Prenatal hyperoxia blunts the hypoxic ventilatory chemosensitivity of the 1-day old chicken hatchling

Hypoxia sustained during the prenatal period lowers the ventilatory (V˙(E)) response to hypoxia of the newborn. This phenomenon probably results from a disturbance in the normal development of the peripheral chemoreceptors, as shown to be the case postnatally after sustained period of low or high oxygen. To test the possibility that prolonged prenatal hyperoxia may have a similar effect, the breathing pattern and the V˙(E) responses to hypoxia or hypercapnia were measured by a modification of the barometric technique in 1-day old chicken hatchlings exposed to 40% O2 or 60% O2 (N=16 each) during the last week of incubation (hatching included), and in controls incubated in normoxia (N=16). During air breathing and moderate hypoxia (15% O2), neither group differed from controls. However, the V˙(E) response to 10% O2 was reduced to less than half normal in both groups of prenatal-hyperoxia hatchlings. The hypoxic drop in oxygen consumption V˙(O2) was more marked than in controls, which probably helped to limit the degree of hypoxemia and to sustain the hyperventilation (increase in V˙(E)-V˙(O2) ratio). The V˙(E) response to hypercapnia was almost normal, suggesting that there was no mechanical limitation on V˙(E). The degree of blunting in the V˙(E) response to hypoxia was very similar to that previously measured in hatchlings exposed to hypoxia during the last week of incubation. The results support to the view that sustained changes in oxygenation during the prenatal period reduce the newborn's V˙(E) response to hypoxia probably because of a major dysfunction of the carotid bodies.     

Ventilatory and heart rate chemosensitivity in track-and-field athletes

Summary Fifty-four male track-and-field athletes and 18 male non-athletes were examined by isocapnic progressive hypoxia and CO₂ rebreathing tests. Ventilatory and heart rate (HR) responses to hypoxia were analysed by a hyperbolic relationship and the ventilatory response to hypercapnia by a linear regression. The results showed that ventilatory sensitivity during hypoxia was significantly attenuated in the long-distance runners and sprinters compared to the non-athletes. Although heart rate sensitivity during hypoxia in none of the athletes showed a significant difference compared to that of the non-athletes, baseline HR in the long-distance runners was significantly lower than that of the non-athletes. None of the athletes showed significant differences in ventilatory sensitivity during hypercapnia compared to the non-athletes.     

Respiratory frequency response to progressive isocapnic hypoxia.

1. Ventilatory, tidal volume and frequency responses to progressive isocapnic hypoxia have been measured in twenty-nine healthy subjects by a rebreathing technique. 2. A strong correlation was found between ventilatory response to hypoxia (deltaVI/DELTASaO2) and frequency response to hypoxia (deltaf/deltaSaO2) (r=0-82, P less than 0-001). There was a lesser correlation between deltaV1/deltaSaO2 and tidal volume response (deltaVT/deltaSaO2) (r=0-50, P less than 0-01). These findings suggest that the wide range of ventilatory response to hypoxia among subjects is mainly determined by differences in frequency response and contrast with previous findings in studies of the response to progressive hypercapnia. 3. The breathing pattern during progressive hypoxia and hypercapnia was compared in ten subjects. Ventilation/tidal volume plots were constructed and patterns of response were further analysed in terms of inspiratory duration (TI), expiratory duration (TE) and mean inspiratory flow rate (VI). 4. Increments in ventilation during hypoxia were achieved with a greater respiratory frequency and a smaller tidal volume than during hypercapnia in eight of the ten subjects studied. In two subjects no difference in breathing pattern during hypoxia and hypercapnia was observed. 5. Changes in respiratory frequency during progressive hypoxia were achieved in all subjects by a progressive shortening of TI and TE. By contrast, TI remained constant during hypercapnia until VT had increased to 3-5 times the eupnoeic value; during hypercapnia the increase in frequency was achieved mainly by a progressive shortening of TE. 6. It is concluded that different mechanisms may be involved in altering respiratory frequency when ventilation is driven progressively by these different chemical stimuli.     

Ventilatory responses in patients with essential hypertension.

We investigated the ventilatory responses to hypoxia and hypercapnia in patients with essential hypertension (HT) as compared with healthy subjects (NV). Further, to evaluate the contribution of the peripheral chemoreceptors to ventilatory response, we used a withdrawal test. Hypoxic ventilatory drive (HVR) was measured as the parameter A denoting the shape of VI (inspiratory minute ventilation)-PETO2 (end-tidal PO2) curve which was calculated by the empirical equation: VI = V0 + A/(PETO2-32). Hypercapnic ventilatory drive (HCVR) was measured as the parameter S denoting the shape of the VI-PETCO2 (end-tidal PCO2) relation which was calculated by the empirical equation: VI = S(PETCO2-B). There were no significant differences in the parameters of HVR and HCVR between NV and HT. A positive correlation between A/BSA and S/BSA was found to be significant in NV (r = 0.873, p less than 0.05). Conversely, there was no significant correlation between A/BSA and S/BSA (r = 0.547) in HT. On the other hand, the withdrawal responses (delta VI/BSA and % delta VI:delta VI/VI x 100%) were obtained from the magnitude of depression in ventilation caused by two breaths of O2 in hypoxic hypercapnia. In the withdrawal responses, delta VI/BSA and % delta VI in HT were significantly higher than those in NV. A/BSA significantly correlated with delta VI/BSA (NV, r = 0.684, p less than 0.05; HT, r = 0.648, p less than 0.05) in both NV and HT. However, delta VI/BSA in HT tended to be higher than that in NV, under the same value of A/BSA. These results suggested that the peripheral chemoreceptor activity was augmented in HT.     

Bilateral carotid body resection in man enhances hypoxic tachycardia

In three groups of subjects we studied heart rate (HR) and ventilatory responses to progressive eucapnic hypoxia, steady-state hypercapnia with and without hypoxia, and hyperoxic and hypoxic breathholding (BH). Groups were six subjects about 25 years after bilateral carotid body resection (BR), eight subjects of an equally long period after unilateral resection (UR), and three control subjects similar to the study groups in age and pulmonary function (C). During progressive hypoxia, HR increased more in BR than in UR and C subjects. Ventilatory response was lowest in BR subjects (as expected). Steady-state hypoxic hypercapnia (end-tidal PO2, 60 Torr) depressed HR significantly more in C than in BR and UR subjects. Again, ventilatory response was lower in BR than in C subjects. HR progressively increased during BH initiated in hyperoxia (end-tidal PO2, 200 Torr) and hypoxia (end-tidal PO2, 70 Torr). In the BR group, the HR increment during hypoxia was significantly larger than that during hyperoxia. No such difference was apparent in UR and C groups. Thus, hypoxia with or without hypercapnia tends to accelerate HR in BR subjects whereas either less tachycardia or slowing is seen in UR and C subjects.     

Cardiorespiratory responses to hypoxia and hypercapnia at rest in vocalists

In order to clarify whether or not ventilatory and circulatory responses to hypoxia and hypercapnia at rest in male vocalists (n = 11) are identical to those of untrained subjects (n = 11), ventilatory responses to hypoxia (HVR) and hypercapnia (HCVR) were estimated as the slope of regression relating .VI to SaO(2) (Delta.VI/DeltaSaO(2)) or the slope factor (A) for the .VI-PETO(2) curve, and as the slope of regression relating .VI to PETCO(2) (Delta.VI/DeltaPETCO(2)), respectively. The respiratory frequency (f), tidal volume (VT), heart rate (HR), and blood pressure (BP) responses to hypoxia and hypercapnia were also estimated as the slope of the line calculated by linear regression related to SaO(2) and PETCO(2). Mean values of Delta.VI/DeltaSaO(2) and A as an index of hypoxic ventilatory response were lower in the vocalist group (0.39 +/- 0.25 l.min(-1).%(-1) and 76.8 +/- 55.7 l.min(-1).torr(-1)) than that in the control group (0.56 +/- 0.46 l.min(-1).%(-1) and 101.6 +/- 85.4 l.min(-1).torr(-1)), and there was no statistically significant difference. The Deltaf/DeltaSaO(2) was significantly (plt;0.05 ) lower in the vocalist group (-0.02 +/- 0.39 breaths.min(-1).%(-1)) than that in the control group (0.43 +/- 0.65 breaths.min(-1).%(-1)). In contrast, mean values of Delta.VI/DeltaPETCO(2) per body mass index were significantly (p<0.05) lower in the vocalist group (0.05 +/- 0.03 l.min(-1).torr(-1)) than those in the control group (0.10 +/- 0.06l.min(-1).torr(-1)). There were also significant differences in DeltaVT/DeltaPETCO(2) and Deltaf/DeltaPETCO(2) between the two groups (p<0.05). However, no significant differences in HR and BP responses to hypoxia and hypercapnia between the two groups were observed. These results suggest that the magnitude of ventilatory response, but not HR and BP, to hypoxia and hypercapnia at rest in vocalists is reduced by chronic vocal training, including breath control and elongation of phonation for long periods.     

Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.     

Enhanced chemosensitivity after intermittent hypoxic exposure does not affect exercise ventilation at sea level

The purpose of the present study was to test the hypothesis that the ventilatory response to exercise at sea level may increase after intermittent hypoxic exposure for 1 week, accompanied by an increase in hypoxic or hypercapnic ventilatory chemosensitivity. One group of eight subjects (hypoxic group) were decompressed in a chamber to 432 torr (where 1 torr=1.0 mmHg, simulating an altitude of 4,500 m) over a period of 30 min and maintained at that pressure for 1 h daily for 7 days. Oxygen uptake and pulmonary ventilation (V_E) were determined at 40%, 70%, and 100% of maximal oxygen uptake at sea level before (Pre) and after (Post) 1 week of daily exposures to hypoxia. The hypoxic ventilatory response (HVR) was determined using the isocapnic progressive hypoxic method as an index of ventilatory chemosensitivity to hypoxia, and the hypercapnic ventilatory response (HCVRSB) was measured by means of the single-breath carbon dioxide method as an index of peripheral ventilatory chemosensitivity to hypercapnia. The same parameters were measured in another group of six subjects (control group). In the hypoxic group, resting HVR increased significantly (P<0.05) after intermittent hypoxia and HCVRSB increased at Post, but the change was not statistically significant (P=0.07). In contrast, no changes in HVR and HCVRSB were found in the control group. There were no changes in either V_E or the ventilatory equivalent for oxygen during maximal and submaximal exercise at sea level throughout the experimental period in either group. These results suggest that the changes in resting hypoxic and peripheral hypercapnic chemosensitivities following short-term intermittent hypoxia have little effect on exercise ventilation at sea level. Electronic Publication     

Ablation of vagal preganglionic neurons innervating the extra-thoracic trachea affects ventilatory responses to hypercapnia and hypoxia

This study tested the hypothesis that during hypercapnia or hypoxia, airway-related vagal preganglionic neurons (AVPNs) of the nucleus ambiguus (NA) release acetylcholine (ACh), which in a paracrine fashion, activates ACh receptors expressed by inspiratory rhythm generating cells. AVPNs in the NA were ablated by injecting a saporin- (SA) cholera toxin b subunit (CTb-SA) conjugate into the extra-thoracic trachea (n=6). Control animals were injected with free CTb (n=6). In CTb treated rats, baseline ventilation and ventilatory responses to hypercapnia (5 and 12% CO(2) in O(2)) or hypoxia (8% O(2) in N(2)) were similar (p>0.05) prior to and 5 days after injection. CTb-SA injected rats maintained rhythmic breathing patterns 5 days post injection, however, tachypneic responses to hypercapnia or hypoxia were significantly reduced. The number of choline acetyltransferase (ChAT) immunoreactive cells in the NA was much lower (p<0.05) in CTb-SA rats as compared to animals receiving CTb only. These results suggest that AVPNs participate in the respiratory frequency response to hypercapnia or hypoxia.     

Effect of chronic ethanol exposure on rat ventilatory responses to hypoxia and hypercapnia

OBJECTIVE:

The effect of chronic ethanol exposure on chemoreflexes has not been extensively studied in experimental animals. Therefore, this study tested the hypothesis that known ethanol-induced autonomic, neuroendocrine and cardiovascular changes coincide with increased chemoreflex sensitivity, as indicated by increased ventilatory responses to hypoxia and hypercapnia.

METHODS:

Male Wistar rats were subjected to increasing ethanol concentrations in their drinking water (first week: 5% v/v, second week: 10% v/v, third and fourth weeks: 20% v/v). At the end of each week of ethanol exposure, ventilatory parameters were measured under basal conditions and in response to hypoxia (evaluation of peripheral chemoreflex sensitivity) and hypercapnia (evaluation of central chemoreflex sensitivity).

RESULTS:

Decreased respiratory frequency was observed in rats exposed to ethanol from the first until the fourth week, whereas minute ventilation remained unchanged. Moreover, we observed an increased tidal volume in the second through the fourth week of exposure. The minute ventilation responses to hypoxia were attenuated in the first through the third week but remained unchanged during the last week. The respiratory frequency responses to hypoxia in ethanol-exposed rats were attenuated in the second through the third week but remained unchanged in the first and fourth weeks. There was no significant change in tidal volume responses to hypoxia. With regard to hypercapnic responses, no significant changes in ventilatory parameters were observed.

CONCLUSIONS:

Our data are consistent with the notion that chronic ethanol exposure does not increase peripheral or central chemoreflex sensitivity.     

Effects of intrathecal morphine on the ventilatory response to hypoxia

BACKGROUND: Intrathecal administration of morphine produces intense analgesia, but it depresses respiration, an effect that can be life-threatening. Whether intrathecal morphine affects the ventilatory response to hypoxia, however, is not known. METHODS: We randomly assigned 30 men to receive one of three study treatments in a double-blind fashion: intravenous morphine (0.14 mg per kilogram of body weight) with intrathecal placebo; intrathecal morphine (0.3 mg) with intravenous placebo; or intravenous and intrathecal placebo. The selected doses of intravenous and intrathecal morphine produce similar degrees of analgesia. The ventilatory response to hypercapnia, the subsequent response to acute hypoxia during hypercapnic breathing (targeted end-tidal partial pressures of expired oxygen and carbon dioxide, 45 mm Hg), and the plasma levels of morphine and morphine metabolites were measured at base line (before drug administration) and 1, 2, 4, 6, 8, 10, and 12 hours after drug administration. RESULTS: At base line, the mean (+/-SD) values for the ventilatory response to hypoxia (calculated as the difference between the minute ventilation during the second full minute of hypoxia and the fifth minute of hypercapnic ventilation) were similar in the three groups: 38.3+/-23.2 liters per minute in the placebo group, 33.5+/-16.4 liters per minute in the intravenous-morphine group, and 30.2+/-11.6 liters per minute in the intrathecal-morphine group (P=0.61). The overall ventilatory response to hypoxia (the area under the curve) was significantly lower after either intravenous morphine (20.2+/-10.8 liters per minute) or intrathecal morphine (14.5+/-6.4 liters per minute) than after placebo (36.8+/-19.2 liters per minute) (P=O.003). Twelve hours after treatment, the ventilatory response to hypoxia in the intrathecal-morphine group (19.9+/-8.9 liters per minute), but not in the intravenous-morphine group (30+/-15.8 liters per minute), remained significantly depressed as compared with the response in the placebo group (40.9+/-19.0 liters per minute) (P= 0.02 for intrathecal morphine vs. placebo). Plasma concentrations of morphine and morphine metabolites either were not detectable after intrathecal morphine or were much lower after intrathecal morphine than after intravenous morphine. CONCLUSIONS: Depression of the ventilatory response to hypoxia after the administration of intrathecal morphine is similar in magnitude to, but longer-lasting than, that after the administration of an equianalgesic dose of intravenous morphine.     

Peripheral chemoreceptor control of ventilation following sustained hypoxia in young and older adult humans

The rate and duration of peripheral chemoreceptor resensitization following sustained hypoxia was characterized in young and older (74-year-old) adults. In addition, cerebral blood velocity (CBV) was measured in young subjects during and following the relief from sustained hypoxia. Following 20 min of sustained eucapnic hypoxia (50 mmHg), subjects were re-exposed to brief (1.5 min) hypoxic pulses (50 mmHg), and the magnitude of the ventilatory response was used to gauge peripheral chemosensitivity. Five minutes after the relief from sustained hypoxia, ventilation (V(E)) increased to 40.3 +/- 4.5% of the initial hypoxic ventilatory response, and by 36 min V(E) increased to 100%, indicating that peripheral chemosensitivity to hypoxia was restored. The V(E) response magnitude plotted versus time demonstrated that V(E), hence peripheral chemosensitivity, was restored at a rate of 1.9% per minute. Cerebral blood flow (CBF, inferred from CBV) remained constant during sustained hypoxia and increased by the same magnitude during the hypoxic pulses, suggesting that CBF has a small, if any, impact on the decline in V(E) during hypoxia and its subsequent recovery. To address the issue of whether hypoxic pulses affect subsequent challenges, series (continuous hypoxic pulses at various recovery intervals) and parallel (only 1 pulse per trial) methods were used. There were no differences in the ventilatory responses between the series and parallel methods. Older adults demonstrated a similar rate of recovery as in the young, suggesting that ageing in active older adults does not affect the peripheral chemoreceptor response.     

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.     

Effect of domperidone on ventilation and polycythemia after 5 weeks of chronic hypoxia in rats

Chronically hypoxic humans and some mammals have attenuated ventilatory responses, which have been associated with high dopamine level in carotid bodies. Alveolar hypoventilation and blunted ventilatory response have been recognized to be at the basis of Chronic Mountain Sickness by generating arterial hypoxemia and polycythemia. To investigate whether dopamine antagonism could decrease the hemoglobin concentration by stimulating resting ventilation (VE) and/or hypoxic ventilatory response, 18 chronically hypoxic rats (5 weeks, PB=433 Torr) were studied with and without domperidone treatment (a peripheral dopamine antagonist). Acute and prolonged treatment significantly increased poikilocapnic ventilatory response to hypoxia (RVE ml/min/kg=VE at 0.1 FI(O(2))-VE at 0.21 FI(O(2))), from 506+/-36 to 697+/-48; and from 394+/-37 to 660+/-81, respectively. In addition, Domperidone treatment decreased hemoglobin concentration from 21.6+/-0.29 to 18.9+/-0.19 (P<0.01) in rats chronically exposed to hypobaric hypoxia. Our study suggests that the stimulant effect of D(2)-R blockade on ventilatory response to hypoxia seems to compensate the low hypoxic peripheral chemosensitivity after chronic exposure and the latter in turn decrease hemoglobin concentration.     

Ventilatory and cerebrovascular responses to hypercapnia in patients with obstructive sleep apnoea: effect of CPAP therapy

The purpose of this study was to assess whether the cerebrovascular response to hypercapnia is blunted in OSA patients and if this could alter the ventilatory response to hypercapnia before and after CPAP therapy. We measured the cerebrovascular, cardiovascular and ventilatory responses to hypercapnia in 8 patients with OSA (apnoea-hypopnoea index=101+/-10) before and after 4-6 weeks of CPAP therapy and in 10 control subjects who did not undergo CPAP therapy. The cerebrovascular and ventilatory responses to hypercapnia were not different between OSA and controls at baseline or follow-up. The cardiovascular response to hypercapnia was significantly increased in the OSA group by CPAP therapy (mean arterial pressure response: 1.30+/-0.16 vs. 2.04+/-0.36 mmHg Torr(-1); p=0.007). We conclude that in normocapnic, normotensive OSA patients without cardiovascular disease, the ventilatory, cerebrovascular, and cardiovascular responses to hypercapnia are normal, but the cardiovascular response to hypercapnia is heightened following 1 month of CPAP therapy.     

Pronounced depression by propofol on carotid body response to CO2 and K+-induced carotid body activation

Propofol is a commonly used anesthetic agent, and it attenuates hypoxic ventilatory response in humans. Propofol reduce in vivo and in vitro carotid body responses to hypoxia as well as to nicotine in experimental animals. In the present study we examined the effects of propofol on carotid body responses to hypercapnia and K(+)-induced carotid body activation and compared these effects with hypoxia in an in vitro rabbit carotid body preparation. Hypoxia, hypercapnia and potassium increased the carotid sinus nerve activity and propofol attenuated the chemoreceptor responses to all three stimuli. However, the magnitude of propofol-induced attenuation was greater for hypercapnic and K(+)-induced carotid body activation compared to the hypoxic response. These observations suggest that propofol-induced attenuation of the hypoxic response is partly secondary to depression of chemoreceptor response to hypercapnia inhibiting the synergistic interactions between O(2) and CO(2) and may involve CO(2)/H(+) sensitive K(+) channels.     

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats. Thus, we hypothesized that 2-week PNH-treated rats would also exhibit blunted chemoafferent responses to acute hypoxia, but would exhibit ventilatory acclimatization to sustained hypoxia. Rats were born into, and exposed to PNH for 2 weeks, followed by chronic room-air exposure. At 3-4 months of age, two studies were performed to assess: (1) carotid sinus nerve responses to asphyxia and sodium cyanide in anesthetized rats and (2) ventilatory and blood gas responses in awake rats before (d0), during (d1 and d7), and 1 day following (d8) sustained hypoxia. Carotid sinus nerve responses to i.v. NaCN and asphyxia (10 s) were significantly reduced in PNH-treated versus control rats; however, neither the acute hypoxic ventilatory response nor the time course or magnitude of ventilatory acclimatization differed between PNH and control rats despite similar levels of PaO2 . Although carotid body volume was reduced in PNH rats, carotid body volumes increased during sustained hypoxia in both PNH and control rats. We conclude that normal acute and chronic ventilatory responses are related to retained (though impaired) carotid body chemoafferent function combined with central neural mechanisms which may include brainstem hypoxia-sensitive neurons and/or brainstem integrative plasticity relating both central and peripheral inputs.     

Effects of alveolar and perfusion hypoxia and hypercapnia on pulmonary vascular resistance in the lamb.

The effects of ventilatory hypoxia and hypercapnia and perfusion hypoxia and hypercapnia on pulmonary vascular resistance were studied in the intact lamb using right heart techniques to isolate and perfuse the left lower lobe. Ventilatory hypoxia increased vascular resistance in the left lower lobe by constricting predominantly vessels upstream from small lobar veins, presumably small arteries. The response to hypoxia was not blocked by phentolamine and diphenhydramine in doses that markedly decreased pressor responses to norepinephrine and histamine in the lung. Perfusion hypoxia did not alter vascular resistance in the perfused lobe. Ventilatory hypercapnia increased vascular resistance in the lung by constricting mainly upstream vessels, whereas perfusion hypercapnia decreased resistance by dilating upstream vessels. These data indicate that histamine and catecholamines are not involved in the response to alveolar hypoxia. These results suggest that the sensor site for ventilatory hypoxia is close to the alveolus since the response is unrelated to lobar arterial Po2. It is concluded that systemic reflexes are not necessarily involved in the response of the pulmonary vascular bed to ventilatory hypoxia or hypercapnia and that the magnitude and rapidity of this response suggest that it may represent an important local mechanism for the control of ventilation-perfusion relationships in this species.     

Hypercapnic and hypoxic responses require intact neural transmission from the pre-Bötzinger complex

The central respiratory network that includes the pre-Bötzinger complex (pre-BötC), a region believed to contain rhythmogenic neurons, is capable of responding to fluctuations in CO₂ and pH. However, the role of inputs from this site in mediating ventilatory responses to hypercapnia and/or hypoxia in nonsedated animals is not well established. Therefore, in the present study we tested the hypothesis that altered transmission from the pre-BötC to its target sites would decrease chemosensory responsiveness to acute hypercapnia and modulate the ventilatory response to hypoxia. Colchicine was used to block axonal transport. At 48 h after bilateral microinjections of colchicine into the pre-BötC (100 μg/uL, 100 nL/site), but not saline, the baseline frequency of breathing decreased; however, rhythmicity was not altered. In addition, there was a significant fall in the ventilatory response to hypercapnia (5 and 12% CO₂) and hypoxia (8% O₂). These findings indicate that, inputs from pre-BötC neurons are of critical importance in providing the normal ventilatory response to both hypercapnia and hypoxia.     

An integrated model of the human ventilatory control system: the response to hypoxia.

The mathematical model of the respiratory control system described in a previous companion paper is used to analyse the ventilatory response to hypoxic stimuli. Simulation of long-lasting isocapnic hypoxia at normal alveolar PCO2 (40 mmHg=5.33 kPa) shows the occurrence of a biphasic response, characterized by an initial peak and a subsequent hypoxic ventilatory decline (HVD). The latter is about as great as 2/3 of the initial peak and can be mainly ascribed to prolonged neural hypoxia. If isocapnic hypoxia is performed during hypercapnia (PACO2=48 mmHg =6.4 kPa), the ventilatory response is stronger and HVD is minimal (about 1/10-1/5 of the initial peak). During poikilocapnic hypoxia, ventilation exhibits smaller changes compared with the isocapnic case, with a rapid return toward baseline within a few minutes. Moreover, a significant undershoot occurs at the termination of the hypoxic period. This undershoot may lead to apnea and to a transient destabilization of the control system if the peripheral chemoreflex gain and time delay are twofold greater than basal.