. The cats of the latter group were exposed to PIO2 of about 70 mm Hg at sea level for 3-4 weeks and showed an attenuated response to hypoxia. All cats were tested under alpha-chloralose anesthesia. Naloxone treatment did not increase appreciably carotid chemoreceptor activity or its responses to hypoxia and hypercapnia in either cat group. Naloxone caused a small ventilatory stimulation in the chronically hypoxic cats, so that the attenuated response to hypoxia was not relieved. By contrast, the chemoreflex ventilatory response to hypoxia was stimulated by naloxone in the chronically normoxic cats. The findings that the depressed ventilatory chemoreflexes in the chronically hypoxic cat were not ameliorated by the opiate antagonist indicate that an increased elaboration of endogenous opiates does not underlie ventilatory adaptation to chronic hypoxia.     

Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.

The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.     

O2-chemoreflex drive of ventilation in awake birds at rest.

Three varieties of birds (a non-flyer, the chicken; a diver, the duck; a flyer, the pigeon) were studied in resting conditions at neutral ambient temperature, while awake, either intact or sham operated, or after bilateral chronic carotid body denervation. Tidal volume (VT), ventilatory period (T) and minute volume (V = VT/T) measured plethysmographically, were recorded breath-by-breath in steady state at two levels of oxygenation, and in the course of transient pure O2 inhalation (60-sec O2-test). O2 partial pressures in the inspired and expired gases (PIO2 and PETO2), and in the arterial blood (PaO2) were also measured. In intact and sham operated birds, the abrupt switch from a normoxic gas mixture (FIO2 = 0.21) to pure O2 resulted shortly in rapid increases of PIO2, PETO2 and paO2, and in a fall of V which was completed within 20--30 sec and accounted for about 30% of the control minute volume. In the animals previously made hypoxic (FIO2 = 0.12) and hyperventilating, the O2-test provoked a 50--60% fall of V. In chickens, a decreased VT and an increased T contributed to the transient ventilatory changes; in ducks, mainly VT changed, and in the pigeon only T changed. In the birds with denervated carotid bodies, there were no ventilatory responses to hypoxia and to the O2-test. A few of these birds developed a tachypneic response to hypoxia with no apparent change in the effective pulmonary ventilation, which was partly overcome during the O2-test. It is concluded that in the three varieties of birds, the O2-chemoreflex drive from the carotid bodies controlled about 30% of the resting minute volume near sea level, and 50--60% in hypoxic conditions duplicating an altitude exposure to 4000 m.     

Central origin of the hypoxic depression of breathing in the newborn

These studies were designed to ascertain whether the mechanism underlying the depressive component of the response to hypoxia in the newborn is similar to that in the fetus. We studied the response to hypoxia in 5-10 day old unanaesthetized rabbit pups before and after decerebration at or near the level of the midbrain/pontine junction. In the intact animal, hypoxia caused an initial stimulation of minute volume (VE) followed by a depression which was due to a decrease in both tidal volume (VT) and respiratory frequency (f). Decerebration abolished the depressive component of the response; the initial increase in VE on exposure to 7% O2 was now maintained, mainly due to a sustained increase in VT. We conclude that there is a central mechanism sited in or above the upper pons which is involved in the depressive component of the biphasic response to hypoxia. It is likely that this mechanism is similar to that mediating the hypoxic depression of breathing in the fetus.     

Attenuation of α-Adrenergic Responsiveness in Hypoxic Shr

Chronic exposure to hypoxia reduces the severity of hypertension in SHR. This study explored the possibility that hypoxic moderation of spontaneous hypertension is caused by a decrease in vascular responsiveness. In vitro studies were conducted with thoracic aortic rings obtained from SHR and Wistar-Kyoto (WKY) rats maintained under hypoxic (H; simulated altitude = 3658 m) and normoxic (N; laboratory altitude = 1520 m) conditions. Vessels were removed prior to the rapid development of hypertension (5 weeks of age; 3 days of altitude exposure), during the rapid hyperteneiondevelopment stage (10 weeks of age; 5 weeks of altitude exposure), and during the established hypertension stage (18 to 20 weeks of age; 11 to 13 weeks of altitude exposure). Dose-response curves were obtained using a non-specific vasoconstrictor (KC1) and an α-adrenergic agonist, phenylephrine. At all ages, WKY vessels developed greater maximal contraction to vasoconstrictor stimuli, whereas vessels from the two older groups of SHR were more sensitive (more responsive at lower dosages) to KC1. hypoxia caused significant (p < 0.05) attenuation of the contractile responses to phenylephrine in young “pre-hypertensive” SHR, while similar, though less marked, attenuation of phenylephrine responsiveness was evident in young WKY-H. Chronically-reduced responsiveness to phenylephrine was found in vessels from SHR-H but not WKY-H. The lack of hypoxia-induced changes in vessel response to the non-specific vasoconstrictor, KC1, suggests a specific hypoxic attenuation of adrenergic vascular responsiveness. thus, hypoxia may protect against the development of spontaneous hypertension through attenuation of α-adrenergic vasoconstrictor mechanisms.     

Hyperoxic ventilatory responses of high altitude acclimatized cats

We have examined the effect of steady-state hyperoxia on the ventilation of sea level (SL) cats and cats acclimatized to simulated high altitude (HA) at 5500 m for three weeks. Three groups of cats were studied. In group I, the ventilatory responses to 10%, 21% and 100% O2 were studied at SL, and after acclimatization to HA, the ventilatory responses to 10% and 100% O2 were measured. In group II the ventilatory responses and femoral artery and superior sagittal sinus blood gases were measured in two sets of cats, one at SL and one at HA, during exposure to the gases outlined in group I. In group III, we examined the effect of chronic vagotomy on the ventilatory responses to the gas mixtures outlined in group I. Breathing 100% O2 at SL had no significant effect on ventilation, tidal volume, respiratory frequency, or cerebral blood flow (inferred from the cerebral veno-arterial CO2 difference). Ventilation was constant in the HA acclimatized cats while breathing 10% and 100% O2, but the ventilatory pattern changed dramatically during hyperoxia: respiratory frequency increased and tidal volume fell. Breathing 100% O2 was associated with changes in CBF, and venous PCO2 that might be expected to stimulate ventilation, but the change in ventilatory pattern suggests to us that hyperoxic disinhibition of central respiratory processes (which were modified by HA acclimatization) is the mechanism whereby ventilation is sustained during hyperoxia at HA. After vagotomy at HA, ventilation remained constant while breathing 100% O2, but the changes in respiratory pattern were no longer apparent. Therefore, vagal afferents seems to have a role in determining the pattern, but not necessarily the absolute level, of ventilation during hyperoxia. Cats vagotomized at SL prior to HA exposure did not show any evidence of HA ventilatory acclimatization; thus, the vagi may also play a heretofore unrecognized role in the process of acclimatization.     

An analysis of respiratory frequency alterations in vagotomized, decerebrate cats.

Changes in inspiratory (TI), expiratory (TE) and total respiratory cycle (TTOT) durations with hypercapnia- of hypoxia-induced tidal volume (VT) elevations were evaluated in midcollicular decerebrate cats. As VT increased, TI, TE, and TTOT decreased for most animals having intact vagi. Following vagotomy, TI, TE, and TTOT increased with hypercapnia for cats which had TI, TE and TTOT values shorter than 1.6, 3.7 and 5.2 sec respectively while breathing 100% O2; values longer than these forecast hypercapnia-induced decreases in each parameter. Similar systematic changes were not evident for hypoxia-induced responses. Varying the midbrain transection level or pentobarbital administration altered TI, TE and TTOT values while breathing 100% O2; however, the predictability of hypercapnia-induced responses, based on data analysis from midcollicular decerebrate cats, was maintained. It is concluded that the vagally-independent brainstem frequency controller is sensitive to hypercapnia and hypoxia. The predictability of hypercapnia-induced TI, TE and TTOT changes in vagotomized animals is considered in the context of previous models for respiratory rhythm generation.     

Role of the carotid bodies in ventilatory acclimation to chronic hypoxia by the awake cat

Steady-state breathing patterns during air and hypoxia (PIO2 = 84 Torr) were measured in awake cats in the following conditions: (1) during 7 months of exposure to air following carotid body resection (CBR; N = 6); (2) during 7 months of hypobaric hypoxia (PIO2 = 84 Torr; N = 5) following CBR; (3) during 5 months of exposure to hypobaric hypoxia (N = 4) while intact and then following CBR. Also, in groups (1) and (2) the aortic nerves were sectioned (ANX) at the end of the acclimation periods. The results show that the awake cat hypoventilates if the carotid bodies have been removed, and hypoxic sensitivity is reduced during long-term exposures to either hypoxia or normoxia. ANX caused a slight increase in respiratory frequency, indicating a minor role for the aortic bodies. CBR after acclimation to hypoxia resulted in decreased tidal volume but no change in respiratory frequency. The slight ventilatory acclimation to hypoxia in CBR cats was solely due to increased respiratory frequency. The phenomenon of 'hypoxic tachypnea' was modulated by acclimation, indicating that the effect of hypoxic acclimation upon respiratory frequency is due to central mechanisms.     

Role of beta adrenergic receptors in carotid body function of the goat

Previous studies in anesthetized or decerebrate cats and rabbits and awake man have shown conflicting results regarding a potential role for beta-adrenergic receptors in carotid body function. Therefore, we sought to clarify the role of beta-adrenergic receptor activity in carotid body function by assessing: the ventilatory response to intravenous isoproterenol infusion in awake and anesthetized carotid body intact and carotid body denervated goats, the effect of propranolol on the ventilatory response to isocapnic hypoxemia, and carotid sinus nerve chemoreceptor discharge rate response to isoproterenol and hypoxia. Isoproterenol increased ventilation to a similar degree in carotid body intact and denervated awake and anesthetized goats. This ventilatory increase was blocked by propranolol. Propranolol did not alter the hypoxic ventilatory response. Although ventilation increased, carotid sinus nerve chemoreceptor discharge rate was not altered by isoproterenol infusion or bolus IV injection in anesthetized goats. Hypoxia did increase carotid sinus nerve discharge rate. In this study, beta-adrenergic stimulation of ventilation did not occur via the carotid body, and beta-adrenergic blockade did not affect the carotid body hypoxic ventilatory response. Therefore, we found no evidence of functional beta-adrenergic activity within the carotid body of the goat.     

The role of brief hypocapnia in the ventilatory response to CO2 with hypoxia.

In conscious cats the ventilatory response curve to physiological range of CO2 is displaced upward by hypoxia (about 45 torr), but it rises, either parallel with, or convergent on, the normoxic curve. Thus, a positive interaction of hypoxia and hypercapnic stimuli is not observed under these circumstances. However, if during the hypoxic exposure, hypocapnia is allowed to develop, the subsequently determined CO2 ventilatory response curve will shift to the left, rise steeply, particularly in the early phase, and demonstrate a positive hypoxic hypercapnic interaction. A demonstrable interactive effect was dependent on a conditioning period of hypocapnia, and this was shown to be associated with an elevated level of lactic acid to a greater degree in cerebral venous blood than in CSF or arterial blood. The interpretation is discussed without reaching a firm conclusion of mechanism, but the results emphasize how a minor change of experimental protocol affects a basic phenomenon in the chemical control of breathing.     

Anaerobic energy metabolism during severe hypoxia in the lungless salamander Desmognathus fuscus (Plethodontidae)

In the lungless salamander Desmognathus fuscus, mean body weight 4.5 g, the changes in total body concentration of adenosine triphosphate (ATP), creatine phosphate (CP) and lactate (LA) were measured during exposure to a severely hypoxic atmosphere (PO2 = 25 Torr) for 48 h at 13 degrees C. ATP and CP decreased, reaching a minimum at 3 h of exposure, and LA increased, attaining maximum values after 12 to 24 h of hypoxia. Thereafter recovery was observed and control values of ATP, CP and LA were reached after 48 h of sustained hypoxia. This behavior is attributed to a biochemical adjustment to hypoxia of the metabolic machinery which leads to normalization of chemical energy stores in spite of O2 uptake being persistently reduced to 30% of its normoxic level. The anaerobic energy yield derived from splitting of ATP and CP and from LA formation corresponded to about 2/3 of the oxidative energy deficit during the first 3 h of hypoxia. Thereafter anaerobic mechanisms were responsible for insignificant contributions to the energy balance.     

Hypoxic ventilatory response in successful extreme altitude climbers.

A very high ventilatory response to hypoxia is believed necessary to reach extreme altitude without oxygen. Alternatively, the excessive ventilation could be counterproductive by exhausting the ventilatory reserve early on. To test these alternatives, 11 elite climbers (2004 Everest-K2 Italian Expedition) were evaluated as follows: 1) at sea level, and 2) at 5,200 m, after 15 days of acclimatisation at altitude. Resting oxygen saturation, minute ventilation, breathing rate, hypoxic ventilatory response, maximal voluntary ventilation, ventilatory reserve (at oxygen saturation = 70%) and two indices of ventilatory efficiency were measured. Everest and K2 summits were reached 29 and 61 days, respectively, after the last measurement. Five climbers summited without oxygen, the other six did not, or succeeded with oxygen (two climbers). At sea level, all data were similar. At 5,200 m, the five summiters without oxygen showed lower resting minute ventilation, breathing rate and ventilatory response to hypoxia, and higher ventilatory reserve and ventilatory efficiency, compared to the other climbers. Thus, the more successful climbers had smaller responses to hypoxia during acclimatisation to 5,200 m, but, as a result, had greater available reserve for the summit. A less sensitive hypoxic response and a greater ventilatory efficiency might increase ventilatory reserve and allow sustainable ventilation in the extreme hypoxia at the summit.     

Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia

Time-dependent ventilatory responses to episodic and continuous isocapnic hypoxia were measured in unidirectionally ventilated, awake ducks. Three protocols were used: (1) ten 3-min episodes of moderate hypoxia (10% O(2)) with 5-min normoxic intervals; (2) three 3-min episodes of severe hypoxia (8% O(2)) with 5-min normoxic intervals; and (3) 30-min of continuous moderate hypoxia. Ventilation (V(I)) increased immediately within a hypoxic episode (acute response), followed by a further slow rise in V(I) (short-term potentiation). The peak V(T) response increased from the first to second moderate hypoxic episode (progressive augmentation), but was unchanged thereafter. During normoxic intervals, V(I) increased progressively (56% following the tenth episode; long term facilitation). Time-dependent changes were not observed during or following 30-min of continuous hypoxia. Although several time-dependent ventilatory responses to episodic hypoxia are observed in awake ducks, they are relatively small and biased towards facilitation versus inhibitory mechanisms.     

Acid-base balance and the control of respiration during anaxic and anoxic-hypercapnic gas breathing in turtles

We studied the ventilatory and blood acid-base response of turtles to 6 of breathing eithe 100% N₂(anoxic) or 95% N₂-5% CO₂ (anoxic-hypercapnic). In both groups, minute ventilation (V̇E) increased promptly with anoxia, with peak ventilation occurring between 1 and 3 h. V̇E then decreased but was still significantly above control at 6h. The increase in V̇E resulted from increases in both respiratory frequency (f) and tidal volume (VT) but after ventilation peaked, f declined to control while VT remained elevated. We observed no significant differences in V̇E between the two groups in spite of significantly lower arterial pH and higher arterial P_CO2 in the anoxic-hypercapnic turtles. During normoxic recovery, V̇E quickly increased to the peak anoxic values due primarily to a greatly increased f. In both groups, plasma [lactate⁻] increased during anoxia. Plasma cation concentrations also increased, partially compensating for the elevated blood lactate. We conclude that the anoxic hyperventilation did not depend on arterial pH and central chemoreceptor control but rather on peripheral hypoxic chemoreceptor control. We believe that the decline in V̇E during prolonged anoxic breathing results from a metabolic arrest response and/or a depression in central nervous function.     

Respiratory and circulatory compensation to hypoxia in crustaceans.

Crustaceans are often tolerant of hypoxic exposure and many regulate O(2) consumption at low ambient O(2). In acute hypoxia, most increase branchial water flow, and many also increase branchial haemolymph flow, both by an increase in cardiac output and by shunting flow away from the viscera. The O(2)-binding affinity of crustacean O(2) carriers increases in hypoxic conditions, as a result of hyperventilation induced alkalosis. In chronic hypoxic exposure some crustaceans do not sustain high ventilatory pumping levels but increased effectiveness of O(2)-uptake across the gills is maintained as a result of the build up of metabolites such as lactate and urate which also function to increase the haemocyanin O(2)-binding affinity. Chronic exposure to hypoxia also may increase O(2)-binding capacity and promote the synthesis of new high O(2)-affinity carrier molecules. Exposure to untenable rates or levels of O(2) depletion causes many decapodan crustaceans to surface and ventilate the gills with air. Burrowing crayfish provide an example of animals, which excel in all these mechanisms. Control mechanisms involved in compensatory responses to hypoxia are discussed.     

Role of catecholamines and beta-receptors in ventilatory response during hypoxic exercise.

The ventilatory response to moderate exercise in hypoxia is potentiated in goats, decreasing PaCO2 more than in normoxic exercise. We investigated the hypothesis that this potentiation results from a ventilatory stimulus provided by increased levels of circulating catecholamines (norepinephrine and/or epinephrine), acting via beta-receptors. Plasma norepinephrine [NE] and epinephrine [E] concentrations, arterial blood gases and ventilation were measured in normoxia and hypoxia (PaO2 = 34-38 Torr) at rest and during moderate exercise (5.6 kph; 5% grade) in seven female goats. PaCO2 decreased from rest to exercise in normoxia (2.9 +/- 0.7 Torr; P less than 0.01), and decreased significantly more from rest during hypoxic exercise (6.4 +/- 0.6 Torr; P less than 0.01). [NE] increased in both normoxic (1.1 +/- 0.4 ng/ml; P less than 0.05) and hypoxic exercise (2.5 +/- 0.5 ng/ml; P less than 0.01); the [NE] increase in hypoxia was significantly greater (P less than 0.01). [E] increased in normoxic (0.3 +/- 0.1 ng/ml; P less than 0.05) but not hypoxic exercise (0.6 +/- 0.5 ng/ml; P greater than 0.2). Experiments were repeated following administration of the beta-adrenergic receptor blocker, propranolol (2 mg/kg, i.v.). After beta-blockade, PaCO2 decreases from rest to exercise in normoxia (3.2 +/- 0.7 Torr; P less than 0.01) and hypoxia (8.1 +/- 0.7 Torr; P less than 0.001) were not significantly different from control. The data indicate that beta-adrenergic receptor stimulation is not necessary for a greater decrease in PaCO2 during hypoxic versus normoxic exercise. The greater rise in [NE] suggests a possible role in ventilatory control during hypoxic exercise, perhaps via alpha-adrenergic receptors. However, recent evidence suggests that NE is inhibitory in goats, and that NE is unlikely to mediate extra ventilatory stimulation during hypoxic exercise.     

Chemoreflex drive and the dynamics of ventilation and gas exchange during exercise at hypoxia

We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO(2) = 12%. The tests began with unloaded pedaling, followed by three constant work rates of 40%, 60%, and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80% ventilatory threshold work rate during normoxia. Using three inhaled 100% O(2) breath tests, a comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then significantly increased proportionally with the increase in work rate. In contrast, HCVR using three inhaled 10% CO(2) breath tests was unaffected by the difference in work rate at hypoxia but did exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was significantly lower than at normoxia. Using a multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and HCVR for 9%. O(2) uptake on-kinetics and off-kinetics under hypoxic conditions were significantly slower than under normoxic conditions, whereas they were not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR with an increase in work rates rather than to HCVR. Otherwise, O(2) uptake dynamics are affected by the lower O(2), not by the changing work rates under hypoxic conditions.