Effect of local vibration on ventilatory response to hypercapnia in normal subjects

We studied the effects of local high frequency mechanical vibration on ventilatory (VE) and occlusion pressure (P0.1) responses to CO2 rebreathing in twelve normal subjects. Three kinds of vibration procedures were employed: a) sustained vibration over the tendon of the quadriceps femoris near the knee, b) sustained vibration of the right 2nd or 3rd parasternal intercostal spaces and c) 'in-phase' chest wall vibration applied during inspiration on the right 2nd or 3rd parasternal intercostal spaces and during expiration on the right 9th or 10th intercostal spaces anterior to the midaxillary line. The slopes of VE response to hypercapnia (delta VE/delta PETCO2) were 2.05 +/- 0.26 (mean +/- SE), 2.48 +/- 0.24, 2.82 +/- 0.32 and 3.35 +/- 0.38 l.min-1/mmHg in the control state, during tendon vibration of quadriceps femoris, sustained chest wall vibration and 'in-phase' chest wall vibration, respectively. This sequential increase in slopes was significant compared to the control values. The effect of vibration on the P0.1 response to hypercapnia was similar to that of VE. We conclude that local mechanical vibration facilitates responsiveness to hypercapnia.     

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.     

Changes in ventilatory responses to hypercapnia and hypoxia after intermittent hypoxia in humans

The purpose of this study was to clarify the changes in hypercapnic and hypoxic ventilatory responses (HCVR and HVR) after intermittent hypoxia and following the cessation of hypoxic exposure. Twenty-nine males were assigned to one of four groups, i.e., a hypoxic (EX1-H, n=7) or a control (EX1-C, n=7) group in Experiment 1, and a hypoxic (EX2-H, n=8) or a control (EX2-C, n=7) group in Experiment 2. In each experiment, the hypoxic tent system was utilized for intermittent hypoxia, and the oxygen levels in the tent were maintained at 12.3+/-0.2%. In Experiment 1, the EX1-H group spent 3 h/day in the hypoxic tent for 1 week. HCVR and HVR were determined before and after 1 week of intermittent hypoxia, and again 1 and 2 week after the cessation of hypoxic exposure. In Experiment 2, the subjects in the EX2-H group performed 3 h/day for 2 weeks in intermittent hypoxia. HCVR and HVR tests were carried out before and after intermittent hypoxia, and were repeated again after 2 weeks of the cessation of hypoxic exposure. The slope of the HCVR in the EX1-H group did not show a significant increase after 1 week of intermittent hypoxia, while HCVR in the EX2-H group increased significantly after 2 weeks of intermittent hypoxia. The HCVR intercept was unchanged following 1 or 2 weeks of intermittent hypoxia. There was a significant increase in the slope of the HVR after 1 and 2 weeks of intermittent hypoxia. The increased HCVR and HVR returned to pre-hypoxic levels after 2 weeks of the cessation of hypoxia. These results suggest that 3 h/day for 2 weeks of intermittent hypoxia leads to an increase in central hypercapnic ventilatory chemosensitivity, which is not accompanied by a re-setting of the central chemoreceptors, and that the increased hypercapnic and hypoxic chemosensitivities are restored within 2 weeks after the cessation of hypoxia.     

Differences in ventilatory responses to hypoxia and hypercapnia between normal and judo athletes with moderate obesity

Summary Hypercapnic and hypoxic ventilatory sensitivities were compared in twenty-one judoists and 24 control subjects with similar degrees of moderate obesity. Data from ten non-obese control subjects were also included as a reference. Mean body weight (BW) and % of ideal body weight in the judoists and the obese and non-obese controls were 100±14.8, 94.4±5.3 and 63.4±6.1 (mean±SD) kg, and 142.3±16.7, 142.2±12.9 and 98.4±10.7%, respectively. Mean body fat in the judoists was 16.2±13.9%, being 25.3±7.7% in the obese control group, the difference being significant (p<0.01).Hypercapnic sensitivities in terms of the CO₂ ventilatory response slope (S) and its normalized value for 70 kg BW (S_N) of the obese controls were higher than the judoists. These findings were also verified by the CO₂-occlusion pressure responses. S and S_N in the obese controls were significantly correlated with BW and % body fat. However, no positive correlation was found between BW and S or S_N in the judoists as well as between lean body mass and S or S_N in the obese control. Hypoxic sensitivity in terms of the ventilation hyperbola slope (A) and its normalized value (A_N) in the obese control was significantly higher than the non-obese control, but the difference from the judoists was not significant. A and A_N were found to increase with increasing % body fat in both judoists and obese controls. We conclude that respiratory compensation to mechanical limitation due to fat accumulation may be one of the possible factors to enhance hypercapnic as well as hypoxic ventilatory chemosensitivities in moderate obesity.     

Effects of five nights of normobaric hypoxia on the ventilatory responses to acute hypoxia and hypercapnia

This study examined the effects of five nights of normobaric hypoxia on ventilatory responses to acute isocapnic hypoxia (AHVR) and hyperoxic hypercapnia (AHCVR). Twelve male subjects (26.6 +/- 4.1 years, standard deviation (S.D.)) slept 8-9 h per day overnight for 5 consecutive days at a simulated altitude of 4,300 m (FiO2= approximately 13.8%). Using the technique of dynamic end-tidal forcing, the AHVR and AHCVR were assessed twice prior to, immediately after, and 5 days following the hypoxic exposure. Immediately following the exposure, AHVR was increased by 1.6 +/- 1.3 L min(-1) %(-1) (P<0.01) when compared with control values. Likewise, after the exposure, ventilation in hyperoxia was increased (P<0.001) and was associated with both an increase in the slope (1.5 +/- 1.4 L min(-1) Torr(-1); P<0.05) and decrease in the intercept (-2.7 +/- 4.3 Torr; P<0.05) of the AHCVR. These results show that five nights of hypoxia can elicit similar perturbations, in both AHVR and AHCVR, as have been reported during more chronic altitude exposures.     

The effects of intermittent exposure to hypoxia during endurance exercise training on the ventilatory responses to hypoxia and hypercapnia in humans

The present study was performed to investigate the effects of a combination of intermittent exposure to hypoxia during exercise training for short periods on ventilatory responses to hypoxia and hypercapnia (HVR and HCVR respectively) in humans. In a hypobaric chamber at a simulated altitude of 4,500?m (barometric pressure 432?mmHg), seven subjects (training group) performed exercise training for 6 consecutive days (30 min?·?day^?1), while six subjects (control group) were inactive during the same period. The HVR, HCVR and maximal oxygen uptake (V˙O_{2 max}) for each subject were measured at sea level before (pre) and after exposure to intermittent hypoxia. The post exposure test was carried out twice, i.e. on the 1st day and 1 week post exposure. It was found that HVR, as an index of peripheral chemosensitivity to hypoxia, was increased significantly (P?V˙O_{2 max} increased significantly in the training group. These results would suggest that endurance training during intermittent exposure to hypoxia depresses the increment of chemosensitivity to hypoxia, and that intermittent exposure to hypoxia in the presence or absence of exercise training does not induce an increase in the chemosensitivity to hypercapnia in humans.     

Comparison between ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia in healthy sleeping man

Ventilatory and mouth occlusion pressure (P0.1) responses to progressive isocapnic-hypoxia and hyperoxic-hypercapnia were compared in eleven healthy sleeping men during the same night. Hypoxic and hypercapnic responses were determined during wakefulness, non-rapid and rapid-eye-movement sleep. The following parameters were measured: minute ventilation (VE), tidal volume (VT), 'duty cycle' (TI/TT), mean inspiratory flow rate (VT/TI) and P0.1, an index of the neuromuscular inspiratory drive. To allow a direct comparison between the two types of chemostimuli, responses were characterized by the value of the different parameters at 'equivalent' levels of hypoxia and hypercapnia, i.e., at levels which produced the same P0.1 during wakefulness: an oxyhaemoglobin saturation (Sao2) of 94% during the isocapnic-hypoxic tests (PETCO2 = 42.5 +/- 1.2 mmHg) was found to be equivalent to a PETCO2 of 47.4 +/- 3.7 mmHg during hypoxic-hypercapnic tests. For both tests, the arousal levels of the stimulus and of P0.1 were similar in all sleep stages. Sleep did not significantly modify P0.1 or breathing pattern responses to hypoxia (Sao2 = 94%). In contrast, at the 'equivalent' level of hypercapnic stimulation, P0.1 (P less than 0.05) and VE (P less than 0.01) responses were significantly impaired, particularly in REM sleep, with a decrease in VT (P less than 0.01) and VT/TI (P less than 0.05) responses. The results suggest that CO2 intracranial receptor mechanisms are more affected by sleep than the O2 peripheral receptor activity.     

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.     

Respiratory,circulatory and neuropsychological responses to acute hypoxia in acclimatized and non-acclimatized subjects

Summary Respiratory, circulatory and neuropsychological responses to stepwise, acute exposure at rest to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers 24 days, SD 11 after descending from Himalayan altitudes of at least 4,000 m with those found in ten non-acclimatized recumbent volunteers. The results showed that hypoxic hyperpnoea and O₂ consumption at high altitudes were significantly lower in the mountaineers, their alveolar gases being, however, similar to those of the control group. In the acclimatized subjects the activation of the cardiovascular system was less marked, systolic blood pressure, pulse pressure, heart rate and thus (calculated) cardiac output being always lower than in the controls; diastolic blood pressure and peripheral vascular resistance, however, were maintained throughout in contrast to the vasomotor depression induced by central hypoxia which occurred in the non-acclimatized subjects at and above 4,000 m [alveolar partial pressure of O₂ < 55–50 mmHg (7.3–6.6 kPa)]. It was concluded that in the acclimatized subjects at high altitude arterial vasodilatation and neurobehavioural impairment, which in the non-acclimatized subjects reflect hypoxia of the central nervous system, were prevented; that acclimatization to high altitude resulted in a significant improvement of respiratory efficiency and cardiac economy, and that maintaining diastolic blood pressure (arterial resistance) at and above 4,000 m may represent a useful criterion for assessing hypoxia acclimatization.Dedicated to Prof. A. Schreiber on the occasion of his 60th birthday     

Human pulmonary vascular responses to hypoxia and hypercapnia

Cardiac uptake of long-chain fatty acids (FA) is mediated predominantly by two membrane-associated proteins, the 43-kDa plasma membrane fatty acid-binding protein (FABPpm) and the 88-kDa fatty acid translocase/CD36 (FAT/CD36). While FABPpm is present constitutively in the sarcolemma, FAT/CD36 is recycled between an intracellular membrane compartment and the sarcolemma. Since the amount of sarcolemmal FAT/CD36 is a major determinant of cellular FA uptake, understanding of the regulation of its recycling is likely to provide new insights into altering substrate preference of the heart. FAT/CD36 recycling displays a remarkable similarity with that of the two glucose transporters (GLUT) in the heart, GLUT1 and GLUT4. Translocation of all three transporters is induced by insulin and by contraction, which stimuli activate distinct signalling cascades. The insulin pathway involves phosphatidylinositol-3 kinase (PI3K) whilst the contraction pathway is dependent on AMP-activated protein kinase (AMPK). For the identification of additional protein components involved in the regulation of FAT/CD36 recycling, valuable lessons can be learned from GLUT1 and GLUT4 recycling. Especially GLUT4 recycling is an intensively studied process in which a number of signalling proteins, both upstream and downstream from PI3 K and AMPK, have been identified, as well as proteins that are part of the translocation machinery involving Rab GTPases and soluble N-ethylmaleimide attachment protein receptors (SNAREs). Comparison of the magnitude of the effects of insulin and contraction on substrate uptake and on transporter appearance in the sarcolemma have revealed that FAT/CD36 recycling resembles GLUT1 recycling more closely than that of GLUT4. This pinpoints the recycling compartment and excludes a pre-endosomal storage compartment as the intracellular storage site for FAT/CD36. Further research will probably establish whether FAT/CD36 translocation is (partly) coupled to that of one or both GLUTs or, alternatively, whether it is a distinct process that also can be induced independently of GLUT1 or GLUT4 movement. In the latter case, a unique set of proteins would be dedicated to FAT/CD36 recycling, which would then provide an attractive target for manipulating cardiac substrate preference.Abbreviations and definitions AICAR 5-aminoimidazole-4-carboxyamide-1--d-ribofuranoside, cell-permeable activator of AMPK - AMPK AMP-activated protein kinase - amrinone specific inhibitor of phosphodiesterase III - CPT-I carnitine palmitoyl transferase I - dibutyryl cyclic AMP cell-permeable analogue of cyclic AMP, mimics cyclic AMP-activated signalling - DNP 2,4-dinitrophenol, mitochondrial uncoupling agent - ERK extracellular signal-regulated kinase - etomoxir specific inhibitor of CPT-I - FA long-chain fatty acid(s) - FABPpm plasma membrane fatty acid-binding protein - FAT/CD36 fatty acid translocase/CD36 - GTPS guanosine 5-O-(3-thiotriphosphate), non-hydrolysable GTP analogue, locks Rab proteins in a persistently active state - IGF-II insulin-like growth factor II - 5-iodotubercidin specific inhibitor of adenosine kinase, prevents conversion of AICAR into ZMP - IRAP insulin-responsive aminopeptidase - IRS insulin receptor substrate - isoproterenol potent -agonist - myristoylated PKC pseudosubstrate cell-permeable, specific inhibitor of atypical PKCs - oligomycin potent inhibitor of mitochondrial F₁F₀-ATPase - PD98059 specific inhibitor of mitogen-activated protein kinase signalling - PI3K phosphatidylinositol-3 kinase - PKB (PKB/Akt) protein kinase B - PKC protein kinase C - rotenone inhibitor of electron transfer in mitochondria - SCAMP secretory carrier membrane protein - SNAP23 synaptosomal-associated protein (23 kDa) - SNARE soluble N-ethylmaleimide attachment protein receptor - SSO sulpho-N-succinimidyloleate, specific inhibitor of transport function of FAT/CD36 - VAMP2 (-3) vesicle-associated membrane protein-2 (-3) - VAP33 vesicle-associated protein 33 - wortmannin inhibitor of PI3K - ZMP 5-monophosphate of AICAR     

Adrenal and pancreatic endocrine responses to hypoxia and hypercapnia in the calf.

1. Adrenal and pancreatic endocrine responses to hypoxia and hypercapnia, of differing degrees of intensity, have been examined in conscious, unrestrained calves 3-5 weeks after birth. 2. The outputs of cortisol and corticosterone from the right adrenal gland were found to vary inversely with arterial Po2 between 17 and 55 mmHg. Significant increase in mean adrenal blood flow was not observed at arterial oxygen tensions above about 30 mmHg. 3. Release of physiologically effective amounts of catecholamines from the adrenal medulla occurred only in response to intense hypoxia (arterial Po2 17-1 +/- 2-8 mmHg) and was effectively abolished by section of both splanchnic nerves. Release of pancreatic glucagon in response to such intense hypoxia was unaffected by section of both splanchnic nerves and administration of atropine. In contrast, the rise in plasma pancreatic glucagon concentration during less intense hypoxia was abolished by autonomic blockade. 4. Hypercapnia produced by inhalation of either 5% or 10% CO2 for 30 min stimulated maximal release of adrenal glucocorticoids and caused a substantial rise in plasma glucagon concentration. In contrast, the adrenal medulla was found to be extremely resistant to hypercapnia. Significant release of catecholamines was only observed during intense hypercapnia (inhalation of 10% CO2) and noradrenaline was invariably found to be the predominant amine. 5. The results of these experiments show how endocrine responses to hypoxia and hypercapnia are graded in the conscious calf. Of the mechanisms we have examined the pituitary-adrenal cortical axis is the most sensitive and the adrenal medulla the most resistant, while the pancreatic alpha cell occupies an intermediate position.     

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.     

In vitro responses of caudal hypothalamic neurons to hypoxia and hypercapnia.

Results from previous studies have suggested that the hypothalamus modulates cardiorespiratory responses to hypoxia and/or hypercapnia. Many neurons in the caudal hypothalamus are stimulated by hypercapnia and hypoxia in vivo; however, it is not known if these responses are dependent upon input from other areas. Whole-cell patch and extracellular recordings from a brain slice preparation were used in the present study to determine the direct effects of hypoxia (5% CO2/95% N2 or 10% O2/5% CO2/85% N2) and hypercapnia (7% CO2/93% O2) on caudal hypothalamic neurons in vitro. Coronal sections (400-500 microns) were obtained from young Sprague-Dawley rats and placed in a recording chamber that was perfused with nutrient media equilibrated with 95% O2/5% CO2. Extracellular recordings demonstrated that hypoxia stimulated over 80% of the neurons tested; the magnitude of the response was dependent upon the degree of hypoxia. In addition, over 80% of cells that were excited by hypoxia retained this response during synaptic blockade. Hypercapnia increased the discharge frequency of 22% of the caudal hypothalamic neurons that were studied. A second set of caudal hypothalamic neurons were studied with whole-cell patch recordings; the mean resting membrane potential of these neurons was -51.8 +/- 1.0 mV with an average input resistance of 399 +/- 49 M omega. Hypoxia produced a depolarization in 76% of these neurons; a poststimulus hyperpolarization often occurred. A depolarization and/or increase in discharge rate during hypercapnia was observed in 35% of the neurons tested. Only 10% of all neurons studied were excited by both hypoxia and hypercapnia. These findings suggest that separate subpopulations of caudal hypothalamic neurons are sensitive to hypoxia and hypercapnia. Thus, this hypothalamic area may be a site of central hypoxic and hypercapnic chemoreception.     

Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia

The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes  ( P _O2∼ 75 Torr)  repeated during 8 h for 2–4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg⁻¹ i.p. , followed by 8–12 mg i.v. ), and ventilatory and cardiovascular responses to NaCN (0.1–100 μg kg⁻¹ i.v. ) and several isocapnic levels of oxygen  ( P _O2∼ 20–740 Torr)  were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory ( V _T and V _I) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia  ( P _O2 < 100 Torr)  were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity.     

Cerebral circulatory responses to hypercapnia and hypoxia in the recovery period following complete and incomplete cerebral ischemia in the rat

In this study we examined the reactions of cerebral vessels to hypercapnia and hypoxia during the recovery period following cerebral ischemia. We used ventilated, lightly anesthetized rats and induced complete ischemia by CSF compression, incomplete ischemia by bilateral carotid occlusion combined with hypotension. After 15 min of ischemia and 60 min of recirculation the animals were rendered hypercapnic or hypoxic for 2–3 min and local CBF was then measured autoradiographically with ¹⁴C-iodoantipyrine. Following complete ischemia vascular CO₂ responsiveness was abolished or attenuated in most structures analysed. However, there was a considerable interstructural heterogeneity. For example, in the cerebellum and the red nucleus flow rates were observed which approached values obtained in hypercapnic control animals, whereas CO₂ responsiveness was abolished in several cortical areas and hippocampus. The response to CO₂ following incomplete (“forebrain”) ischemia varied considerably. In the cerebral cortices areas with low flow rates were often mixed with hyperemic zones, and in most structures that had very low flow rates during ischemia, CO₂ responsiveness was lost or grossly attenuated. Structures that had suffered moderate or only mild ischemia had better retained or completely preserved CO₂ response. The cerebrovascular reaction to hypoxia was found to be attenuated in most, but not abolished in any of the structures examined. In general, the vascular response to hypoxia was better preserved than that to hypercapnia. Reactivity was similar following complete and incomplete ischemia. As observed during hypercapnia, there were pronounced interstructural variations with considerable increases in flow rates e.g. in the substantia nigra and the cerebellum.     

Short-latency ventilatory responses to sudden withdrawal of hypoxia at normal and raised body temperature in man

Approximately isopnoeic conditions (VE=40 l/min) were achieved by the inhalation of asphyxial gas mixtures (PA,O2 60 torr, PA,CO2 40-45 torr) in normothermia after a rise in rectal temperature of 1.6 degrees C had been induced by a heated flying suit. Arterial chemoreceptor drive was transiently reduced by either isocapnic removal of hypoxia (type (1) tests: two breaths of CO2 in O2) or simultaneous withdrawal of both hypercapnia and hypoxia (type (2) tests: two breaths of O2). 8-13 tests of each type were performed at both temperature conditions in 6 expts. on 4 healthy human subjects. Expired volume, total breath duration and inspiratory time were recorded, and minute ventilation and expiratory time subsequently computed breath by breath. In hyperthermia the steady-state ventilation of 40 l/min (at a relatively higher respiratory frequency and a correspondingly lower tidal volume) was achieved at a PA,CO2 which was 5 torr lower than in normothermia. Ventilation decreased significantly in all tests. Tested with a 3-way analysis of variance significant differences between the ventilatory responses at the two temperature conditions, and between the two test types were found. The rate of change of ventilation was greater in hyperthermia than in normothermia, and also greater in type (2) tests than in type (1) tests. Since isopnoeic conditions existed prior to the tests, this implies that the arterial chemoreceptor contribution to the total ventilatory drive is increased in hyperthermia. In type (2) tests a significant lengthening of expiratory time was observed in the first test breath. This finding confirms the effect in man of changes in airway PCO2 on lung stretch receptor discharge.     

Blunted ventilatory response to hypoxia/hypercapnia in mice with cigarette smoke-induced emphysema

It has been reported that the degree of emphysema induced by chronic cigarette smoke (CS) is greater in female C3H/HeN mice as compared to other mouse strains. We hypothesized that these mice would develop the similar major characteristics seen in hypercapnic patients with chronic obstructive pulmonary disease (COPD), including emphysema, pulmonary inflammation, hypercapnia/hypoxemia, rapid breathing, and attenuated ventilatory response (AVR). Mice were exposed either to CS or filtered air (FA) for 16 weeks. After exposure, arterial blood gases and minute ventilation were measured before and during chemical challenges in anesthetized and spontaneously breathing mice. We found that as compared to FA, CS exposure caused emphysema and pulmonary inflammation associated with: (1) hypercapnia and hypoxemia, (2) rapid breathing, and (3) AVR to 25 breaths of pure N(2), 5% CO(2) alone, and 5% CO(2) coupled with 10% O(2). The similarity of these pathophysiological characteristics between our mouse model and COPD patients suggests that this model could be effectively applied to study COPD pathophysiology, especially central mechanisms of the AVR genesis.     

Hemodynamic and ventilatory response to different levels of hypoxia and hypercapnia in carotid body-denervated rats

OBJECTIVE:

Chemoreceptors play an important role in the autonomic modulation of circulatory and ventilatory responses to changes in arterial O₂ and/or CO₂. However, studies evaluating hemodynamic responses to hypoxia and hypercapnia in rats have shown inconsistent results. Our aim was to evaluate hemodynamic and respiratory responses to different levels of hypoxia and hypercapnia in conscious intact or carotid body-denervated rats.

METHODS:

Male Wistar rats were submitted to bilateral ligature of carotid body arteries (or sham-operation) and received catheters into the left femoral artery and vein. After two days, each animal was placed into a plethysmographic chamber and, after baseline measurements of respiratory parameters and arterial pressure, each animal was subjected to three levels of hypoxia (15, 10 and 6% O₂) and hypercapnia (10% CO₂).

RESULTS:

The results indicated that 15% O₂ decreased the mean arterial pressure and increased the heart rate (HR) in both intact (n = 8) and carotid body-denervated (n = 7) rats. In contrast, 10% O₂ did not change the mean arterial pressure but still increased the HR in intact rats, and it decreased the mean arterial pressure and increased the heart rate in carotid body-denervated rats. Furthermore, 6% O₂ increased the mean arterial pressure and decreased the HR in intact rats, but it decreased the mean arterial pressure and did not change the HR in carotid body-denervated rats. The 3 levels of hypoxia increased pulmonary ventilation in both groups, with attenuated responses in carotid body-denervated rats. Hypercapnia with 10% CO₂ increased the mean arterial pressure and decreased HR similarly in both groups. Hypercapnia also increased pulmonary ventilation in both groups to the same extent.

CONCLUSION:

This study demonstrates that the hemodynamic and ventilatory responses varied according to the level of hypoxia. Nevertheless, the hemodynamic and ventilatory responses to hypercapnia did not depend on the activation of the peripheral carotid chemoreceptors.     

Effect of airway anaesthesia on the ventilatory and heart rate responses to isocapnic progressive hypoxia

The effect of airway anaesthesia by lidocaine inhalation on the hypoxic ventilatory response was examined together with the heart rate response by the isocapnic progressive hypoxia test in human subjects. During the test, end-tidal PCO2 (PETCO2) was maintained at the resting level. However, because resting PETCO2 tends to decrease by airway anaesthesia, we conducted the test at the resting PETCO2 determined both before (normocapnic) and after lidocaine (hypocapnic). Ventilatory and heart rate response were evaluated as a linear function of oxygen saturation of the arterial blood (SaO2). In the "hypocapnic" runs, ventilatory responses tended to be depressed, while the slope of heart rate response-PETCO2 relationship increased after lidocaine. However, when PETCO2 was restored to the normocapnic level, ventilation apparently increased from the control, and the augmented slope in the heart rate response disappeared. Although the elevated ventilation in normocapnic hypoxia might be due simply to the increased ventilatory response to CO2, we suggested that the augmented slope in the heart rate response in hypocapnic hypoxia might be related not only to PETCO2 level itself but also to the direct effect of airway anaesthesia.     

Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice

The c-ret proto-oncogene encodes a tyrosine-kinase receptor involved in survival and differentiation of neural crest cell lineages. Previous studies have shown that homozygous c-ret-/- mice die soon after birth and have impaired ventilatory responses to hypercapnia. Heterozygous c-ret +/- mice develop normally, but their respiratory phenotype has not been described in detail. We used whole-body flow plethysmography to compare baseline breathing and ventilatory and arousal responses to chemical stimuli in unrestrained heterozygous c-ret +/- newborn mice and their wild-type c-ret +/+ littermates at 10-12 h of postnatal age. The hyperpnoeic and arousal responses to hypoxia and hypercapnia were not significantly different in these two groups. However, the number and total duration of apnoeas and periodic breathing episodes were significantly higher in c-ret +/- than in c-ret +/+ pups during hypoxia and post-hypoxic normoxia. These results are further evidence that respiratory control at birth is heavily dependent on genes involved in the neural determination of neural crest cells.