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Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia., Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes., Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes., Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use., Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M., Competing Interests: XZ, SN, CX, SE, JG, AZ, AD, LB, MM, PC, MD, GS, EF, AZ, KB, TS, NR, IB, FP, SC No competing interests declared, (© 2022, Zheng et al.)

Background: Cardiovascular (baroreflex) and respiratory (chemoreflex) control mechanisms were studied separately in diabetes, but their reciprocal interaction (well known for diseases like heart failure) had never been comprehensively assessed. We hypothesized that prevalent autonomic neuropathy would depress both reflexes, whereas prevalent autonomic imbalance through sympathetic activation would depress the baroreflex but enhance the chemoreflexes., Methods: In 46 type-1 diabetic subjects (7.0±0.9year duration) and 103 age-matched controls we measured the baroreflex (average of 7 methods), and the chemoreflexes, (hypercapnic: ventilation/carbon dioxide slope during hyperoxic progressive hypercapnia; hypoxic: ventilation/oxygen saturation slope during normocapnic progressive hypoxia). Autonomic dysfunction was evaluated by cardiovascular reflex tests., Results: Resting oxygen saturation and baroreflex sensitivity were reduced in the diabetic group, whereas the hypercapnic chemoreflex was significantly increased in the entire diabetic group. Despite lower oxygen saturation the hypoxic chemoreflex showed a trend toward a depression in the diabetic group., Conclusion: Cardio-respiratory control imbalance is a common finding in early type 1 diabetes. A reduced sensitivity to hypoxia seems a primary factor leading to reflex sympathetic activation (enhanced hypercapnic chemoreflex and baroreflex depression), hence suggesting a functional origin of cardio-respiratory control imbalance in initial diabetes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The present study evaluated the effects of a preacclimatization program comprising seven passive 1-h exposures to 4500-m normobaric hypoxia on the prevalence and severity of acute mountain sickness (AMS) during a subsequent exposure to real high altitude in persons susceptible to AMS., Methods: The project was designed as a randomized controlled trial including 32 healthy female and male participants with known susceptibility to AMS symptoms. After baseline measurements, participants were randomly assigned to the hypoxia or the control group to receive the preacclimatization program (seven passive 1-h exposures within 7 d to normobaric hypoxia or sham hypoxia). After completing preacclimatization, participants were transported (bus, cog railway) to real high altitude (3650 m, Mönchsjoch Hut, Switzerland) and stayed there for 45 h (two nights). Symptoms of AMS and physiological responses were determined repeatedly., Results: AMS incidence and severity did not significantly differ between groups during the high-altitude exposure. In total, 59% of the hypoxia and 67% of the control group suffered from AMS at one or more time points during the high-altitude exposure. Hypoxic and hypercapnic ventilatory responses were not affected by the preacclimatization program. Resting ventilation at high altitude tended to be higher (P = 0.06) in the hypoxia group compared with the control group. No significant between-group differences were detected for heart rate variability, arterial oxygen saturation, and hematological and ventilatory parameters during the high-altitude exposure., Conclusion: Preacclimatization using seven passive 1-h exposures to normobaric hypoxia corresponding to 4500 m did not prevent AMS development during a subsequent high-altitude exposure in AMS-susceptible persons.

Controlled slow breathing (at 6/min, a rate frequently adopted during yoga practice) can benefit cardiovascular function, including responses to hypoxia. We tested the neural substrates of cardiorespiratory control in humans during volitional controlled breathing and hypoxic challenge using functional magnetic resonance imaging (fMRI). Twenty healthy volunteers were scanned during paced (slow and normal rate) breathing and during spontaneous breathing of normoxic and hypoxic (13% inspired O2) air. Cardiovascular and respiratory measures were acquired concurrently, including beat-to-beat blood pressure from a subset of participants (N = 7). Slow breathing was associated with increased tidal ventilatory volume. Induced hypoxia raised heart rate and suppressed heart rate variability. Within the brain, slow breathing activated dorsal pons, periaqueductal grey matter, cerebellum, hypothalamus, thalamus and lateral and anterior insular cortices. Blocks of hypoxia activated mid pons, bilateral amygdalae, anterior insular and occipitotemporal cortices. Interaction between slow breathing and hypoxia was expressed in ventral striatal and frontal polar activity. Across conditions, within brainstem, dorsal medullary and pontine activity correlated with tidal volume and inversely with heart rate. Activity in rostroventral medulla correlated with beat-to-beat blood pressure and heart rate variability. Widespread insula and striatal activity tracked decreases in heart rate, while subregions of insular cortex correlated with momentary increases in tidal volume. Our findings define slow breathing effects on central and cardiovascular responses to hypoxic challenge. They highlight the recruitment of discrete brainstem nuclei to cardiorespiratory control, and the engagement of corticostriatal circuitry in support of physiological responses that accompany breathing regulation during hypoxic challenge.

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5-6 short periods of hypoxia each day over 1-3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies.

Objective: Hypoxia may cause functional autonomic imbalance in diabetes. Intermittent hypoxia (IH), a technique improving the adaptation to hypoxia, might improve cardiorespiratory reflexes and, ultimately, blood glucose concentrations in patients with type 2 diabetes. We tested whether a single bout of IH could initiate a long-lasting response potentially leading to better adaptation to hypoxia., Research Design and Methods: In 14 patients with type 2 diabetes without autonomic complications, we measured blood pressure, heart rate, oxygen saturation, chemoreflex (hypoxic and hypercapnic ventilatory responses, ventilatory recruitment threshold), and baroreflex sensitivity before, immediately after, and 3 and 6 h after a 1-h single bout of IH (6-min breathing of 13% oxygen mixture 5 times each separated by 6-min recovery). The measurements were repeated on a placebo day (at least 1 week apart, in random sequence) when subjects were only breathing room air (single-blind protocol)., Results: IH significantly increased hypercapnic ventilatory responses and reduced ventilatory recruitment threshold, and increased oxygen saturation and blood pressures, whereas increases in heart rate variability and baroreflex sensitivity were not significant. Blood glucose significantly decreased after IH. No such changes were observed during the placebo day, except an increase in oxygen saturation. Some of the effects lasted 3 h after IH, and some even persisted until 6 h after IH., Conclusions: A single bout of IH induced an initial adaptation to hypoxia, with improvement in cardiorespiratory reflexes and reduction in blood glucose. Patients with type 2 diabetes could potentially benefit from the application of a full (>2 weeks) IH intervention.

Intermittent hypoxic exposure (IHE) has been shown to induce aspects of altitude acclimatization which affect ventilatory, cardiovascular and metabolic responses during exercise in normoxia and hypoxia. However, knowledge on altitude-dependent effects and possible interactions remains scarce. Therefore, we determined the effects of IHE on cardiorespiratory and metabolic responses at different simulated altitudes in the same healthy subjects. Eight healthy male volunteers participated in the study and were tested before and 1 to 2 days after IHE (7 × 1 hour at 4500 m). The participants cycled at 2 submaximal workloads (corresponding to 40% and 60% of peak oxygen uptake at low altitude) at simulated altitudes of 2000 m, 3000 m, and 4000 m in a randomized order. Gas analysis was performed and arterial oxygen saturation, blood lactate concentrations, and blood gases were determined during exercise. Additionally baroreflex sensitivity, hypoxic and hypercapnic ventilatory response were determined before and after IHE. Hypoxic ventilatory response was increased after IHE (p<0.05). There were no altitude-dependent changes by IHE in any of the determined parameters. However, blood lactate concentrations and carbon dioxide output were reduced; minute ventilation and arterial oxygen saturation were unchanged, and ventilatory equivalent for carbon dioxide was increased after IHE irrespective of altitude. Changes in hypoxic ventilatory response were associated with changes in blood lactate (r = -0.72, p<0.05). Changes in blood lactate correlated with changes in carbon dioxide output (r = 0.61, p<0.01) and minute ventilation (r = 0.54, p<0.01). Based on the present results it seems that the reductions in blood lactate and carbon dioxide output have counteracted the increased hypoxic ventilatory response. As a result minute ventilation and arterial oxygen saturation did not increase during submaximal exercise at simulated altitudes between 2000 m and 4000 m.

Objectives: Chronic obstructive pulmonary disease (COPD) is associated with cardiac autonomic nervous system dysregulation. This study evaluates the effects of interval hypoxic training on cardiovascular and respiratory control in patients with mild COPD., Methods: In 18 eucapnic normoxic mild COPD patients (age 51.7 +/- 2.4 years, mean +/- SEM), randomly assigned to either training or placebo group, and 14 age-matched healthy controls (47.7 +/- 2.8 years), we monitored end-tidal carbon dioxide, airway flow, arterial oxygen saturation, electrocardiogram, and continuous noninvasive blood pressure at rest, during progressive hypercapnic hyperoxia and isocapnic hypoxia to compare baroreflex sensitivity to hypoxia and hypercapnia before and after 3 weeks of hypoxic training. In double-blind fashion, both groups received 15 sessions of passive intermittent hypoxia (training group) or normoxia (placebo group). For the hypoxia group, each session consisted of three to five hypoxic (15-12% oxygen) periods (3-5 min) with 3-min normoxic intervals. The placebo group inhaled normoxic air., Results: Before training, COPD patients showed depressed baroreflex sensitivity, as compared with healthy individuals, without evident chemoreflex abnormalities. After training, in contrast to placebo group, the training group showed increased (P < 0.05) baroreflex sensitivity up to normal levels and selectively increased hypercapnic ventilatory response (P < 0.05), without changes in hypoxic ventilatory response., Conclusion: Eucapnic normoxic mild COPD patients already showed signs of cardiovascular autonomic abnormalities at baseline, which normalized with hypoxic training. If confirmed in more severe patients, interval hypoxic training may be a therapeutic strategy to rebalance early autonomic dysfunction in COPD patients.

The effects of repeated short-term hypoxia on exercise tolerance in patients at risk for, or with mild COPD were investigated. Eighteen patients (10 males, 8 females; 33-72 years) were randomly assigned in a double-blind fashion to receive 15 sessions of intermittent hypoxia (FiO(2): 0.15-0.12) or normoxia within 3 weeks. Three weeks of intermittent hypoxia increased total haemoglobin mass (+4% vs. 0%, p<0.05), total exercise time (+9.7% vs. 0%, p<0.05) and the exercise time to the anaerobic threshold (+13% vs. -7.8%, p<0.05) compared to controls. Changes in the total exercise time were positively related to the changes in total haemoglobin mass (r=0.59, p<0.05) and changes in the time to the anaerobic threshold were positively related to the changes in the lung diffusion capacity for carbon monoxide (r=0.48, p<0.05). Intermittent hypoxia treatment may be a valuable addition to therapy designed to improve exercise tolerance in patients at risk for, or with mild COPD.

Yoga induces long-term changes in respiratory function and control. We tested whether it represents a successful strategy for high-altitude adaptation. We compared ventilatory, cardiovascular and hematological parameters in: 12 Caucasian yoga trainees and 12 control sea-level residents, at baseline and after 2-week exposure to high altitude (Pyramid Laboratory, Nepal, 5,050 m), 38 active lifestyle high-altitude natives (Sherpas) and 13 contemplative lifestyle high-altitude natives with practice of yoga-like respiratory exercises (Buddhist monks) studied at 5,050 m. At baseline, hypoxic ventilatory response (HVR), red blood cell count and hematocrit were lower in Caucasian yoga trainees than in controls. After 14 days at altitude, yoga trainees showed similar oxygen saturation, blood pressure, RR interval compared to controls, but lower HVR (-0.44 +/- 0.08 vs. -0.98 +/- 0.21 l/min/m/%SaO(2), P < 0.05), minute ventilation (8.3 +/- 0.9 vs. 10.8 +/- 1.6 l/min, P < 0.05), breathing rate (indicating higher ventilatory efficiency), and lower red blood cell count, hemoglobin, hematocrit, albumin, erythropoietin and soluble transferrin receptors. Hypoxic ventilatory response in monks was lower than in Sherpas (-0.23 +/- 0.05 vs. -0.63 +/- 0.09 l/min/m/%SaO(2), P < 0.05); values were similar to baseline data of yoga trainees and Caucasian controls, respectively. Red blood cell count and hematocrit were lower in monks as compared to Sherpas. In conclusion, Caucasian subjects practicing yoga maintain a satisfactory oxygen transport at high altitude, with minimal increase in ventilation and with reduced hematological changes, resembling Himalayan natives. Respiratory adaptations induced by the practice of yoga may represent an efficient strategy to cope with altitude-induced hypoxia.

Background: The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (nCPAP) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity., Objectives: To assess the effect of nCPAP treatment or placebo (sham nCPAP) on ventilatory control in patients with OSA., Setting: Sleep laboratory of Azienda Ospedaliera Garibaldi., Patients: Twenty-five patients with moderate-to-severe OSA., Design and Measurements: Patients were randomly assigned to either therapeutic nCPAP (use of optimal pressure, n = 15) or sham nCPAP (suboptimal pressure of 1 to 2 cm H2O, n = 10) in a double-blind fashion and treated for 1 month. A rebreathing test to assess ventilatory response to normocapnic hypoxia and normoxic hypercapnia was performed at basal condition and after 1 month of treatment., Results: The use of therapeutic nCPAP or sham nCPAP did not affect daytime percentage of arterial oxygen saturation (SaO2%) or end-tidal P(CO2). The normocapnic hypoxic ventilatory response was reduced after 1 month of treatment with nCPAP (the slope was 1.08 +/- 0.02 L/min/SaO2% at basal condition and 0.53 +/- 0.07 L/min/SaO2% after 1 month of treatment, p = 0.008) [mean +/- SD], but not in patients treated with sham nCPAP (slope, 0.83 +/- 0.09 L/min/SaO2% and 0.85 +/- 0.19 L/min/SaO2% at basal condition and after 1 month, respectively). The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both groups. No changes in ventilatory response to either hypoxia or hypercapnia were observed after a single night of nCPAP treatment., Conclusion: The ventilatory response to hypoxia is reduced during regular treatment, but not after short-term treatment, with nCPAP. Readjusted peripheral oxygen chemosensitivity during nCPAP treatment may be a side effect of both reduced sympathetic activity and increased baroreflex activity, or a possible continuous positive airway pressure-related mechanism leading to a reduced activation of autonomic nervous system per se.

A very high ventilatory response to hypoxia is believed necessary to reach extreme altitude without oxygen. Alternatively, the excessive ventilation could be counterproductive by exhausting the ventilatory reserve early on. To test these alternatives, 11 elite climbers (2004 Everest-K2 Italian Expedition) were evaluated as follows: 1) at sea level, and 2) at 5,200 m, after 15 days of acclimatisation at altitude. Resting oxygen saturation, minute ventilation, breathing rate, hypoxic ventilatory response, maximal voluntary ventilation, ventilatory reserve (at oxygen saturation = 70%) and two indices of ventilatory efficiency were measured. Everest and K2 summits were reached 29 and 61 days, respectively, after the last measurement. Five climbers summited without oxygen, the other six did not, or succeeded with oxygen (two climbers). At sea level, all data were similar. At 5,200 m, the five summiters without oxygen showed lower resting minute ventilation, breathing rate and ventilatory response to hypoxia, and higher ventilatory reserve and ventilatory efficiency, compared to the other climbers. Thus, the more successful climbers had smaller responses to hypoxia during acclimatisation to 5,200 m, but, as a result, had greater available reserve for the summit. A less sensitive hypoxic response and a greater ventilatory efficiency might increase ventilatory reserve and allow sustainable ventilation in the extreme hypoxia at the summit.

We investigated the interaction between hypoxia and hypercapnia on ventilation and on cerebro-cardio-vascular control. A group of 12 healthy subjects performed rebreathing tests to determine the ventilatory response to hypoxia, at different levels of carbon dioxide (CO(2)), and to normoxic hypercapnia. Oxygen saturation (SaO(2)), end-tidal CO(2) (et-CO(2)), minute ventilation, blood pressure, R-R interval and mid-cerebral artery flow velocity (MCFV) were continuously recorded. The hypoxic ventilatory response significantly increased under hypercapnia and decreased under hypocapnia (slopes L/min/% Sa O(2): -0.33 +/- 0.05, -0.74 +/- 0.02 and -1.59 +/- 0.3, p < 0.0001, in hypocapnia, normocapnia and hypercapnia, respectively). At similar degrees of ventilation, MCFV increased more markedly during normocapnic hypoxia than normoxic hypercapnia; the slopes linking MCFV to hypoxia remained unchanged at increasing levels of et-CO(2), whereas the regression lines were shifted upward. The R-R interval decreased more markedly during normocapnic hypoxia than normoxic hypercapnia and the arterial baroreflex sensitivity was decreased only by hypoxia. Cardiovascular responses to hypoxia were not affected by different levels of et-CO(2). We conclude that concomitant hypoxia and hypercapnia, while increasing ventilation synergistically, exert an additive effect on cerebral blood flow. Increased sympathetic activity (and reduced baroreflex sensitivity) is one of the mechanisms by which hypoxia stimulates cardiac sympathetic activity.

To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6 +/- 1.3% and 5.4 +/- 0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EE than in controls (83.7 +/- 0.3% versus 85.6 +/- 0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0 +/- 0.8% in EE and to 82.8 +/- 0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction in oxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for the increase in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.

Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD.

Objective: To investigate whether breathing more slowly modifies the sensitivity of the chemoreflex and baroreflex., Design Setting: University of Pavia, IRCCS Policlinico S. Matteo., Participants: Fifteen healthy individuals., Interventions: Progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were measured during spontaneous breathing and during a breathing rate fixed at 6 and 15 breaths per minute (b.p.m.)., Main Outcome Measures: Variations in chemo- and baroreflex sensitivity (by monitoring ventilation, oxygen saturation, end-tidal carbon dioxide, R-R interval and blood pressure) induced by different breathing rates., Results: Breathing at 6 b.p.m. depressed (P < 0.01) both hypoxic and hypercapnic chemoreflex responses, compared with spontaneous or 15 b.p.m. controlled breathing. Hypoxic and hypercapnic responses during spontaneous breathing correlated with baseline spontaneous breathing rate (r = -0.52 and r = +0.51, respectively; P = 0.05). Baroreflex sensitivity was greater (P < 0.05) during slow breathing at baseline and remained greater at end rebreathing., Conclusions: Slow breathing reduces the chemoreflex response to both hypoxia and hypercapnia. Enhanced baroreflex sensitivity might be one factor inhibiting the chemoreflex during slow breathing. A slowing breathing rate may be of benefit in conditions such as chronic heart failure that are associated with inappropriate chemoreflex activation.

Chemoreceptors are known to respond to changes in composition of the gases in the inspired air by changing pulmonary ventilation. Whereas, less known it is the role that they play in many both physiologic and pathologic conditions. In this review we do not only consider the anatomic and physiologic chemoreceptor features but also we analyse the relationship between chemoreflex and baroreflex in the cardiovascular control, their role in the pathogenesis of essential hypertension and in the increase of blood pressure in subjects affected by obstructive sleep apnea, their implication in the genesis of dyspnea in chronic heart failure and their role in pulmonary disease. In this review we also analyse the chemoreflex changes with relation to physiologic situations such as aging, obesity, exercise, training and high altitude. Three methods are described for the study of the chemoreflex function, but more attention is paid to the new rebreathing technic. The aim of this paper is to underline the interactions between chemoreceptors and cardiovascular system and to analyse their functional changes in both physiologic and pathologic conditions.

Objective: To assess the influence of different breathing patterns on autonomic cardiovascular modulation during acute exposure to altitude-induced hypoxia., Design: We measured relative changes in minute ventilation (VE), oxygen saturation (%SaO2), spectral analysis of RR interval and blood pressure, and response to stimulation of carotid baroreceptors (neck suction) at baseline and after acute (1 h) hypobaric hypoxia (equivalent to 5,000 m, in a hypobaric chamber)., Methods: We studied 19 human subjects: nine controls and 10 Western yoga trainees of similar age, while breathing spontaneously, at 15 breaths/min (controlled breathing) and during 'complete yogic breathing' (slow diaphragmatic + thoracic breathing, approximately 5 breaths/min) in yoga trainees, or simple slow breathing in controls., Results: At baseline %SaO2, VE and autonomic pattern were similar in both groups; simulated altitude increased VE in controls but not in yoga trainees; %SaO2 decreased in all subjects (P< 0.0001), but more in controls than in yoga trainees (17 versus 12%, 14 versus 9%, 14 versus 8%, all P< 0.05 or better, during spontaneous breathing, controlled breathing and yogic or slow breathing, respectively). Simulated altitude decreased RR interval (from 879 +/- 45 to 770 +/- 39, P < 0.01) and increased indices deducted from spectral analysis of heart rate variability (low frequency/high frequency (LF/HF) ratio from 1.6 +/- 0.5 to 3.2 +/- 1.1, P < 0.05) and systolic blood pressure (low-frequency fluctuations from 2.30 +/- 0.31 to 3.07 +/- 0.24 In-mmHg2, P< 0.05) in controls, indicating sympathetic activation; these changes were blunted in yoga trainees, and in both groups during slow or yogic breathing. No effect of altitude was seen on stimulation of carotid baroreceptors in both groups., Conclusions: Well-performed slow yogic breathing maintains better blood oxygenation without increasing VE (i.e. seems to be a more efficient breathing) and reduces sympathetic activation during altitude-induced hypoxia.

Aim: Interval hypoxic training was proposed as a technique for adapting hypoxia of various origins. Its effects on the hypoxic ventilatory response and on cardiovascular autonomic control are unknown., Methods and Results: We recorded ventilation, end-tidal oxygen (PETO2) and carbon dioxide partial pressures, RR interval and blood pressure during progressive isocapnic hypoxia, before and after 14 days of: (a) interval hypoxic training (three to four periods of 7 min progressive hypoxia in 1 h, each day) in 12 healthy men (training group); (b) breathing into a spirometer by six age-matched male controls. The hypoxic ventilatory response was estimated by the hyperbolic relationship between PETO2 and ventilation (shape factor A). Spectral analysis was used to characterize low- (mainly sympathetic) and high-frequency (vagal) cardiovascular fluctuations. Shape factor A was increased in the interval hypoxic training group from 268+/-59 to 984+/-196 l x mmHg(-1)(P<0.003), but not in the control group (from 525+/-180 to 808+/-245 l x mmHg(-1), P=ns). Before interval hypoxic training, progressive hypoxia decreased, to a similar extent in both groups, mean RR, RR variability and high-frequency power. After interval hypoxic training, RR still decreased significantly, but the decrease in RR variability and high-frequency power was no longer significant in the training group. No significant changes were observed in blood pressure fluctuations. No changes were observed in the control group., Conclusions: Two weeks of interval hypoxic training increased the hypoxic ventilatory response, in association with reduced vagal withdrawal during progressive hypoxia., (Copyright 2001 The European Society of Cardiology.)

Objectives: Regulation of the vascular system may limit physical performance and contribute to adaptation to high altitude. We evaluated vascular function in 10 Himalayan high-altitude natives and 10 recently acclimatized sea-level natives at an altitude of 5,050 m., Methods: We registered electrocardiogram, blood flow velocity in the common femoral artery, and blood pressure in the radial artery using non-invasive methods under baseline conditions, and during maximal vasodilation after 2 min leg occlusion. Vascular mechanics were characterized by estimating pulse wave velocity and input impedance., Results: Pulse wave velocity and parameters of input impedance did not differ between groups under baseline conditions. In the post-ischemic period, the ratio between maximal hyperemic and baseline blood flow velocity was significantly higher in the high-altitude than in the sea-level natives (5.7 +/- 2.5 versus 3.8 +/- 1.2, P < 0.05). The leg vascular resistance decreased in the post-occlusive period without differences between groups. Characteristic impedance decreased in the post-ischemic period by about one third of the baseline level without differences between groups. The post-ischemic decrease of input impedance modulus was more marked in the high-altitude than in the sea-level natives at low frequencies (28 +/- 12 versus 6.4 +/- 20% at 2 Hz, P < 0.01)., Conclusions: Our results demonstrate a superior ability to increase blood flow velocity as a response to muscular ischemia in high-altitude natives compared to sea-level natives. This phenomenon may be associated with a more effective coupling between blood pressure and blood flow which is probably caused by differences in conduit vessel function.

Ventilatory responses to isocapnic, progressive hypoxic rebreathing (HVR), in supine and sitting positions, lung ventilation and gas exchange while breathing air and during 5 min of breathing 11% O2 in N2 were studied in 12 healthy young (20-28 years), 5 old (57-73 years) male subjects, and in 7 male patients with Parkinson's disease (PD) aged 55-67 years. The piecewise linear approximation technique was used for evaluation of the ventilatory response curves, which allowed a separate analysis of slopes during minor and severe hypoxia. It has been shown that body position affected HVR. In the range of PETO2 from 60 to 35 mm Hg, the ventilatory response in the sitting position was higher than supine: in young persons by 43%, in healthy old persons by 76%, and in the PD patients by 211%. No significant differences in HVR to minor hypoxia (PETO2 from 100 to 60 mm Hg) were found in the 3 groups. During severe hypoxia (PETO2 from 60 to 35 mm Hg) the slope of minute ventilation versus O2 was 4.6 (supine) and 2.6 (sitting) times greater in healthy old men than PD patients' slopes. PD patients compared to old controls had 32% lower alveolar ventilation, 10% lower PETO2 and 15% elevation of PETCO2 while breathing air; similar differences were found while the patients were breathing 11% O2. The reduced alveolar ventilation under severe hypoxia in patients with PD could not be attributed to mechanical restriction of lung function. We suggest that the discrepancy in HVR under minor and severe hypoxia results from dysfunction in chemoreception associated with Parkinsonism.

Abstract: The relationship between work rate (WR) and its tolerable duration (t LIM) has not been investigated at high altitude (HA). At HA (5050m) and at sea level (SL), six subjects therefore performed symptom-limited cycle-ergometry: an incremental test (IET) and three constant-WR tests (% of IET WRmax, HA and SL respectively: WR1 70±8%, 74±7%; WR2 86±14%, 88±10%; WR3 105±13%, 104±9%). The power asymptote (CP) and curvature constant (W′) of the hyperbolic WR–t LIM relationship were reduced at HA compared to SL (CP: 81±21 vs. 123±38W; W′: 7.2±2.9 vs. 13.1±4.3kJ). HA breathing reserve (estimated maximum voluntary ventilation minus end-exercise ventilation) was also compromised (WR1: 25±25 vs. 50±18lmin−1; WR2: 4±23 vs. 38±23lmin−1; WR3: −3±18 vs. 32±24lmin−1) with near-maximal dyspnea levels (Borg) (WR1: 7.2±1.2 vs. 4.8±1.3; WR2: 8.8±0.8 vs. 5.3±1.2; WR3: 9.3±1.0 vs. 5.3±1.5). The CP reduction is consistent with a reduced O2 availability; that of W′ with reduced muscle–venous O2 storage, exacerbated by ventilatory limitation and dyspnea. [Copyright &y& Elsevier]

Headache is common in Cerro de Pasco (CP), Peru (altitude 4338 m) and was present in all patients with chronic mountain sickness (CMS) in CP reported here. Forty-seven percent of inhabitants report headache. Twenty-four percent of men have migraine with aura, with an average of 65 attacks a year.We assessed vasoreactivity of the cerebral vessels to CO2 by rebreathing and to NO by the administration of isosorbite dinitrate (IDN), a nitric oxide (NO) donor, using transcranial Doppler ultrasound in the middle cerebral artery (MCA) in natives of CP, some of whom suffered from CMS. We repeated the measurements in Lima (altitude 150 m) in the same subjects within 24 h of arrival.Vasodilatation in the middle cerebral artery supply territory in response to CO2 and NO, both physiologic vasodilators, is defective in Andean natives at altitude and in the same subjects at sea level.Incapacitating migraine can occur with impaired cerebral vasoreactivity to physiologic vasodilators. We propose that susceptibility to migraine might depend in part on gene expression with consequent alterations of endothelial function. [Copyright &y& Elsevier]