Peripheral and central dopamine receptors in respiratory control

The role of peripheral and central dopaminergic mechanisms in respiratory control was studied in anesthetized cats. In one series, we simultaneously measured carotid chemoreceptor and ventilatory responses to hypoxia and hypercapnia before and after a saturation dose of intravenous domperidone, a peripheral dopamine (D2) receptor antagonist. Both carotid chemoreceptor and ventilatory responses were augmented by domperidone essentially in proportion, suggesting that they reflected the increase of peripheral chemoreceptor activity. Haloperidol which crosses into the brain from blood, given subsequent to domperidone, did not further affect carotid chemoreceptor responses but attenuated ventilatory responses to hypoxia without significantly altering those to hypercapnia. Thus, the additional ventilatory effect of haloperidol is mediated through central dopaminergic mechanisms involving peripheral chemoreflex pathway alone. In another series, the anesthetized cats were paralyzed and artificially ventilated to study carotid chemoreceptor responses to step increases in the end-tidal PCO2 before and after domperidone. Domperidone significantly augmented the responses to CO2. The results support the hypothesis that both peripheral and central dopaminergic mechanisms play a significant modulatory role in chemoreflex respiratory control.     

Domperidone-induced potentiation of ventilatory responses in awake goats

Dopamine has been implicated in maintaining tonic inhibition of carotid body activity. We tested this hypothesis by assessing the ventilatory effects of a peripheral dopamine antagonist, domperidone. The effects of this agent on the ventilatory responses to hypoxia and hypercapnia were also examined. The study was performed in awake carotid body intact and carotid body denervated goats. Resting minute ventilation increased while PaCO2 decreased (4 Torr) following domperidone administration (0.5 mg/kg, I.V.) in carotid body intact goats. This response did not occur in carotid body denervated goats supporting the hypothesis that endogenous dopamine provides tonic inhibition in the carotid body. Hypoxic and hypercapnic ventilatory responses were significantly augmented following domperidone administration in the carotid body intact goats. This supports the concept of dopaminergic modulation of the response of the carotid body to stimuli. Domperidone allows study of carotid chemoreceptor dopaminergic activity in awake animals because of its high affinity for carotid body D2 dopamine receptors and its lack of CNS effects.     

Sleep deprivation and the control of ventilation

Sleep deprivation is common in acutely ill patients because of their underlying disease and can be compounded by aggressive medical care. While sleep deprivation has been shown to produce a number of psychological and physiologic events, the effects on respiration have been minimally evaluated. We therefore studied resting ventilation and ventilatory responses to hypoxia and hypercapnia before and after 24 h of sleeplessness in 13 healthy men. Hypoxic ventilatory responses (HVR) were measured during progressive isocapnic hypoxia, and hypercapnic ventilatory responses (HCVR) were measured using a rebreathing technique. Measures of resting ventilation, i.e., minute ventilation, tidal volume, arterial oxygen saturation, and end-tidal gas concentrations, did not change with short-term sleep deprivation. Both HVR and HCVR, however, decreased significantly after a single night without sleep. The mean hypoxic response decreased 29% from a slope of 1.20 +/- 0.22 (SEM) to 0.85 +/- 0.15 L/min/% saturation (p less than 0.02), and the slope of the HCVR decreased 24% from 2.07 +/- 0.17 to 1.57 +/- 0.15 L/min/mmHg PCO2 (p less than 0.01). These data indicate that ventilatory chemosensitivity may be substantially attenuated by even short-term sleep deprivation. This absence of sleep could therefore contribute to hypoventilation in acutely ill patients.     

Depression of peripheral chemosensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome.

In the present study, respiratory drives to chemical stimuli and peripheral chemosensitivity were evaluated in patients with obstructive sleep apnoea (OSAS). The effects of oral administration of domperidone, a selective dopamine D2-receptor antagonist, were also examined, to study the respiratory effects of endogenous dopamine on peripheral chemoreceptors. Sixteen patients with OSAS and nine normal control subjects were studied. Respiratory responses to hypercapnia and hypoxia were measured using the rebreathing method and isocapnic progressive hypoxia method, respectively. The hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% O2 under mild hypercapnic hypoxic conditions (end-tidal oxygen and carbon dioxide tensions approximately 8.0 kPa and 5.3-6.7 kPa, respectively), was used to evaluate peripheral chemosensitivity. In the patients with OSAS, ventilatory responses to hypercapnia and hypoxia were significantly decreased compared with those of control subjects. Hypoxic withdrawal tests showed that peripheral chemosensitivity was significantly lower in patients with OSAS than in normal subjects. Hypercapnic ventilatory response and peripheral chemosensitivity were enhanced by administration of domperidone in the patients with OSAS, although no changes in either of these were observed in the control subjects. The hypoxic ventilatory response and peripheral chemosensitivity in the patients with OSAS were each significantly correlated with severity of hypoxia during sleep. These findings suggest that peripheral chemosensitivity in patients with obstructive sleep apnoea syndrome may be decreased as a result of abnormality in dopaminergic mechanisms and that the reduced chemosensitivity observed in patients with obstructive sleep apnoea syndrome may affect the severity of hypoxia during sleep.     

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.     

Comparative human ventilatory adaptation to high altitude

Studies of ventilatory response to high altitudes have occupied an important position in respiratory physiology. This review summarizes recent studies in Tibetan high-altitude residents that collectively challenge the prior consensus that lifelong high-altitude residents ventilate less than acclimatized newcomers do as the result of acquired 'blunting' of hypoxic ventilatory responsiveness. These studies indicate that Tibetans ventilate more than Andean high-altitude natives residing at the same or similar altitudes (PET[CO(2)]) in Tibetans=29.6+/-0.8 vs. Andeans=31.0+/-1.0, P<0.0002 at approximately 4200 m), a difference which approximates the change that occurs between the time of acute hypoxic exposure to once ventilatory acclimatization has been achieved. Tibetans ventilate as much as acclimatized newcomers whereas Andeans ventilate less. However, the extent to which differences in hypoxic ventilatory response (HVR) are responsible is uncertain from existing data. Tibetans have an HVR as high as those of acclimatized newcomers whereas Andeans generally do not, but HVR is not consistently greater in comparisons of Tibetan versus Andean highland residents. Human and experimental animal studies demonstrate that inter-individual and genetic factors affect acute HVR and likely modify acclimatization and hyperventilatory response to high altitude. But the mechanisms responsible for ventilatory roll-off, hyperoxic hyperventilation, and acquired blunting of HVR are poorly understood, especially as they pertain to high-altitude residents. Developmental factors affecting neonatal arterial oxygenation are likely important and may vary between populations. Functional significance has been investigated with respect to the occurrence of chronic mountain sickness and intrauterine growth restriction for which, in both cases, low HVR seems disadvantageous. Additional studies are needed to address the various components of ventilatory control in native Tibetan, Andean and other lifelong high-altitude residents to decide the factors responsible for blunting HVR and diminishing ventilation in some native high-altitude residents.     

Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients

RATIONALE: Methadone is a long-acting mu-opioid and is an effective treatment for heroin addiction. Opioids depress respiration, and patients receiving methadone maintenance treatment (MMT) have higher mortality than the general population. Few studies have investigated ventilatory responses to both hypercapnia and hypoxia in these patients. STUDY OBJECTIVES: We measured hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) and investigated possible factors associated with both in clinically stable patients receiving MMT. DESIGN AND SETTING: Patients receiving long-term, stable doses of methadone recruited from a statewide MMT program, and normal, non-opioid-using subjects matched for age, sex, height, and body mass index were studied with HCVR and HVR. RESULTS: Fifty MMT patients and 20 normal subjects were studied, and significantly decreased HCVR and increased HVR were found in MMT patients compared to normal subjects (HCVR [mean +/- SD], l.27 +/- 0.61 L/min/mm Hg vs 1.64 +/- 0.57 L/min/mm Hg [p = 0.01]; HVR, 2.14 +/- 1.58 L/min/% arterial oxygen saturation measured by pulse oximetry [Sp(O2)] vs 1.12 +/- 0.7 L/min/% Sp(O2) [p = 0.008]). Respiratory rate and not tidal volume changes were the major physiologic responses contributing to both HCVR and HVR differences between the groups. Variables associated with HCVR in the MMT patients are as follows: obstructive sleep apnea/hypopnea index (t = 5.1, p = 0.00001), Pa(CO2) (t = - 3.6, p = 0.001), body height (t = 2.6, p = 0.01) and alveolar-arterial oxygen pressure gradient (t = 2.5, p = 0.02). Variables associated with HVR in MMT patients are body height (t = 3.2, p = 0.002) and Pa(CO2) (t = - 2.8, p = 0.008). CONCLUSIONS: Stable long-term MMT patients have blunted central and elevated peripheral chemoreceptor responses. The mechanisms and clinical significance of these findings need further investigation.     

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.     

Changes in dopamine D(2)-receptor modulation of the hypoxic ventilatory response with chronic hypoxia

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.     

Regulation of ventilation before and after sleep in patients with obstructive sleep apnoea

The objective was to examine whether abnormal breathing during sleep may affect regulation of ventilation after awakening in patients with obstructive sleep apnoea (OSAS). In 19 patients with OSA and 12 normal subjects we examined ventilatory responses to hypoxia (HVR) and to hypercapnia (HCVR) before and after sleep (BS and AS), and compared the changes in ventilatory responses with respiratory events during sleep. In the OSA group, the values of resting ventilation were significantly smaller in AS than those in BS and end-tidal partial pressure of CO2 in arterial blood (Pco2) (PETCO2) rose significantly from BS to AS. The slopes of the HVR or HCVR did not differ between BS and AS. However, both the response lines shifted downward and minute ventilation (VE)80 (VE at arterial oxygen saturation (Sao2) of 80%) in HVR and VE60 (VE at PETCO2 of 60 mmHg) in HCVR decreased significantly from BS to AS. The percentage changes of VE80 and VE60 were significantly correlated with mean Sao2, total sleep time below Sao2 of 90% and lowest Sao2 during sleep. However, in normal subjects we observed no circadian variation in their ventilatory responses. These data support the hypothesis that repeated episodes of nocturnal hypoxia and hypercapnia may modify the regulation of ventilation after awakening in patients with OSA.     

Carotid body dopaminergic mechanisms are functional after acclimatization to hypoxia in goats

Ventilatory acclimatization to sustained hypoxia (VASH) is the time-dependent increase in ventilation that occurs during prolonged exposure to hypoxia. We tested the hypothesis that carotid body (CB) dopaminergic mechanisms are down-regulated during VASH, which would allow CB afferent discharge and ventilation to increase beyond the initial response to hypoxia. Domperidone (DOM; 1.0 mg·kg⁻¹) was administered intravenously to block CB dopamine (DA) receptors after VASH was complete in awake goats. DOM caused a significant augmentation of the ventilatory response to hypoxia in acclimatized goats, failing to support the hypothesis. We conclude that inhibitory CB dopaminergic function is not significantly reduced following prolonged hypoxia, and that down-regulation of CB dopaminergic mechanisms may not be involved in VASH in the goat.     

Dopamine blockade alters ventilatory acclimatization to hypoxia in goats

Dopamine (DA) is generally accepted to be an inhibitory neurotransmitter in the carotid body (CB). It is released and depleted from the CB by acute hypoxia. From this background we made the hypothesis that hypoxic depletion of CB DA could be responsible for a time-dependent increase in CB afferent output and the early phase of ventilatory acclimatization to hypoxia (VAH) in goats. We reasoned, then, that blockade of DA receptors in the CB would accelerate the time course of VAH in the goat, i.e. produce a greater acute response to hypoxia (first 15 min) followed by a reduced rate of change of the subsequent time-dependent hyperventilation. We tested this hypothesis by exposing 7 adult female goats to up to 28 h of hypobaric hypoxia (PB = 380 Torr) on 3 different occasions separated by at least 2 months. The first was as control. During the second and third exposures different doses of the DA antagonist, domperidone, were administered prior to and during the hypoxic exposure (0.5 mg/kg followed by 0.25 mg/kg every 3 h and in the second study 1.0 mg/kg followed by 0.5 mg/kg every 2 h). The time course of acclimatization was assessed by measurement of arterial blood gases and pH in the awake goats. The data obtained in the first 4-5 h of hypoxia in domperidone treated animals appeared to support the hypothesis. Domperidone treated animals had a significantly greater acute ventilatory response to hypoxia followed by a lower rate of progressive hyperventilation in this period. However, variation in control values, greater respiratory alkalosis and a secondary significant hyperventilation after 6-7 h of hypoxia in the domperidone treated animals prevents a clear conclusion as to the precise role of CB dopaminergic mechanisms in acclimatization to hypoxia. Nevertheless, peripheral DA receptor blockade with domperidone does alter the time course and magnitude of hyperventilation during the first 7 h of hypobaric hypoxia in goats.     

The contribution of central mechanisms rostral to the pons in high altitude ventilatory acclimatization

In order to explore the role of suprapontine mechanisms in the ventilatory features of acclimatization to high altitude (HAVA) a study was made of: (a) normal cats after 48 h of exposure to a simulated altitude of 5500 m; (b) those same acclimatized cats 6 h following mid-collicular decerebration; (c) decerebrate cats after 48 h of exposure to a simulated altitude of 5500 m; (d) decerebrate cats after 48 h of exposure to room air at sea level. In a pilot study in which high altitude exposure was maintained for 30 days it was determined that normal cats show all of the manifestations of HAVA after 48 h. These were: increase of VI over acute hypoxic value and a maintained hyperventilation with normoxic inhaled gas; increase of both VT and f, the latter predominantly due to shortened TE; increase of VT/TI. Following decerebration the ventilatory pattern of these cats reverted to the preoperative, acute hypoxic exposure characteristics. Decerebrate cats maintained under normoxic conditions for 48 h showed no changes that were statistically significant, but brief (20 min) hypoxic tests indicated an increase of ventilatory response at the end of the second day. Decerebrate cats maintained for 48 h in the hypoxic environment showed all of the main features of HAVA. We conclude that suprapontine mechanisms in the intact cat exert a facilitatory influence which supports the development of HAVA, but if the structures in which those mechanisms normally reside are chronically removed, a comparable mechanism in the ponto-medullary region is capable of assuming the same function.     

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.     

Association between ventilatory response to hypercapnia and obstructive sleep apnea–hypopnea index in asymptomatic subjects

The majority of awake ventilatory control studies have shown normal or decreased ventilatory response to hypercapnia (HCVR) in obstructive sleep apnea–hypopnea syndrome (OSAHS) patients. These findings are contrary to experimental studies suggesting increased loop gain and greater breathing instability in OSAHS patients. We have investigated the relationship between central chemoreflex sensitivity tested by HCVR and obstructive sleep apnea/hypopnea index (OSAHI) in asymptomatic subjects. Twenty normal volunteers (10 men and 10 women) from the general population without physical complaints including sleep-related symptoms were included. The subjects were studied for awake ventilatory responses to hypoxia (HVR) and hypercapnia. Overnight polysomnography (PSG) was performed in two consecutive nights with the first night used as acclimatization. The subjects have an average body mass index (BMI) of 27 ± 5 SD kg/m², ages of 35 ± 9 SD years and Epworth sleepiness scale of 2.1 ± 1.8 SD. A positive linear relationship was found between HCVR and logarithmically transformed OSAHI (r = 0.67, p = 0.001). BMI and age were not significantly correlated to HCVR or Log OSAHI. No relationship was found between HVR and Log OSAHI (r = 0.25, p = 0.29). Percentage oxygen saturation nadir during sleep was found to significantly correlate to both daytime HCVR (r = −0.60, p = 0.005) and Log OSAHI (r = −0.65, p = 0.002) and tended to correlate to HVR (r = −0.41, p = 0.07). Arousal index during sleep was not associated with either HCVR (p = 0.93) or HVR (p = 0.26). In conclusion, heightened central chemosensitivity was positively related to OSAHI in asymptomatic volunteers. We believe these findings are in keeping with the evolving theory of loop gain being a significant factor for respiratory control instability and obstructive apnea genesis. The mechanism can be applied to asymptomatic subjects with even minimal sleep-disordered breathing.     

Effects of intermittent hypoxia on the isocapnic hypoxic ventilatory response and erythropoiesis in humans

Isocapnic hypoxic ventilatory response (HVR) and hematological variables were measured in nine adult males (age: 29.3+/-3.4) exposed to normobaric intermittent hypoxia (IH, 2 h daily at FI(O(2))=0.13, equivalent to 3800 m altitude) for 12 days. Mean HVR significantly increased during IH, however, after reaching a peak on Day 5 (0.79+/-0.12 vs. 0.27+/-0.11 L.min(-1).%(-1) on Day 1, P<0.05), it progressively decreased toward a lower value (0.46+/-0.16 L min(-1) x %(-1) on Day 12). In contrast, the subjects showed no changes in the ventilatory data and arterial O(2)-saturation in normoxia or poikilocapnic hypoxia (PET(CO(2)) uncontrolled). Hematocrit and hemoglobin concentration did not change, but the reticulocyte count increased by Day 5 (P<0.01). Our results suggest that moderate intermittent hypoxia induces changes in ventilatory O(2)-sensitivity and triggers the hematological acclimatization by increasing the percentage of reticulocytes in the blood. Normal ventilatory acclimatization to hypoxia was, however, not observed and the mechanisms involved in the biphasic changes in HVR we observed remain to be determined.     

Carotid body chemoreceptor and ventilatory responses to sustained hypoxia and hypercapnia in the cat

To understand the role of carotid chemoreceptor activity in the ventilatory responses to sustained hypoxia (30 min) the following measurements were made in cats anesthetized with alpha-chloralose: (1) carotid chemoreceptor and ventilatory responses to isocapnic hypoxia and to hypercapnia during hyperoxia; (2) carotid chemoreceptor responses to isocapnic hypoxia after dopamine receptor blockade; and (3) ventilatory responses to hypoxia after bilateral section of carotid sinus nerves (CSN). Transition to hypoxia (PaO2 approximately equal to 52 Torr) from hyperoxia gradually increased carotid chemoreceptor activity by ten fold and ventilation by two fold without any detectable overshoot. Termination of isocapnic hypoxia with hyperoxia (PaO2 greater than 300 Torr) at 30 min promptly restored the carotid chemoreceptor activity to prehypoxic level. Ventilation also decreased promptly, but remained above the control value. Induction of hypercapnia (from 31.8 Torr to 43.9 Torr) during hyperoxia was followed by a prompt increase in the chemoreceptor activity by four fold which subsequently diminished, and by a gradual four fold increase in ventilation. Termination of hypercapnia after 30 min was followed by a prompt return of chemoreceptor activity and by a slow return of ventilation to near control levels. Dopamine receptor blockade increased carotid chemoreceptor responsiveness to acute hypoxia but did not alter the response pattern during sustained hypoxia. After bilateral CSN section, ventilation decreased during maintained hypoxia. Thus, a stimulatory peripheral and inhibitory central effects of hypoxia could produce a biphasic ventilatory response to short-term hypoxia in the anesthetized cat with intact CSN but did not manifest it. The results suggest that the chemosensory input not only promptly stimulates ventilation but also prevents the subsequent depressant effect of hypoxia on the brain-stem respiratory mechanisms and hence presumably a biphasic ventilatory response in the anesthetized cat.     

Ventilatory responses to chemosensory stimuli in quadriplegic subjects

We tested the hypothesis that interruption of motor traffic running down the spinal cord to respiratory muscle motoneurons suppresses the ventilatory response to increased chemical drive. We compared the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses, based on the rebreathing technique, before and during inspiratory flow-resistive loading in 17 quadriplegic patients with low cervical spinal cord transection and in 17 normal subjects. The ventilatory response was evaluated from minute ventilation (VE) and mouth occlusion pressure (P0.2) slopes on arterial oxygen saturation (SaO2) or on end-tidal PCO2 (PACO2), and from absolute VE values at SaO2 80% or at PACO2 55 mmHg. We found no difference in the unloaded HVR or HCVR between the quadriplegic and normal subjects. In the loaded HVR, the delta VE/delta SaO2 slope tended to decrease similarly in both groups of subjects. The delta P0.2/delta SaO2 slope was shifted upwards in normal subjects, yielding a significantly higher P0.2 at a given SaO2. In contrast, this rise in the P0.2 level during loaded HVR was absent in quadriplegics. Loaded HCVR yielded qualitatively similar results in both groups of subjects; delta VE/delta PACO2 decreased and delta P0.2/delta PACO2 increased significantly. The results show that the ventilatory chemosensory responses were unsuppressed in quadriplegics, although they displayed a disturbance in load-compensation, as reflected by occlusion pressure, in hypoxia. We conclude that the descending drive to respiratory muscle motoneurons is not germane to the operation of the chemosensory reflexes.     

Geriatric men at altitude: hypoxic ventilatory sensitivity and blood dopamine changes

BACKGROUND: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. OBJECTIVE: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. METHODS: Nine elderly climbers (group 1:61+/-1.4 years) and 7 young healthy subjects (group 2: 23+/-2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. RESULTS: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. CONCLUSION: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.     

Ventilatory response to 2-h sustained hypoxia in humans

We used two protocols to determine if hypoxic ventilatory decline (HVD) involves changes in slope and/or intercept of the isocapnic HVR (hypoxic ventilatory response, expressed as the increase in VI per percentage decrease in SaO2). Isocapnia was defined as 1.5 mmHg above hyperoxic PET(CO2). HVD was recorded in protocol I during two sequential 25 min exposures to isocapnic hypoxia (85 and 75% SaO2, n=7) and in protocol II during 14 min of isocapnic hypoxia (90% SaO2, FIO2=0.13, n=15), extended to 2 h of hypoxia with CO2-uncontrolled in eight subjects. HVR was measured by the step reduction to sequentially lower levels of SaO2 in protocol I and by 3 min steps to 80% SaO2 at 8, 14 and 120 min in protocol II. The intercept of the HVR (VI predicted at SaO2=100%) decreased after 14 and 25 min in both protocols (P<0.05). Changes in slope were observed only in protocol I at SaO2=75%, suggesting that the slope of the HVR is more sensitive to depth than duration of hypoxic exposure. After 2 h of hypoxia the HVR intercept returned toward control value (P<0.05) with still no significant changes in the HVR slope. We conclude that HVD in humans involves a decrease in hyperoxic ventilatory drive that can occur without significant change in slope of the HVR. The partial reversal of the HVD after 2 h of hypoxia may reflect some components of ventilatory acclimatization to hypoxia.