Characterisation of the ventilatory response to hypoxia in a model of transgenic anemic mice

Both polycythemia and the increase in hypoxic ventilatory response (HVR) are considered as important factors of acclimatization to hypoxia. The objective of this study was to characterise the ventilation pattern at different inspired oxygen fraction in a model of chronic anemic mice. These mice have a targeted disruption in the 5' untranslated region of the Epo gene that reduces Epo expression such that the homozygous animal is severely anemic. Ventilation in normoxia in Epo-TAg(h) mice was significantly greater than in wild type, and the difference was mainly due to a higher tidal volume. HVR was higher in Epo-TAg(h) mice at every FIO2 suggesting a higher chemosensitivity. Resting oxygen consumption was maintained in anemic mice. Maximal oxygen consumption was 30% lower while hemoglobin was 60% lower in anemic mice compared to wild type. This small decrease in maximal oxygen consumption is probably due a greater cardiac output and/or a better tissue oxygen extraction and would allow these anemic mice to acclimatize to hypoxia in spite of low oxygen carrying capacity. In conclusion, Epo-TAg(h) anemic mice showed increased ventilation and hypoxic ventilatory response. However, whether these adaptations will contribute to acclimatization in chronic hypoxia remains to be determined.     

Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans

Chronic hypoxia is associated with elevated sympathetic activity and hypertension in patients with chronic pulmonary obstructive disease. However, the effect of chronic hypoxia on systemic and regional sympathetic activity in healthy humans remains unknown. To determine if chronic hypoxia in healthy humans is associated with hyperactivity of the sympathetic system, we measured intra-arterial blood pressure, arterial blood gases, systemic and skeletal muscle noradrenaline (norepinephrine) spillover and vascular conductances in nine Danish lowlanders at sea level and after 9 weeks of exposure at 5260 m. Mean blood pressure was 28% higher at altitude ( P < 0.01) due to increases in both systolic (18% higher, P < 0.05) and diastolic (41% higher, P < 0.001) blood pressures. Cardiac output and leg blood flow were not altered by chronic hypoxia, but systemic vascular conductance was reduced by 30 % ( P < 0.05). Plasma arterial noradrenaline (NA) and adrenaline concentrations were 3.7- and 2.4-fold higher at altitude, respectively ( P < 0.05). The elevation of plasma arterial NA concentration was caused by a 3.8-fold higher whole-body NA release ( P < 0.001) since whole-body noradrenaline clearance was similar in both conditions. Leg NA spillover was increased similarly (× 3.2, P < 0.05). These changes occurred despite the fact that systemic O₂ delivery was greater after altitude acclimatisation than at sea level, due to 37 % higher blood haemoglobin concentration. In summary, this study shows that chronic hypoxia causes marked activation of the sympathetic nervous system in healthy humans and increased systemic arterial pressure, despite normalisation of the arterial O₂ content with acclimatisation.     

Chronic hypoxia modulates NMDA-mediated regulation of the hypoxic ventilatory response in an amphibian, Bufo marinus

This study examined whether a hypoxia-tolerant amphibian, the Cane toad, undergoes mammalian-like ventilatory acclimatisation to hypoxia (VAH) and whether chronic hypoxia (CH) alters NMDA-mediated regulation of the acute hypoxic ventilatory response (HVR). Toads were exposed to 10 days of CH (10% O2) followed by acute hypoxic breathing trials or an intra-arterial injection of NaCN. Trials were conducted before and after i.p. treatment with an NMDA-receptor channel blocker (MK801). CH blunted the acute HVR but did not alter resting breathing. MK801 did not alter resting ventilation. In control animals, MK801 augmented breathing frequency (fR) during acute hypoxia by increasing the number of breaths per episode. This effect was attenuated following CH although MK801 did enhance the number of episodes per minute during acute hypoxia. MK801 enhanced the fR response to NaCN in both groups. The results indicate that CH did not produce mammalian-like VAH (i.e. increased resting ventilation and an augmented acute HVR) but did alter MK801-sensitive regulation of breathing pattern and the acute HVR.     

Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B

Earlier studies on cell culture models suggested that immediate early genes (IEGs) play an important role in cellular adaptations to hypoxia. Whether IEGs are also necessary for hypoxic adaptations in intact animals is not known. In the present study we examined the potential importance of fos B, an IEG in ventilatory acclimatization to hypoxia. Experiments were performed on wild type and mutant mice lacking the fos B gene. Ventilation was monitored by whole body plethysmography in awake animals. Baseline ventilation under normoxia, and ventilatory response to acute hypoxia and hypercapnia were comparable between wild type and mutant mice. Hypobaric hypoxia (0.4 atm; 3 days) resulted in a significant elevation of baseline ventilation in wild type but not in mutant mice. Wild type mice exposed to hypobaric hypoxia manifested an enhanced hypoxic ventilatory response compared to pre-hypobaric hypoxia. In contrast, hypobaric hypoxia had no effect on the hypoxic ventilatory response in mutant mice. Hypercapnic ventilatory responses, however, were unaffected by hypobaric hypoxia in both groups of mice. These results suggest that the fos B, an immediate early gene, plays an important role in ventilatory acclimatization to hypoxia in mice.     

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.     

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.     

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.     

The influence of chronic hypoxia upon chemoreception

Carotid body chemoreceptors are essential for time-dependent changes in ventilatory control during chronic hypoxia. Early theories of ventilatory acclimatization to hypoxia focused on time-dependent changes in known ventilatory stimuli, such as small changes in arterial pH that may play a significant role in some species. However, plasticity in the cellular and molecular mechanisms of carotid body chemoreception play a major role in ventilatory acclimatization to hypoxia in all species studied. Chronic hypoxia causes changes in (a) ion channels (potassium, sodium, calcium) to increase glomus cell excitability, and (b) neurotransmitters (dopamine, acetylcholine, ATP) and neuromodulators (endothelin-1) to increase carotid body afferent activity for a given PO(2) and optimize O(2)-sensitivity. O(2)-sensing heme-containing molecules in the carotid body have not been studied in chronic hypoxia. Plasticity in medullary respiratory centers processing carotid body afferent input also contributes to ventilatory acclimatization to hypoxia. It is not known if the same mechanisms occur in patients with chronic hypoxemia from lung disease or high altitude natives.     

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.     

Epo deficiency alters cardiac adaptation to chronic hypoxia

The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAg^h) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O₂T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O₂T remained lower than in WT mice. In CHx Epo-TAg^h mice, LV hypertrophy, CO and O₂T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAg^h mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues.     

An Analysis of Hypoxia in Sheep Brain using a Mathematical Model

Cerebral blood flow (CBF) increases as arterial oxygen content falls with hypoxic (low PO₂), anemic (low hemoglobin) and carbon monoxide (CO) (high carboxyhemoglobin) hypoxia. Despite a higher arterial PO₂, CO hypoxia provokes a greater increase in CBF than hypoxic hypoxia. We analyzed published data using a compartmental mathematical model to test the hypothesis that differences in PO₂ in tissue, or a closely related vascular compartment, account for the greater response to CO hypoxia. Calculations showed that tissue, but not arteriolar, PO₂ was lower in CO hypoxia because of the increased oxyhemoglobin affinity with CO hypoxia. Analysis of studies in which oxyhemoglobin affinity was changed independently of CO supports the conclusion that changes in tissue PO₂ (or closely related capillary or venular PO₂) are predictive of alterations in CBF. We then sought to determine the role of tissue PO₂ in anemic hypoxia, with no change in arterial and little, if any, change in venous PO₂. Calculations predict a small fall in tissue PO₂ as hematocrit decreases from 55% to 20%. However, calculations show that changes in blood viscosity can account for the increase in CBF in anemic hypoxia over this range of hematocrits. © 1998 Biomedical Engineering Society. PAC98: 8710+e, 8722-q, 8745Ft     

Effect of potassium on ventilation in the rhesus monkey.

Increasing the concentration of arterial plasma K+ to 6-8 mM increased ventilation in two sedated analgesic-treated rhesus monkeys who had their end-tidal CO2 held constant during euoxia (arterial oxygen pressure, Pa,O2, ca 100 Torr) and hypoxia (Pa,O2, ca 40 Torr). During euoxia and hypoxia, hyperkalaemia increased ventilation up to 40 and 250%, respectively. This effect was reduced in euoxia and virtually abolished in hypoxia following an abrupt switch to 100% oxygen. Thus the ventilatory response of this primate to hyperkalaemia is at least as sensitive as that of the cat and if hypoxia is added the two stimuli generate a powerful drive to breathing.     

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.     

Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: effect of acclimation to 3-week hypobaric hypoxia

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.     

Tibetans retained innate ability resistance to acute hypoxia after long period of residing at sea level

Could the intrinsic characteristics of tolerance to hypoxia be retained in Tibetan high-altitude natives after they had migrated to a low altitude? To answer this question, we undertook a study of 33 healthy male adolescent Tibetans born and raised in a high plateau (3,700 m [12,140 ft] above sea level) who migrated to Shanghai (sea level) for 4 years. Ten age-matched healthy male Han adolescents born and raised in Shanghai were regarded as the control group. Acute hypoxia was induced in a hypobaric chamber for 2 h to simulate the 3,700 m altitude. At sea level, maximal oxygen consumption (VO2 max) was not significantly different between the two groups. During acute hypoxia, the values of VO2 max, tissue oxygen extraction, arterial oxygen pressure, and the arterial oxygen saturation showed markedly higher in Tibetan subjects than in Han subjects (1.41 +/- 0.04 l/min/M2 vs.1.25 +/- 0.04 l/min/M2, 55.0 +/- 4.2% vs. 47.3 +/- 9.1%, 7.2 +/- 0.6 vs. 5.5 +/- 0.2 kPa, and 87.9 +/- 3.3% vs. 78.2 +/- 1.6%, respectively, P < 0.05). The calculated "oxygen reserve capacity" and "cardiac reserve capacity" were better in the Tibetans than in the Han natives (P < 0.05), which suggests that physical work capacity is greater in the Tibetan group. The sympathetic stimulation was less, and there was no noticeable change in cardiac function during acute hypoxia in the Tibetan group. The results indicate that the better tolerance to hypoxia in the Tibetans is retained during the 4-year stay at sea level, implying that the intrinsic hypoxic adaptation still exists in the Tibetan high-altitude natives.     

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.     

Oxygen limited thermal tolerance in fish?--Answers obtained by nuclear magnetic resonance techniques

In various phyla of marine invertebrates limited capacities of both ventilatory and circulatory performance were found to set the borders of the thermal tolerance window with limitations in aerobic scope and onset of hypoxia as a first line of sensitivity to both cold and warm temperature extremes. The hypothesis of oxygen limited thermal tolerance has recently been investigated in fish using a combination of non-invasive nuclear magnetic resonance (NMR) methodology with invasive techniques. In contrast to observations in marine invertebrates arterial oxygen tensions in fish were independent of temperature, while venous oxygen tensions displayed a thermal optimum. As the fish heart relies on venous oxygen supply, limited cardio-circulatory capacity is concluded to set the first level of thermal intolerance in fish. Nonetheless, maximized ventilatory capacity is seen to support circulation in maintaining the width of thermal tolerance windows. The interdependent setting of low and high tolerance limits is interpreted to result from trade-offs between optimized tissue functional capacity and baseline oxygen demand and energy turnover co-determined by the adjustment of mitochondrial densities and functional properties to a species-specific temperature range. At temperature extremes, systemic hypoxia will elicit metabolic depression, thereby widening the thermal window transiently sustained especially in those species preadapted to hypoxic environments.     

Soluble erythropoietin receptor is present in the mouse brain and is required for the ventilatory acclimatization to hypoxia

While erythropoietin (Epo) and its receptor (EpoR) have been widely investigated in brain, the expression and function of the soluble Epo receptor (sEpoR) remain unknown. Here we demonstrate that sEpoR, a negative regulator of Epo's binding to the EpoR, is present in the mouse brain and is down-regulated by 62% after exposure to normobaric chronic hypoxia (10% O₂ for 3 days). Furthermore, while normoxic minute ventilation increased by 58% in control mice following hypoxic acclimatization, sEpoR infusion in brain during the hypoxic challenge efficiently reduced brain Epo concentration and abolished the ventilatory acclimatization to hypoxia (VAH). These observations imply that hypoxic downregulation of sEpoR is required for adequate ventilatory acclimatization to hypoxia, thereby underlying the function of Epo as a key factor regulating oxygen delivery not only by its classical activity on red blood cell production, but also by regulating ventilation.     

Facial cooling and peripheral chemoreflex mechanisms in humans

Aim: Reductions in arterial oxygen partial pressure activate the peripheral chemoreceptors which increase ventilation, and, after cessation of breathing, reduce heart rate. We tested the hypothesis that facial cooling facilitates these peripheral chemoreflex mechanisms. Methods: Chemoreflex control was assessed by the ventilatory response to hypoxia (10% O₂ in N₂) and the bradycardic response to voluntary end‐expiratory apnoeas of maximal duration in 12 young, healthy subjects. We recorded minute ventilation, haemoglobin O₂ saturation, RR interval (the time between two R waves of the QRS complex) and the standard deviation of the RR interval (SDNN), a marker of cardiac vagal activity throughout the study. Measurements were performed with the subject’s face exposed to air flow at 23 and 4 °C. Results: Cold air decreased facial temperature by 11 °C (P < 0.0001) but did not affect minute ventilation during normoxia. However, facial cooling increased the ventilatory response to hypoxia (P < 0.05). The RR interval increased by 31 ± 8% of the mean RR preceding the apnoea during the hypoxic apnoeas in the presence of cold air, compared to 17 ± 5% of the mean RR preceding the apnoea in the absence of facial cooling (P < 0.05). This increase occurred despite identical apnoea durations and reductions in oxygen saturation. Finally, facial cooling increased SDNN during normoxia and hypoxia, as well as during the apnoeas performed in hypoxic conditions (all P < 0.05). Conclusion: The larger ventilatory response to hypoxia suggests that facial cooling facilitates peripheral chemoreflex mechanisms in normal humans. Moreover, simultaneous diving reflex and peripheral chemoreflex activation enhances cardiac vagal activation, and favours further bradycardia upon cessation of breathing.     

The effects of long-term oxygen therapy on the EEG in patients with chronic stable ventilatory failure.

A homogeneous sample of 14 patients with advanced chronic bronchitis and emphysema complicated by secondary polycythaemia and pulmonary hypertension was examined. Eight patients who were receiving long-term oxygen therapy (LTO2) for 15-20 h in the 24 h day showed a significantly faster, that is more normal, frequency of the dominant EEG activity and a higher level of arterial oxygenation when breathing air than six similar patients not receiving LTO2. Acute administration of oxygen (2 1/min) for 15 min did not change the EEG pattern in either group of patients. The frequency of the dominant EEG activity in all 14 patients showed a significant positive correlation with the arterial oxygen saturation and negative correlation with the level of polycythaemia. Occurrence of intermixed EEG show activity theta and delta was positively correlated both with hypoxaemia and hypercapnia. The results suggest that the LTO2 in patients with chronic ventilatory failure has a beneficial effect on cerebral function as measured by EEG.