Hypocapnic Hypoxia Research Articles

P374 THE BAD COUSIN OF PULMONARY EMBOLISM: PRIMARY PULMONARY ARTERY SARCOMA

Abstract A young man of 29 years presented to the Emergency Room reporting worsening dyspnea for about 2 weeks. He had never had previous cardiovascular disease nor had risk factors for them. Hemodynamics were stable, but arterial blood gases showed hypocapnic hypoxia. The ECG revealed a S1Q3T3 pattern, incomplete right bundle branch block and signs of right ventricular overload. D–dimer was 4493 ng/ml. CT pulmonary angiogram (CTPA) showed massive bilateral embolism with thrombotic material in the right ventricle (RV) and almost complete obliteration of pulmonary trunk and main pulmonary arteries; moreover, there were subpleural nodularities in upper pulmonary lobes. Echocardiogram showed a dilated and hypokinetic RV, moderate tricuspid regurgitation with a sPAP of 80 mmHg, thrombotic pulmonary trunk obliteration and floating thrombi adhered to the tricuspid valve. UFH therapy was started. After ten days, there was no improvement in clinical status, echocardiography and CTPA. So, we decided to perform mechanical thrombectomy. In addition to thrombotic material, fibrous tissue was extracted and histologically analyzed. At the end of the procedure, the patient became hemodynamically unstable (BP 80/40 mmHg and HR 130 bpm) with dyspnea and tachypnea. ABG showed mixed acidosis. Right ventricular function worsened due to high afterload for the persistence of thrombotic material in the pulmonary trunk, defining a picture of obstructive shock. We started fibrinolysis (with rtPA), enoximone and norepinephrine, but asystole occurred and the patient eventually died. The histological examination revealed that the mass was a pleomorphic rhabdomyosarcoma of the pulmonary artery. Primary pulmonary artery sarcoma is an extremely rare and histologically heterogeneous disease. It develops mainly from great pulmonary arteries and then it grows up in the lumen of vessels. It may involve pulmonary valve and RV and invade pulmonary parenchyma and loco–regional lymph nodes. Diagnosis is challenging, because it simulates pulmonary embolism in clinical, echocardiographic and radiological presentation. Suspicion may arise from lack of benefit from anticoagulant therapy. Nodular pulmonary infiltrates are typical. There are two surgical approaches: pneumectomy or endarterectomy (as palliation). Prognosis is poor: mean survival of 1,5 month without therapy and 10 months with pneumectomy. In addition to the progression of the disease, death can occur for obstructive shock, as in our patient.

Neurovascular Coupling Remains Intact During Incremental Ascent to High Altitude (4240 m) in Acclimatized Healthy Volunteers.

Neurovascular coupling (NVC) is the temporal link between neuronal metabolic activity and regional cerebral blood flow (CBF), supporting adequate delivery of nutrients. Exposure to high altitude (HA) imposes several stressors, including hypoxia and hypocapnia, which modulate cerebrovascular tone in an antagonistic fashion. Whether these contrasting stressors and subsequent adaptations affect NVC during incremental ascent to HA is unclear. The aim of this study was to assess whether incremental ascent to HA influences the NVC response. Given that CBF is sensitive to changes in arterial blood gasses, in particular PaCO2, we hypothesized that the vasoconstrictive effect of hypocapnia during ascent would decrease the NVC response. 10 healthy study participants (21.7 ± 1.3 years, 23.57 ± 2.00 kg/m2, mean ± SD) were recruited as part of a research expedition to HA in the Nepal Himalaya. Resting posterior cerebral artery velocity (PCAv), arterial blood gasses (PaO2, SaO2, PaCO2, [HCO3-], base excess and arterial blood pH) and NVC response of the PCA were measured at four pre-determined locations: Calgary/Kathmandu (1045/1400 m, control), Namche (3440 m), Deboche (3820 m) and Pheriche (4240 m). PCAv was measured using transcranial Doppler ultrasound. Arterial blood draws were taken from the radial artery and analyzed using a portable blood gas/electrolyte analyzer. NVC was determined in response to visual stimulation (VS; Strobe light; 6 Hz; 30 s on/off × 3 trials). The NVC response was averaged across three VS trials at each location. PaO2, SaO2, and PaCO2 were each significantly decreased at 3440, 3820, and 4240 m. No significant differences were found for pH at HA (P > 0.05) due to significant reductions in [HCO3-] (P < 0.043). As expected, incremental ascent to HA induced a state of hypoxic hypocapnia, whereas normal arterial pH was maintained due to renal compensation. NVC was quantified as the delta (Δ) PCAv from baseline for mean PCAv, peak PCAv and total area under the curve (ΔPCAv tAUC) during VS. No significant differences were found for Δmean, Δpeak or ΔPCAv tAUC between locations (P > 0.05). NVC remains remarkably intact during incremental ascent to HA in healthy acclimatized individuals. Despite the array of superimposed stressors associated with ascent to HA, CBF and NVC regulation may be preserved coincident with arterial pH maintenance during acclimatization.

The Neurovascular Coupling Response Remains Intact During Incremental Ascent to High Altitude (4370m) in Acclimatized Healthy Volunteers

Neurovascular coupling (NVC) is the link between neuronal metabolic activity and regional cerebral blood flow. NVC is responsible for ensuring adequate delivery of nutrients (O2 and glucose) during periods of increased neuronal metabolic demand. Exposure to high‐altitude (HA) elicits ventilatory and acid‐base adjustments for maintaining blood pH. Acute exposure to HA causes hypoxic vasodilation. Hypoxia also drives a ventilatory response, inducing hypocapnia, a potent vasoconstrictor. Whether these dynamic and conflicting responses affect NVC during incremental ascent to HA is unclear.The aim of this project was to assess whether changes in arterial blood gases (ABGs) associated with ascent to HA influences the NVC response. Given that CBF is particularly sensitive to changes in PaCO2, we hypothesized that hypocapnic vasoconstriction during ascent would decrease the NVC response with ascent.10 healthy study participants (21.7±1.3 yrs, 70.46±13.65kg, mean±SD) were recruited as part of a research expedition to Everest base camp, Nepal. Resting posterior cerebral artery velocity (PCAv), ABGs (PaO2, PaCO2), SaO2, arterial blood pH and bicarbonate [HCO3−] were measured at four locations: Calgary (1045m; baseline; BL), Namche (3440m), Deboche (3820m) and Pheriche (4370m). Resting PCAv was measured using transcranial Doppler ultrasound. Arterial blood draws were taken from the radial artery and analysed using a portable blood gas/electrolyte analyser used to monitor changes in ABGs (PaCO2, PaO2, SaO2), pH and [HCO3−] during ascent. NVC was tested via visual stimulation (VS; Strobe light; 6Hz; 30sec on/off ×3). The NVC response was averaged across three VS trials at each location. NVC was quantified as the change (delta) in mean and peak PCAv from baseline, during VS.A one‐factor‐repeated measures analysis of variance (ANOVA) was used to assess for differences in baseline PCAv, NVC, ABGs, blood pH and [HCO3−] between locations. PaO2, PaCO2 and SaO2 were significantly decreased from BL at each altitude (P&lt;0.001, P&lt;0.016 and P&lt;0.013, respectively). No significant differences were found for pH at any location compared to BL (P&gt;0.05) due to reductions in arterial [HCO3−] (P&lt;0.043). No significant differences were found in baseline PCAv between locations (P&gt;0.05) or for mean or peak NVC responses (P&gt;0.085 and P&gt;0.08 respectively).As expected, incremental ascent to HA induced a state of hypoxic hypocapnia, as demonstrated by significant reductions in PaO2, SaO2 and PaCO2, whereas arterial pH was maintained via reductions in [HCO3−]. Our data suggests that NVC remains remarkably intact during incremental ascent to HA in healthy acclimatized individuals. Despite the array of superimposed stressors associated with ascent to HA, CBF and NVC regulation may be a unique function of arterial pH maintenance.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

LBPS 01-25 MECHANISMS OF PRESSOR AND BRADYCARDIC RESPONSES TO ACUTE EPISODIC HYPOXIA IN CONSCIOUS RATS

Objective: Pronounced pressor and bradyarrhythmic responses are frequently observed in patients with obstructive sleep apnea, and has been recapitulated in rodents subjected to intermittent hypoxia (Fletcher et al., Hypertension, 1992). Some substances such as acetylcholine (ACh) and adenosine are known to cause bradycardia, and have reported to be increased in the myocardium during experimental myocardial ischemia. We therefore tested the hypothesis that the adenosine-signaling, along with ACh signaling are responsible for the pressor and bradycardic responses observed during acute hypoxia. Design and Method: Male Wistar rats (n = 6) previously implanted with telemetry devices to monitor arterial blood pressure (TRM54P, TR-Millar) and heart rate were exposed to either 90-s of episodic hypocapnic (nadir inspired O2 fraction = 5%) or eucapnic (nadir inspired O2 fraction = 5%; peak inspired CO2 fraction = 5%) hypoxia in a sealed chamber. Results: Both acute hypocapnic and eucapnic hypoxia elicited a marked pressor response, followed by significant bradycardia; eucapnic hypoxia evoked greater cardiovascular responses. The observed cardiovascular responses were not mediated solely by the baroreflex, as α1-adrenergic receptor blockade with prazosin (2 mg/kg, ip) suppressed pressor only, but not bradycardic responses during acute hypoxia. Both M2-ACh receptor selective antagonist AF-DX116 (1 mg/kg, ip) and adenosine A1-R selective antagonist DPCPX (2 mg/kg, ip) significantly attenuated non-baroreflex mediated bradycardia. Interestingly, desensitization of TRPV1 expressing neurons by systemic capsaicin treatment (50 mg/kg ip) abolished both pressor and bradycardic responses in hypocapnic hypoxia but not in eucapnic hypoxia. Conclusions: Non-baroreflex mediated bradycardia during acute hypoxic hypoxia is mainly due to stimulations of both adenosine A1 and muscarinic ACh receptors. These signal pathways may play important roles in decelerating heart rate in order to protect heart against ATP depletion followed by cell death during severe tissue hypoxia. TRPV1-expressing neurons also play an important role in these cardiovascular responses as a peripheral O2 sensor during acute hypoxia.

Proton detection and breathing regulation by the retrotrapezoid nucleus.

We discuss recent evidence which suggests that the principal central respiratory chemoreceptors are located within the retrotrapezoid nucleus (RTN) and that RTN neurons are directly sensitive to [H(+) ]. RTN neurons are glutamatergic. In vitro, their activation by [H(+) ] requires expression of a proton-activated G protein-coupled receptor (GPR4) and a proton-modulated potassium channel (TASK-2) whose transcripts are undetectable in astrocytes and the rest of the lower brainstem respiratory network. The pH response of RTN neurons is modulated by surrounding astrocytes but genetic deletion of RTN neurons or deletion of both GPR4 and TASK-2 virtually eliminates the central respiratory chemoreflex. Thus, although this reflex is regulated by innumerable brain pathways, it seems to operate predominantly by modulating the discharge rate of RTN neurons, and the activation of RTN neurons by hypercapnia may ultimately derive from their intrinsic pH sensitivity. RTN neurons increase lung ventilation by stimulating multiple aspects of breathing simultaneously. They stimulate breathing about equally during quiet wake and non-rapid eye movement (REM) sleep, and to a lesser degree during REM sleep. The activity of RTN neurons is regulated by inhibitory feedback and by excitatory inputs, notably from the carotid bodies. The latter input operates during normo- or hypercapnia but fails to activate RTN neurons under hypocapnic conditions. RTN inhibition probably limits the degree of hyperventilation produced by hypocapnic hypoxia. RTN neurons are also activated by inputs from serotonergic neurons and hypothalamic neurons. The absence of RTN neurons probably underlies the sleep apnoea and lack of chemoreflex that characterize congenital central hypoventilation syndrome.

An integrated mathematical model of the human cardiopulmonary system: model validation under hypercapnia and hypoxia.

A novel integrated physiological model of the interactions between the cardiovascular and respiratory systems has been in development for the past few years. The model has hundreds of parameters and variables representing the physical and physiological properties of the human cardiopulmonary system. It can simulate many dynamic states and scenarios. The description of the model and the results in normal resting conditions were presented in a companion paper (Albanese A, Cheng L, Ursino M, Chbat NW.Am J Physiol Heart Circ Physiol 310: 2016; doi:10.1152/ajpheart.00230.2014), where model predictions were compared against average population data from literature. However, it is also essential to test the model in abnormal or pathological conditions to prove its consistency. Hence, in this paper, we concentrate on testing the cardiopulmonary model under hypercapnic and hypoxic conditions, by comparing model's outputs to population-averaged cardiorespiratory data reported in the literature. The utility of this comprehensive model is demonstrated by testing the internal consistency of the simulated responses of a significant number of cardiovascular variables (heart rate, arterial pressure, and cardiac output) and respiratory variables (tidal volume, respiratory rate, minute ventilation, alveolar O2 and CO2 partial pressures) over a wide range of perturbations and conditions; namely, hypercapnia at 3-7% CO2 levels and hypoxia at 7-9% O2 levels with controlled CO2(isocapnic hypoxia) and without controlled CO2(hypocapnic hypoxia). Finally, a sensitivity analysis is performed to analyze the role of the main cardiorespiratory control mechanisms triggered by hypercapnia and hypoxia.

Hypocapnic Hypoxia Silences the Retrotrapezoid Nucleus (RTN)

Rationale and objectivesIn conscious mammals, hypoxia produces respiratory alkalosis which is assumed to silence central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia changes the activity of the RTN, a likely CRC and chemoreflex integrator.MethodsRTN and nearby C1 neurons were bilaterally transduced with archaerhodopsin using a lentiviral vector (PRSx8‐ArchT‐EYFP‐LVV). We first showed that RTN neurons were silenced by green light in anesthetized rats. We then recorded the effect of RTN inhibition (10s) on breathing (fR, VT), BP, EEG and neck EMG in conscious rats exposed to normoxia, hypocapnic hypoxia (12 or 15% O2), isocapnic hypoxia (12% O2 + 3% CO2) or hypoxia in presence of acetazolamide (ACTZ). Arterial PO2, PCO2, pH and HCO3 were measured in each condition.ResultsIn normoxia RTN inhibition reduced breathing equally during non‐REM sleep and quiet wake and BP was unchanged. ΔfR was largest in normoxia, reduced in 15% O2, nul in 12% O2 and back to control (normoxia level) in normocapnic hypoxia.ΔVT followed the same trend. RTN inhibition caused much larger fR and VT reductions in ACTZ‐treated rats. Overall the bradypnea caused by RTN inhibition was linearly correlated with pHa (p &lt; 0.0002). Above pHa 7.5, no fR change was elicited.ConclusionsRTN neurons regulate breathing equally during sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN is silent above pHa 7.5 and increasingly active below this value. Under hypocapnic hypoxia carotid body stimulation drives breathing via pathways that bypass RTN. ACTZ increases breathing by activating RTN. Funding: HL074011 (PGG), 5T32HL007284‐38 (TMB).

Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.

The Effect of Adding CO2 to Hypoxic Inspired Gas on Cerebral Blood Flow Velocity and Breathing during Incremental Exercise

Hypoxia increases the ventilatory response to exercise, which leads to hyperventilation-induced hypocapnia and subsequent reduction in cerebral blood flow (CBF). We studied the effects of adding CO2 to a hypoxic inspired gas on CBF during heavy exercise in an altitude naïve population. We hypothesized that augmented inspired CO2 and hypoxia would exert synergistic effects on increasing CBF during exercise, which would improve exercise capacity compared to hypocapnic hypoxia. We also examined the responsiveness of CO2 and O2 chemoreception on the regulation ventilation (E) during incremental exercise. We measured middle cerebral artery velocity (MCAv; index of CBF), E, end-tidal PCO2, respiratory compensation threshold (RC) and ventilatory response to exercise (E slope) in ten healthy men during incremental cycling to exhaustion in normoxia and hypoxia (FIO2 = 0.10) with and without augmenting the fraction of inspired CO2 (FICO2). During exercise in normoxia, augmenting FICO2 elevated MCAv throughout exercise and lowered both RC onset andE slope below RC (P<0.05). In hypoxia, MCAv and E slope below RC during exercise were elevated, while the onset of RC occurred at lower exercise intensity (P<0.05). Augmenting FICO2 in hypoxia increased E at RC (P<0.05) but no difference was observed in RC onset, MCAv, or E slope below RC (P>0.05). The E slope above RC was unchanged with either hypoxia or augmented FICO2 (P>0.05). We found augmenting FICO2 increased CBF during sub-maximal exercise in normoxia, but not in hypoxia, indicating that the ‘normal’ cerebrovascular response to hypercapnia is blunted during exercise in hypoxia, possibly due to an exhaustion of cerebral vasodilatory reserve. This finding may explain the lack of improvement of exercise capacity in hypoxia with augmented CO2. Our data further indicate that, during exercise below RC, chemoreception is responsive, while above RC the ventilatory response to CO2 is blunted.

Hypocapnia is associated with increased upper airway expiratory resistance during sleep

We hypothesized that hypocapnia is responsible for increased expiratory resistance during NREM sleep. Hypocapnia was induced by hypoxic hyperventilation in 21 subjects (aged 29.4 ± 7.8 yrs, 10 women, BMI 24.4 ± 4.3 kg/m(2)). Isocapnic hypoxia was induced in 12 subjects of whom, 6 underwent hypocapnic hypoxia in the same night. Upper airway resistance (R(UA)) was measured at the linear pressure-flow relationship during inspiration and expiration. Inspiratory flow limitation (IFL) was defined as the dissociation in pressure-flow relationship. (1) Expiratory R(UA) increased during hypocapnic but not isocapnic hypoxia relative to control (11.0 ± 5.6 vs. 8.2 ± 3.6 cm H(2)O/L/s; p < 0.05, and 11.45.0 vs. 10.94.4 cm H(2)O/L/s; p = NS, respectively). (2) No gender difference was found in R(UA) (p = NS). (3) Increased expiratory R(UA) correlated with the IFL change during hypocapnic but not isocapnic hypoxia. (4) No changes were noted in inspiratory R(UA) or IFL. Expiratory R(UA) increased during hypocapnia and was associated with IFL, indicating upper airway narrowing. Gender does not influence the upper airway response to hypocapnic hypoxia.

The effect of oxygen on dynamic cerebral autoregulation: critical role of hypocapnia

Hypoxia is known to impair cerebral autoregulation (CA). Previous studies indicate that CA is profoundly affected by cerebrovascular tone, which is largely determined by the partial pressure of arterial O(2) and CO(2). However, hypoxic-induced hyperventilation via respiratory chemoreflex activation causes hypocapnia, which may influence CA independent of partial pressure of arterial O(2). To identify the effect of O(2) on dynamic cerebral blood flow regulation, we examined the influence of normoxia, isocapnia hyperoxia, hypoxia, and hypoxia with consequent hypocapnia on dynamic CA. We measured heart rate, blood pressure, ventilatory parameters, and middle cerebral artery blood velocity (transcranial Doppler). Dynamic CA was assessed (n = 9) during each of four randomly assigned respiratory interventions: 1) normoxia (21% O(2)); 2) isocapnic hyperoxia (40% O(2)); 3) isocapnic hypoxia (14% O(2)); and 4) hypocapnic hypoxia (14% O(2)). During each condition, the rate of cerebral regulation (RoR), an established index of dynamic CA, was estimated during bilateral thigh cuff-induced transient hypotension. The RoR was unaltered during isocapnic hyperoxia. Isocapnic hypoxia attenuated the RoR (0.202 +/- 0.003/s; 27%; P = 0.043), indicating impairment in dynamic CA. In contrast, hypocapnic hypoxia increased RoR (0.444 +/- 0.069/s) from normoxia (0.311 +/- 0.054/s; +55%; P = 0.041). These findings indicated that hypoxia disrupts dynamic CA, but hypocapnia augments the dynamic CA response. Because hypocapnia is a consequence of hypoxic-induced chemoreflex activation, it may provide a teleological means to effectively maintain dynamic CA in the face of prevailing arterial hypoxemia.

Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxia

Augmented breaths, or "sighs," commonly destabilize respiratory rhythm, precipitating apneas and variability in the depth and rate of breathing, which may then exacerbate sleep-disordered breathing in vulnerable individuals. We previously demonstrated that hypocapnia is a unique condition associated with a high prevalence of augmented breaths during exposure to hypoxia; the prevalence of augmented breaths during hypoxia can be returned to normal simply by the addition of CO(2) to the inspired air. We hypothesized that counteracting the effect of respiratory alkalosis during hypocapnic hypoxia by blocking carbonic anhydrase would yield a similar effect. We, therefore, investigated the effect of acetazolamide on the prevalence of augmented breaths in the resting breathing cycle in five awake, adult male rats. We found a 475% increase in the prevalence of augmented breaths in animals exposed to hypocapnic hypoxia compared with room air. Acetazolamide treatment (100 mg/kg i.p. bid) for 3 days resulted in a rapid and potent suppression of the generation of augmented breaths during hypoxia. Within 90 min of the first dose of acetazolamide, the prevalence of augmented breaths in hypoxia fell to levels that were no greater than those observed in room air. On cessation of treatment, exposure to hypocapnic hypoxia once again caused a large increase in the prevalence of augmented breaths. These results reveal a novel means by which acetazolamide acts to stabilize breathing and may help explain the beneficial effects of the drug on breathing stability at altitude and in patients with central forms of sleep-disordered breathing.

Sensitivity of Cerebral Blood Flow to Hypoxia and Hypoxic Hypocapnia in Ethiopian Highlanders

Sensitivity of Cerebral Blood Flow to Hypoxia and Hypoxic Hypocapnia in Ethiopian Highlanders

Cerebrovascular Responses to Hypoxia and Hypocapnia in Ethiopian High Altitude Dwellers

Cerebrovascular responses to hypoxia and hypocapnia in Peruvian altitude dwellers are impaired. This could contribute to the high incidence of altitude-related illness in Andeans. Ethiopian high altitude dwellers may show a different pattern of adaptation to high altitude. We aimed to examine cerebral reactivity to hypoxia and hypocapnia in healthy Ethiopian high altitude dwellers. Responses were compared with our previous data from Peruvians. We studied 9 Ethiopian men at their permanent residence of 3622 m, and one day after descent to 794 m. We continuously recorded cerebral blood flow velocity (CBFV; transcranial Doppler). End-tidal oxygen (P(ET)o(2)) was decreased from 100 mm Hg to 50 mm Hg with end-tidal carbon dioxide (P(ET)co(2)) clamped at the subject's resting level. P(ET)co(2) was then manipulated by voluntary hyper- and hypoventilation, with P(ET)o(2) clamped at 100 mm Hg (normoxia) and 50 mm Hg (hypoxia). During spontaneous breathing, P(ET)co(2) increased after descent, from 38.2+/-1.0 mm Hg to 49.8+/-0.6 mm Hg (P<0.001). There was no significant response of CBFV to hypoxia at either high (-0.19+/-3.1%) or low (1.1+/-2.9%) altitudes. Cerebrovascular reactivity to normoxic hypocapnia at high and low altitudes was 3.92+/-0.5%.mm Hg(-1) and 3.09+/-0.4%.mm Hg(-1); reactivity to hypoxic hypocapnia was 4.83+/-0.7%.mm Hg(-1) and 2.82+/-0.5%.mm Hg(-1). Responses to hypoxic hypocapnia were significantly smaller at low altitude. The cerebral circulation of Ethiopian high altitude dwellers is insensitive to hypoxia, unlike Peruvian high altitude dwellers. Cerebrovascular responses to P(ET)co(2) were greater in Ethiopians than Peruvians, particularly at high altitude. This, coupled with their high P(ET)co(2) levels, would lead to high cerebral blood flows, and may be advantageous for altitude living.

Medullary Respiratory Neural Activity During Hypoxia in NREM and REM Sleep in the Cat

Intact unanesthetized cats hyperventilate in response to hypocapnic hypoxia in both wakefulness and sleep. This hyperventilation is caused by increases in diaphragmatic activity during inspiration and expiration. In this study, we recorded 120 medullary respiratory neurons during sleep in hypoxia. Our goal was to understand how these neurons change their activity to increase breathing efforts and frequency in response to hypoxia. We found that the response of medullary respiratory neurons to hypoxia was variable. While the activity of a small majority of inspiratory (58%) and expiratory (56%) neurons was increased in response to hypoxia, the activity of a small majority of preinspiratory (57%) neurons was decreased. Cells that were more active in hypoxia had discharge rates that averaged 183% (inspiratory decrementing), 154% (inspiratory augmenting), 155% (inspiratory), 230% (expiratory decrementing), 191% (expiratory augmenting), and 136% (expiratory) of the rates in normoxia. The response to hypoxia was similar in non-rapid-eye-movement (NREM) and REM sleep. Additionally, changes in the profile of activity were observed in all cell types examined. These changes included advanced, prolonged, and abbreviated patterns of activity in response to hypoxia; for example, some inspiratory neurons prolonged their discharge into expiration during the postinspiratory period in hypoxia but not in normoxia. Although changes in activity of the inspiratory neurons could account for the increased breathing efforts and activity of the diaphragm observed during hypoxia, the mechanisms responsible for the change in respiratory rate were not revealed by our data.

Cerebrovascular responses to hypoxia and hypocapnia in high‐altitude dwellers

Cerebral blood flow is known to increase in response to hypoxia and to decrease with hypocapnia. It is not known, however, whether these responses are altered in high-altitude dwellers who are not only chronically hypoxic and hypocapnic, but also polycythaemic. Here we examined cerebral blood flow responses to hypoxia and hypocapnia, separately and together, in Andean high-altitude dwellers, including some with chronic mountain sickness (CMS), which is characterized by excessive polycythaemia. Studies were carried out at high altitude (Cerro de Pasco (CP), Peru; barometric pressure (P(B)) 450 mmHg) and repeated, following relief of the hypoxia, on the day following arrival at sea level (Lima, Peru; P(B) 755 mmHg). We compared these results with those from eight sea-level residents studied at sea level. In nine high-altitude normal subjects (HA) and nine CMS patients, we recorded middle cerebral artery mean blood flow velocity (MCAVm) using transcranial Doppler ultrasonography, and expressed responses as changes from baseline. MCAVm responses to hypoxia were determined by changing end-tidal partial pressure of oxygen (P(ET,O2)) from 100 to 50 mmHg, with end-tidal partial pressure of carbon dioxide clamped. MCAVm responses to hypocapnia were studied by voluntary hyperventilation with (P(ET,O2)) clamped at 100 and 50 mmHg. There were no significant differences between the cerebrovascular responses of the two groups to any of the interventions at either location. In both groups, the MCAVm responses to hypoxia were significantly greater at Lima than at CP (HA, 12.1 +/- 1.3 and 6.1 +/- 1.0%; CMS, 12.5 +/- 0.8 and 5.6 +/- 1.2%; P < 0.01 both groups). The responses at Lima were similar to those in the sea-level subjects (13.6 +/- 2.3%). The responses to normoxic hypocapnia in the altitude subjects were also similar at both locations and greater than those in sea-level residents. During hypoxia, both high-altitude groups showed responses to hypocapnia that were significantly smaller at Lima than at CP (HA, 2.17 +/- 0.23 and 3.29 +/- 0.34% mmHg(-1), P < 0.05; CMS, 1.87 +/- 0.16 and 3.23 +/- 0.24% mmHg(-1); P < 0.01). The similarity of the results from the two groups of altitude dwellers suggests that haematocrit is unlikely to greatly affect cerebrovascular reactivity to hypoxia and hypocapnia. The smaller vasodilatation to hypoxia and larger vasoconstriction to hypoxic hypocapnia at high altitude suggest that cerebrovascular responses may be impaired at the high altitude, i.e. a maladaptation. The changes in the responses within less than 24 h at sea level indicate that this impairment is rapidly reversible.

Time-dependent modulation of carotid body afferent activity during and after intermittent hypoxia

The ventilatory response to several minutes of hypoxia consists of various time-dependent phenomena, some of which occur during hypoxia (e.g., short-term depression), whereas others appear on return to normoxia (e.g., posthypoxic frequency decline). Additional phenomena can be elicited by acute, intermittent hypoxia (e.g., progressive augmentation, long-term facilitation). Current data suggest that these phenomena originate centrally. We tested the hypothesis that carotid body afferent activity undergoes time-dependent modulation, consistent with a direct role in these ventilatory phenomena. Using an in vitro rat carotid body preparation, we found that 1) afferent activity declined during the first 5 min of severe (40 Torr Po(2)), moderate (60 Torr Po(2)), or mild (80 Torr Po(2)) hypoxia; 2) after return to normoxia (100 Torr Po(2)) and after several minutes of moderate or severe hypoxia, afferent activity was transiently reduced compared with prehypoxic levels; and 3) with successive 5-min bouts of mild, moderate, or severe hypoxia, afferent activity during bouts increased progressively. We call these phenomena sensory hypoxic decline, sensory posthypoxic decline, and sensory progressive augmentation, respectively. These phenomena were stimulus specific: similar phenomena were not seen with 5-min bouts of normoxic hypercapnia (100 Torr Po(2) and 50-60 Torr Pco(2)) or hypoxic hypocapnia (60 Torr Po(2) and 30 Torr Pco(2)). However, bouts of either normoxic hypercapnia or hypocapnic hypoxia resulted in sensory long-term facilitation. We suggest time-dependent carotid body activity acts in parallel with central mechanisms to shape the dynamics of ventilatory responses to respiratory chemostimuli.

A Computational Model of the Human Respiratory Control System: Responses to Hypoxia and Hypercapnia

Although recent models offer realistic descriptions of the human respiratory system, they do not fulfill all characteristics of a stable, comprehensive model, which would allow us to evaluate a variety of hypotheses on the control of breathing. None of the models offer completely realistic descriptions of the gaseous components of blood, and their description of delays associated with the propagation of changes in partial pressures of respiratory gases between the lungs and brain and tissue compartments have shortcomings. These deficiencies are of particular significance in an analysis of periodic breathing where dynamic alterations in the circulation and in blood chemical stimuli are likely to assume considerable importance. We developed a computational model of the human respiratory control system which is an extension of the model of Grodins et al. (F. S. Grodins, J. Buell, and A. J. Bart. J. Appl. Physiol. 22(2):260-276, 1967). Our model combines an accurate description of a plant with a novel controller design that treats minute ventilation as a sum of central and peripheral components. To ensure that the developed model is stable and sufficiently robust to act as a test platform for hypotheses about control of ventilation, we simulated a series of challenging physiological conditions, specifically, the response to eucapnic hypoxia, the development of periodic breathing during hypocapnic hypoxia, and the open loop response to hypercapnic step. These steady state and transient responses of the model were compared with results from similar physiological experiments. Our simulations suggest that for a particular value of arterial Po2, the steady state difference between brain and arterial Pco2 remains approximately constant as a function of arterial Pco2. The model indicates that hypoxia-induced changes in cerebral blood flow contribute significantly to the ventilatory decline observed during eucapnic hypoxia. The model exibits hypoxic-induced periodic breathing, which can be eliminated by small increases in F(I)co2. The dynamics of the model's open loop hypercapnic ventilatory response approximates experimental data well.

Morphological changes in the rat carotid body 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia.

Morphological changes in the rat carotid bodies 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia (10% O2 for 8 weeks) were examined by means of morphometry and immunohistochemistry. The rat carotid bodies after 8 weeks of hypoxic exposure were enlarged several fold with vascular expansion. The carotid bodies 1 and 2 weeks after the termination of 8 weeks of hypoxic exposure were diminished in size, although their diameter remained larger than the normoxic controls. The expanded vasculature in chronically hypoxic carotid bodies returned to the normoxic control state. In the carotid bodies 1 week after the termination of chronic hypoxia, the density of NPY fibers was remarkably increased and that of VIP fibers was dramatically decreased in comparison with the density in chronically hypoxic carotid bodies. In the carotid bodies 2 and 4 weeks after the termination of hypoxia, the density of SP and CGRP fibers was gradually increased. In the carotid bodies 8 weeks after the termination of hypoxia, the appearance of the carotid body returned to a nearly normoxic state, and the density of SP, CGRP, VIP, and NPY fibers also recovered to that of normoxic controls. These results suggest that the morphological changes in the recovering carotid bodies start at a relatively early period after the termination of chronic hypoxia, and a part of these processes may be under the control of peptidergic innervation.

Modelling study of the acute cardiovascular response to hypocapnic hypoxia in healthy and anaemic subjects.

The present study analyses the cardiovascular response to acute hypocapnic hypoxia (simulating the effect of respiration at high altitude) both in healthy, unacclimatised subjects and in subjects with moderate anaemia, by means of a mathematical model of short-term cardiovascular regulation. During severe hypoxia, cardiac output and heart rate (HR) exhibit a significant increase compared with the basal level (cardiac output: +90%; HR: +64%). Systemic arterial pressure remains quite constant or shows a mild increase. Coronary blood flow increases dramatically (+200%), thus maintaining a constant oxygen delivery to the heart. However, blood oxygen utilisation in the heart augments, to fulfil the increased power of the cardiac pump during hypoxia. Cerebral blood flow rises only at very severe hypoxia but, owing to the vasoconstrictory effect of hypocapnia, its increase (+80%) is insufficient to maintain oxygen delivery to the brain. The model suggests that a critical level for the aerobic metabolism in these organs (heart and brain) is reached at an oxygen partial pressure in arterial blood (PaO2) of approximately 25 mmHg. Moderate anaemia during normoxia is compensated by an increase in cardiac output (+22%), a decrease in total peripheral resistance (-30%) and an increase in O2 extraction from blood (+40%). As cardiovascular regulation mechanisms are already recruited in anaemic subjects at rest, their action soon becomes exhausted during hypocapnic hypoxia. Critical levels for vital functions are already reached at a PaO2 of approximately 45 mmHg.