Peripheral Chemoreceptor Response Research Articles

Single breath of CO2 as a clinical test of the peripheral chemoreflex.

Peripheral chemoreceptor responsiveness is usually examined clinically by hypoxic testing, but the usefulness of this approach is limited by safety considerations, and the interpretation of results may be confounded by the direct central nervous system effects of hypoxia. Therefore we examined the single-breath (SB) CO2 test to determine its reproducibility and applicability as a clinical test of peripheral chemoreceptor function. The technique involved the inhalation of a SB of 13% CO2 in air. The ventilatory response was determined from the increase in ventilation (VE) during the first 20 s after the test breath and from the difference in end-tidal PCO2 between the test breath and preceding control breaths. The peak increase in VE occurred during the second or third breath after the test breath, corresponding to a delay of approximately 10 s. The mean of 10 SB tests administered at 2- to 3-min intervals was taken as the subject's response. Five healthy subjects were tested in this manner on each of 6 consecutive days with the response having an interday coefficient of variation of 25 +/- 6% (SD). The response in 26 healthy females (aged 22-61 yr) was 0.32 +/- 0.11 l.min-1.Torr-1, and in 26 healthy males (aged 24-69 yr) the response was 0.38 +/- 0.14 (P NS). No significant correlation was found between the age of the subjects and their ventilatory response. Thirty-six of the subjects also underwent hyperoxic CO2 rebreathing tests, the response to which is dependent on central chemoreceptor function. No correlation was found between rebreathing and SB tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia.

Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.

Interindividual variation in hypoxic ventilatory response: potential role of carotid body.

There is considerable interindividual variation in ventilatory response to hypoxia in humans but the mechanism remains unknown. To examine the potential contribution of variable peripheral chemorecptor function to variation in hypoxic ventilatory response (HVR), we compared the peripheral chemoreceptor and ventilatory response to hypoxia in 51 anesthetized cats. We found large interindividual differences in HVR spanning a sevenfold range. In 23 cats studied on two separate days, ventilatory measurements were correlated (r = 0.54, P less than 0.01), suggesting stable interindividual differences. Measurements during wakefulness and in anesthesia in nine cats showed that although anesthesia lowered the absolute HVR it had no influence on the range or the rank of the magnitude of the response of individuals in the group. We observed a positive correlation between ventilatory and carotid sinus nerve (CSN) responses to hypoxia measured during anesthesia in 51 cats (r = 0.63, P less than 0.001). To assess the translation of peripheral chemoreceptor activity into expiratory minute ventilation (VE) we used an index relating the increase of VE to the increase of CSN activity for a given hypoxic stimulus (delta VE/delta CSN). Comparison of this index for cats with lowest (n = 5, HVR A = 7.0 +/- 0.8) and cats with highest (n = 5, HVR A = 53.2 +/- 4.9) ventilatory responses showed similar efficiency of central translation (0.72 +/- 0.06 and 0.70 +/- 0.08, respectively). These results indicate that interindividual variation in HVR is associated with comparable variation in hypoxic sensitivity of carotid bodies. Thus differences in peripheral chemoreceptor sensitivity may contribute to interindividual variability of HVR.

Effect of a single breath of 100% oxygen on respiration in neonates during sleep

To determine the effect of a single breath of 100% O2 on ventilation, 10 full-term [body wt 3,360 +/- 110 (SE) g, gestational age 39 +/- 0.4 wk, postnatal age 3 +/- 0.6 days] and 10 preterm neonates (body wt 2,020 +/- 60 g, gestational age 34 +/- 2 wk, postnatal age 9 +/- 2 days) were studied during active and quiet sleep states. The single-breath method was used to measure peripheral chemoreceptor response. To enhance response and standardize the control period for all infants, fractional inspired O2 concentration was adjusted to 16 +/- 0.6% for a control O2 saturation of 83 +/- 1%. After 1 min of control in each sleep state, each infant was given a single breath of O2 followed by 21% O2. Minute ventilation (VE), tidal volume (VT), breathing frequency (f), alveolar O2 and CO2 tension, O2 saturation (ear oximeter), and transcutaneous O2 tension were measured. VE always decreased with inhalation of O2 (P less than 0.01). In quiet sleep, the decrease in VE was less in full-term (14%) than in preterm (40%) infants (P less than 0.001). Decrease in VE was due primarily to a drop in VT in full-term infants as opposed to a fall in f and VT in preterm infants (P less than 0.05). Apnea, as part of the response, was more prevalent in preterm than in full-term infants. In active sleep the decrease in VE was similar both among full-term (19%) and preterm (21%) infants (P greater than 0.5). These results suggest greater peripheral chemoreceptor response in preterm than in full-term infants, reflected by a more pronounced decrease in VE with O2. The results are compatible with a more powerful peripheral chemoreceptor contribution to breathing in preterm than in full-term infants.

EFFECT OF A SINGLE BREATH OF 100% OXYGEN ON RESPIRATION IN NEONATES DURING SLEEP

To determine the effect of a single breath of 100% O2 on ventilation, 10 term (BW 3360±110g (SE); GA 39±.4 wk, postnatal age 3±.6days) and 10 preterm neonates (BW 2020±60 g, GA 34±2 wk, PNA 9±2 days) were studied during active and quiet sleep states. The single breath method was used to measure peripheral chemoreceptor response. To enhance response and standardize the control period for all infants, FiO2 was adjusted to 16±0.6% for a control O2 saturation of 83±1%. After 1 minute of control in each sleep state, each infant was given a single breath of O2 followed by 21% O2. VE, VT, f, PAO2, PACO2, O2 saturation (ear oximeter) and TcPO2 were measured. VE always decreased with inhalation of O2 (p 0.5). These results suggest greater peripheral chemoreceptor response in preterm than in term infants, reflected by a more pronounced decrease in VE with O2. The results are compatible with a more powerful peripheral chemoreceptor contribution to breathing in preterm than in term infants.

Role of peripheral chemoreceptors and central chemosensitivity in the regulation of respiration and circulation.

Adjustments of respiration and circulation in response to alterations in the levels of oxygen, carbon dioxide and hydrogen ions in the body fluids are mediated by two distinct chemoreceptive elements, situated peripherally and centrally. The peripheral arterial chemoreceptors, located in the carotid and aortic bodies, are supplied with sensory fibres coursing in the sinus and aortic nerves, and also receive sympathetic and parasympathetic motor innervations. The carotid receptors, and some aortic receptors, are essential for the immediate ventilatory and arterial pressure increases during acute hypoxic hypoxaemia, and also make an important contribution to respiratory compensation for acute disturbances of acid-base balance. The vascular effects of peripheral chemoreceptor stimulation include coronary vasodilation and vasoconstriction in skeletal muscle and the splanchnic area. The bradycardia and peripheral vasoconstriction during carotid chemoreceptor stimulation can be lessened or reversed by effects arising from a concurrent hyperpnoea. Central chemoreceptive elements respond to changes in the hydrogen ion concentration in the interstitial fluid in the brain, and are chiefly responsible for ventilatory and circulatory adjustments during hypercapnia and chronic disturbances of acid-base balance. The proposal that the neurones responsible for central chemoreception are located superficially in the ventrolateral portion of the medulla oblongata is not universally accepted, mainly because of a lack of convincing morphological and electrophysiological evidence. Central chemosensitive structures can modify peripheral chemoreceptor responses by altering discharges in parasympathetic and sympathetic nerves supplying these receptors, and such modifications could be a factor contributing to ventilatory unresponsiveness in mild hypoxia. Conversely, peripheral chemoreceptor drive can modulate central chemosensitivity during hypercapnia.

Effect of peripheral chemoreceptor denervation on acclimatization of goats during hypoxia

The purpose of this study was to determine the effect of peripheral chemoreceptor denervation on ventilatory acclimatization of goats during chronic hypoxia. After 1 h of stimulated altitude (PB 450 Torr), arterial O2 tension (PaO2) in seven normal goats averaged 42 Torr, and arterial CO2 tension (PaCO2) was 1.3 Torr below control (P less than 0.001). In these goats nearly 66% of the increase in alveolar ventilation (VA) associated with acclimatization occurred between 1.5 and 4 h of hypoxia. Acclimatization was complete by the 3rd day of hypoxia, and it caused 1) a 23% increase in VA/CO2 output (P less than 0.001); 2) a 5-Torr increase in PaO2 (P less than 0.001); and 3) a 6.5-Torr decrease in PaCO2 (P less than 0.001). Denervation of the carotid chemoreceptors in seven goats caused hypoventilation during eupnea at sea level (PaCO2 change from control +7 Torr, P less than 0.001). Denervation also attenuated but did not eliminate peripheral chemoreceptor responsiveness. No additional changes were observed following attempted denervation of the aortic chemoreceptors. After 1 h of simulated altitude (PB 530 Torr), PaO2 in the denervated goats averaged 46 Torr, and PaCO2 was increased 1.1 Torr above control (P less than 0.001). In these goats VA did not change significantly during the subsequent 3 days of hypoxia. Accordingly, we conclude that the peripheral chemoreceptors are essential for ventilatory acclimatization of goats during chronic hypoxia.

Depression of ventilation by dopamine in goats — effects of carotid body excision

Dopamine (DA) given IV by bolus injection (5, 10, 20 μg/kg) and by slow IV infusion (20 μg·kg·min) depressed V̇ E significantly in awake normoxic goats. These responses were attenuated but not eliminated during hypoxia ( Fi O 2 = 0.14 ) and hyperoxia ( Fi O 2 = 1.0 ). After administering haloperidol (0.3 mg/kg) or removing the carotid bodies (CBE) there was greater attenuation of teh response to DA. In normal goats haloperidol also caused a significant increase in ventilatory response to acute hypoxia and exaggerated depression of V̇ e after 3–5 breaths O 2 during steady-state hypoxia. After CBE haloperidol caused mild hypoventilation ( ΔPa CO 2 = +2.5 Torr). CBE induced hypoventilation in goats ( ΔPa CO 2 = +7.8 Torr) and reduced, but did not totally eliminate, peripheral chemoreceptor responses to acute stimuli (NaCN injection, transient N 2 and transient O 2 breathing). Attempted aortic body denervation did not eliminate these residual responses. We conclude: (1) DA may function as a modulator of carotid body (CB) function in the goat, (2) there may be central excitatory DA receptors in the goat, (3) the CB is important in regulating resting ventilation in the goat.

Significance of peripheral chemoreceptor response and adaptation in the regulation of breathing.

The objective of this presentation is to focus attention on some neglected aspects of peripheral chemoreflexes in the regulation of breathing. Since the work of Gesell and White1 the phase dependent effect of carotid chemoreceptor stimulation on volume and duration of breaths in resting animals has been firmly established by Black and Torrance2 and Eldridge3, 4 In recent years these observations on the stimulating effect dominated the literature on peripheral chemoreflex control of breathing. But stimulation is not the only aspect of this reflex. Withdrawal of stimulation is a natural occurrence. Waxing and waning of peripheral chemoreceptor activity occurs with respiration5 and blood flow (unpublished observation). A phase relationship between these aspects and respiratory oscillations is expected to determine in part the extent of stimulation and effects of withdrawal. We examined simultaneously the effect of withdrawal of arterial stimulus on carotid chemoreceptor activity and ventilation and related ventilation to carotid chemoreceptor activity. These results emphasize the importance of overall dynamic aspects of peripheral chemoreceptor activity on single breaths as well as on minute ventilation.

POSTNATAL DEVELOPMENT OF THE HYPOXIC VENTILATORY RESPONSE IN THE LAMB

The ventilatory response time of the fetal lamb to a hypoxic stimulus is relatively slow and appears to be centrally mediated (Woodrum, et al., J. App. Physiol., in press). To ascertain when the rapid peripheral chemoreceptor response appears postnatally, the hypoxic response was studied in unanesthesized newborn lambs before and after carotid body denervation. The response time was defined as the time from ↓ in aortic arch SaO2 (fiber optic catheter) to a sustained increase in tidal volume or frequency. Twenty-three studies were done on 5 animals immediately following birth and 46 studies were done on 7 animals during the 2nd week of life. Prior to denervation the tidal volume response time decreased from 5.7 ± 4 sec. on day 1 to 1.8 ± .8 sec. during days 9-12 (P < .025). Following denervation the hypoxic response persisted (75% trials), occurring after a delay of 29 ± 32.5 sec. on day 1 and 12 ± 6 sec. in the older group. The frequency response was similar but more delayed than the volume response. The data indicate a maturational change in the hypoxic ventilatory response time of the newborn lamb over the first two weeks of life. There is a definite central hypoxic response in the newborn lamb up to 12 days of age. The mechanism of this response is unknown but may involve a specific central hypoxic receptor, or a CNS response to factors associated with hypoxemia (↑ cerebral blood flow, acidosis or altered arousal).

THE EFFECT OF HALOTHANE AND THIOPENTONE ON VENTILATORY RESPONSES MEDIATED BY THE PERIPHERAL CHEMORECEPTORS IN MAN

The activity and responsiveness of the peripheral ventilatory chemoreflex were assessed by the transient depression of ventilation following two breaths of oxygen in air-breathing subjects, and the differing times of onset of the ventilatory response to i.v. sodium bicarbonate in subjects breathing either air or oxygen. In patients premedicated with pethidine, in whom anaesthesia was induced with thiopentone, it was found that halothane, in an inspired concentration of 0.7-0.8%, reduced the activity and responsiveness of the peripheral ventilatory chemoreflex markedly. When halothane was discontinued and anaesthesia was maintained wtih intermittent injections of thiopentone (0.2 mg/kg/min) evidence of peripheral chemoreceptor activity and responsiveness returned.

Respiratory studies of monotremes. IV. Normal respiratory functions of echidnas and ventilatory response to inspired oxygen and carbon dioxide

Respiratory measurements were made on four resting adult echidnas of mean weight 2.3 kg. Mean values were: V t 18.8 ml; respiratory frequency 8.9 min −1; P a co 2 , (end tidal) 53 mm Hg. Arterial blood gases were obtained serially in one animal. Mean values were: Pa o 2 61 mm Hg; Pa co 2 53 mm Hg; pHa 7.429; HCO − 3 37.2 meq/1; P a o 2 -Pao, 40 mm Hg. Ventilatory response curves indicated a decreased sensitivity to inspired CO 2. Doubling of minute ventilation required an increase of approximately 22 mm Hg compared to about 5 mm Hg in the human. Hypoxie response curves revealed a sensitivity close to that of the human and rabbit. There was a delay of at least 30 sec in ventilatory response to changes in inspired CO 2 or 0 2. Single breaths of gas mixtures containing high CO 2 or low 0 2 concentrations did not result in a ventilatory response. These studies suggest that there is an altered peripheral chemoreceptor response in the echidna consistent with adaptation to increased concentrations of environmental CO 2.

Ventilatory Response to Inhaled CO&lt;sub&gt;2&lt;/sub&gt; at High Altitude

Central and peripheral chemoreceptor response to stimulation by carbon dioxide was assessed in 20 lowlanders studied at sea level as well as during the first and second weeks of their arrival at an altitude of 3,658 m. 13 permanent highlanders were also studied at the same altitude. The lowlanders exhibited an increase in the central as well as peripheral chemoreceptor response at high altitude. The high-landers, on the other hand, had a markedly blunted peripheral chemoreceptor response, although their central chemoreceptor sensitivity was normal. It appears that the high-landers exhibit a profound insensitivity to hypercapnia in addition to hypoxia at the peripheral chemoreceptor level.

CEREBROSPINAL FLUID IN MAN NATIVE TO HIGH ALTITUDE.

CSF pH was shown in a prior report to remain essentially constant during 8 days of acclimatization to 3,800 m. In order to further evaluate the possible role of CSF acid-base equilibria in the regulation of respiration, 20 Peruvian Andean natives were studied at altitudes of 3,720–4,820 m. In ten subjects at 3,720 m, means were: CSF pH 7.327, Pco2 43, HCO3- 21.5, Na+ 136, K+ 2.6, Cl- 124, lactate 30 mg/100 ml. Arterial blood: pH 7.43, Pco2 32.5, HCO3- 21.3, Na+ 136, K+ 4.2, Cl- 107, hematocrit 49, SaOO2 89.6. In six subjects at 4,545 m and four at 4,820 m CSF values were not significantly different; mean arterial Pco2 was 32.6 and 32.3, respectively. The only significant variations with altitude were the expected lowering of PaOO2 to 47 and 43.5 mm Hg, and of SaOO2 to 84.2 and 80.7, and increase of hematocrit to 67% and 75%, respectively. The natives differed from recently acclimatized sea-level residents in showing less ventilation (higher Pco2) in response to the existing hypoxia, and less alkaline arterial blood. The difference appears to relate to peripheral chemoreceptor response to hypoxia rather than central medullary chemoreceptor. respiratory regulation at high altitude; chronic acclimatization to altitude; peripheral chemoreceptor response to hypoxia; CSF and medullary respiratory chemoreceptors Submitted on June 12, 1963