Eucapnic Hypoxia Research Articles

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia.

The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end-organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady-state eucapnic hypoxia were measured in a cohort of 82 middle-aged individuals. Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals. It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required. Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor-driven levels of sympathetic nervous system activity and respiratory drive. Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor-driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady-state eucapnic hypoxia in middle-aged men and women (n = 82) with continuous positive airway pressure-treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (-35 ± 14% and -42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test-retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady-state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.

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.

Can intravenous endothelin-1 be used to enhance hypoxic pulmonary vasoconstriction in healthy humans?

BackgroundHypoxic pulmonary vasoconstriction (HPV) helps match pulmonary perfusion to ventilation. The peptide endothelin-1 (ET-1) may be involved in the cellular mechanisms of this response. We hypothesized that increasing plasma ET-1 concentration during hypoxia would enhance HPV in humans and might represent a strategy for improving gas exchange during single-lung anaesthesia or respiratory disease. MethodsNine healthy volunteers were each exposed twice to a 7-h protocol consisting of 1 h breathing air, 4 h of eucapnic hypoxia (end-tidal Po2, 50 mm Hg), and 2 h of eucapnic euoxia (end-tidal Po2, 100 mm Hg). Volunteers received a 7-h i.v. infusion of ET-1 during one protocol (1.0–2.5 ng kg−1 min−1) and normal saline during the other. At intervals of 30–60 min, cardiac output and the maximum tricuspid pressure gradient during systole (ΔPmax, an index of HPV) were measured using Doppler echocardiography, systemic arterial pressure was measured using sphygmomanometry, and plasma samples were obtained to determine ET-1 concentration. ResultsDuring hypoxia, ΔPmax increased for around 2 h before reaching a plateau. Compared with saline, ET-1 had no effect on ΔPmax, either at baseline or during hypoxia. ET-1 infusion slightly increased diastolic arterial pressure and reduced cardiac output, but had no specific effect on the change in these variables during hypoxia. During the final 1 h of hypoxia, plasma ET-1 concentration was 1.7 (0.4) pg ml−1 [mean (sd)] in the saline protocol and 21.9 (12.2) pg ml−1 in the ET-1 protocol. ConclusionsET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia.

Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity

Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension (PH) and right heart failure, similar to chronic sustained hypoxia (CH). Supplemental CO(2), however, attenuates hypoxic PH. We therefore hypothesized that, similar to CH, IH elicits PH and associated increases in arterial endothelial nitric oxide synthase (eNOS) expression, ionomycin-dependent vasodilation, and receptor-mediated pulmonary vasoconstriction. We further hypothesized that supplemental CO(2) inhibits these responses to IH. To test these hypotheses, we measured eNOS expression by Western blot in intrapulmonary arteries from CH (2 wk, 0.5 atm), hypocapnic IH (H-IH) (3 min cycles of 5% O(2)/air flush, 7 h/day, 2 wk), and eucapnic IH (E-IH) (3 min cycles of 5% O(2), 5% CO(2)/air flush, 7 h/day, 2 wk) rats and their respective controls. Furthermore, vasodilatory responses to the calcium ionophore ionomycin and vasoconstrictor responses to the thromboxane mimetic U-46619 were measured in isolated saline-perfused lungs from each group. Hematocrit, arterial wall thickness, and right ventricle-to-total ventricle weight ratios were additionally assessed as indexes of polycythemia, arterial remodeling, and PH, respectively. Consistent with our hypotheses, E-IH resulted in attenuated polycythemia, arterial remodeling, RV hypertrophy, and eNOS upregulation compared with H-IH. However, in contrast to CH, neither H-IH nor E-IH increased ionomycin-dependent vasodilation. Furthermore, H-IH and E-IH similarly augmented U-46619-induced pulmonary vasoconstriction but to a lesser degree than CH. We conclude that maintenance of eucapnia decreases IH-induced PH and upregulation of arterial eNOS. In contrast, increases in pulmonary vasoconstrictor reactivity following H-IH are unaltered by exposure to supplemental CO(2).

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (DeltaPmax), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6-24 h to measure spontaneous diurnal variations in DeltaPmax and cardiac output. Cardiac output varied by up to approximately 2.5 l/min; DeltaPmax varied little with cardiac output [0.61+/-0.74 (SD) mmHg min l(-1)]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal PO2 = 50 mmHg) for 8 h. In this group DeltaPmax rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in DeltaPmax during air breathing with changes in DeltaPmax during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in DeltaPmax during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of DeltaPmax to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.

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.

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

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

Ascorbic Acid Enhances Hypoxic Ventilatory Reactivity in Elderly Subjects

The reducing properties of ascorbic acid in the carotid body make it a likely modifier of hypoxia-sensing mechanisms. This open-label study aimed to determine the effect of ascorbic acid on the hypoxic ventilatory response (HVR) in a population of elderly women, in whom both hypoxic reactivity and ascorbic acid levels may be deficient. We examined the HVR to progressive eucapnic hypoxia in 18 healthy females aged 60-80 years, before and after 10 days' ascorbic acid supplementation, given as a sustained release preparation of 1 g twice daily. Respiratory variables were recorded breath by breath, and hypoxic sensitivity was assessed from the linear slopes of minute ventilation and mouth occlusion pressure plotted against oxygen saturation. We found that ascorbic acid increased the HVR by a mean of 44%, this effect being driven by a higher occlusion pressure. We conclude that augmentation of hypoxic reactivity by ascorbic acid may have therapeutic potential in pathologies associated with hypoxia, which frequently develop in old age.

Acute hypoxia activates human 8–12 Hz physiological tremor

Hypoxia causes arousal. Therefore, we hypothesized that hypoxia activates the human somatomotor system and should augment tremor. We determined the effects of hypoxia, PET O2=45±2.2 mm Hg, hypocapnia, and the hypocapnic–hypoxic interaction on finger tremor during elastic loading. A total of 12 healthy male volunteers were studied during five conditions: eupnea, hypocapnic hypoxia, eucapnic hypoxia, hypocapnic normoxia, and eucapnic normoxia. Acceleration power spectra were computed to quantify 8–12 Hz tremor. Hypoxia significantly augmented 8–12 Hz physiological tremor ( P=0.002). Furthermore, six subjects (50%) exhibited significantly more tremor during hypocapnic hypoxia (hH) than during eucapnic hypoxia (eH). We conclude that acute hypoxia augments 8–12 Hz physiological tremor, and hypocapnia further augments this tremor in some subjects. As such, hypoxic tremor is activated physiological tremor, and entrainment of spinal α-motoneuron activity may be the final common pathway.

Ventilatory responses to sustained eucapnic hypoxia in healthy males during wakefulness and NREM sleep.

The effects of sustained eucapnic hypoxia (SEH, 20 minutes SaO2, approximately 80%) on ventilation and supraglottic airflow resistance (Rua) plus genioglossal (gg) and diaphragmatic (di) electromyograms (EMGs) were compared during wakefulness and nonrapid eye movement (NREM) sleep in six healthy normal male subjects. Early augmentation of ventilation was followed by decline or roll-off in both states. The augmentation of ventilation was less in sleep than wakefulness (e.g., after 5 minutes hypoxia, 140% and 167% of baseline, respectively, p < 0.05). This appeared to be due to three factors: 1) sleep-related increases in Rua [the ventilatory responses to SEH (sleep vs. awake) were inversely related to changes in Rua (sleep vs. awake) (p < 0.05)], 2. reduced central neural drive (inspiratory phasic EMG di after 5 minutes SEH, 111% and 121% of baseline, p < 0.05), and 3) failure to increase respiratory frequency during SEH sleep. There was also a nonsignificant trend to a biphasic response in EMG gg and a small increase in Rua during SEH.

Ventilatory-control abnormalities in familial sleep apnea.

The role of ventilatory-control abnormalities in predisposing to familial sleep-disordered breathing (SDB) was assessed in 31 subjects 28 +/- 10 yr of age (mean +/- SD). Subjects with (n = 10) and without SDB (n = 12) were recruited from 13 families having two or more members with SDB. Nine age- and gender-matched controls were recruited from families having no member with SDB. Respiratory responses to eucapnic hypoxia, and ventilatory and occlusion pressure responses to hyperoxic hypercapnia with and without added resistive loads (6.5 cm H2O/L/s), were assessed through rebreathing. Age, FEV1, and FVC did not differ among the groups. Hypoxic responses (delta VE/delta SaO2) were significantly lower among the first-degree relatives of SDB families than among controls (-0.76 +/- 0.47 L/min/% SaO2, and -1.32 +/- 0.92 L/min/% SaO2, respectively, p < 0.05). Respiratory responses to hypercapnia during unloaded conditions were similar among the groups. With resistive loading, inspiratory impedance, as measured through the relationship of mouth occlusion pressure (P100) to inspiratory flow (VT/TI), increased with increasing hypercapnia to a greater extent in members of SDB families than in controls (0.169 +/- 0.054 cm H2O/L/min versus 0.122 +/- 0.051, respectively, p < 0.05). These data suggest that familial SDB may be based partly on a familial abnormality in ventilatory control associated with blunting of the hypoxic ventilatory response. The greater increase in impedance during inspiratory loading in members of affected families also suggests a propensity for dynamic airway narrowing.

Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats

Using a rat model, we investigated whether episodic eucapnic hypoxia was a more potent stimulus to acute blood pressure (BP) elevation and bradycardia than episodic hypocapnic hypoxia. We also investigated the role of sympathetic and parasympathetic nervous system in this cardiovascular response. Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats were exposed to repetitive 30-s cycles of hypocapnic or eucapnic hypoxia before and after intravenous injection of the alpha1-adrenergic blocker prazosin, alpha2-adrenergic blocker yohimbine, or atropine. Eucapnic hypoxia caused a threefold elevation in systolic BP from baseline (83.5 +/- 3.5 mmHg in WKY, 70.6 +/- 4.6 mmHg in SD) and greater bradycardia (-178 +/- 20 beats/min in WKY, -178 +/- 21 beats/min in SD) compared with hypocapnic hypoxia (29.8 +/- 3.6 mmHg and -43 +/- 15 beats/min in WKY, 19.0 +/- 4.1 mmHg and -45 +/- 12 beats/min in SD). After prazosin, the BP increase from eucapnic hypoxia was blunted, yohimbine showed no effect, and atropine blocked the bradycardia. Direct measurement of sympathetic nerve activity confirmed that adding CO2 to the hypoxic gas mixture caused a 61% increase in sympathetic nerve activity. WKY rats seem more vulnerable than SD rats to both hypoxia exposures in terms of the elevation in BP. We conclude that, in the rat, eucapnic hypoxia is a more potent stimulus to acute BP elevation and bradycardia than is hypocapnic hypoxia. An increased sympathetic tone appears to be involved in the BP response to acute episodic hypoxia.

Pulmonary artery pressure response to hypoxia in sleep apnea.

The pulmonary artery pressure (Ppa) responses to short runs of acute hypoxia at two different levels of end-tidal CO2 were measured in nine normal subjects and in 20 patients with moderate to severe obstructive sleep apnea (OSA). In normal subjects the mean increase in Ppa in response to eucapnic hypoxia was 8 +/- 2 mm Hg (SEM) and was not different from the response to hypercapnic hypoxia (9 +/- 2 mm Hg, p > 0.2). In patients with OSA, the mean increase of Ppa was 8 +/- 1 mm Hg to eucapnic hypoxia, and the response to hypercapnic hypoxia was higher at 10 +/- 1 mm Hg (p = 0.01). Pulmonary pressor response to hypoxia was augmented (> 10 mm Hg) by hypercapnia in four of 20 patients with OSA but in none of the normal subjects. Normoxic hypercapnia alone was a weak stimulus, increasing Ppa by > 5 mm Hg in only two of nine patients with OSA studied. In conclusion, Ppa increases in both normal subjects and patients with OSA exposed to a ramp of acute isocapnic hypoxia. There were clear interindividual differences in pulmonary artery response. Hypercapnia did not produce clinical significant changes in Ppa in either group.

Effect of episodic eucapnic and hypocapnic hypoxia on systemic blood pressure in hypertension-prone rats.

Repetitive episodic (18-24 s twice per minute) hypocapnic hypoxia (HH) administered chronically (7 h/day, 35 days) to Sprague-Dawley or Wistar-Kyoto rats results in a sustained increase in daytime blood pressure (BP). We examined acute and chronic BP response to episodic HH and eucapnic hypoxia (EH) in borderline hypertensive rats [first generation (F1) cross between spontaneously hypertensive and Wistar-Kyoto rats]. We hypothesized that episodic HH and EH would create a greater increase in acute and chronic BP in this breed of rat than in previously studied strains. We also examined neural mechanisms by which BP changes from hypoxia are induced. BP and heart rate were examined acutely in nine F1 rats during baseline, HH, EH, EH with prazosin, and EH with prazosin and atropine. Five groups of male F1 rats were studied after 35-day exposure to the following: Unhandled (n = 8): no treatment; Sham (n = 10): episodic compressed air; HH (n = 14): daily episodic hypoxia (2.7%); EH1 (n = 12); hypoxia 2.9%, CO2 8.4%; and EH2 (n = 11): hypoxia 2.8% and CO2 10.5%. Under acute conditions, HH caused a 34.2-mmHg and EH a 77.9-mmHg increase in mean BP. Prazosin partially blocked the increase in BP. Under chronic conditions, HH caused a 10.3-mmHg increase in daytime mean BP, whereas EH caused a fall in mean BP of 16.6 and 9.3 mmHg in the two separately studied groups. In the F1 rat, acute EH causes an elevation of BP but chronic EH causes a fall in BP. The acute response to EH is not predictive of what occurs after chronic exposure in the hypertension-prone F-1 rat.

Effects of chronic episodic hypoxia on monoamine metabolism and motor activity

Chronic episodic hypoxia produces a wide array of cardiovascular dysfunctions in rats, including increases in blood pressure, heart rate, and sympathetic nerve activity. The action of episodic hypoxia might be related to low oxygen itself (hypoxemia) and/or combined with low CO 2 (hypocapnia) resulting from hyperventilation. It is unknown whether or not the cardiovascular abnormalities are related to alterations in the central nervous system (CNS) that may be manifested as neurotransmitter and/or behavioral changes. In this study, we investigated effects of episodic eucapnic and hypocapnic hypoxia on monoamine metabolism in both CNS and adrenal glands, and on motor behavioral activity. Thirty-five male rats were divided into 3 groups. Experimental rats were exposed 8 h daily to varying fractional concentrations of inspired oxygen (FiO 2) and carbon dioxide (FiCO 2) for 35 days. These consisted of brief exposures (3–6 s) of episodic (twice every min) eucapnic (3.5% FiO 2 and 10% FiCO 2, n = 6) or hypocapnic (3.5% FiO 2 and 0% FiCO 2, n = 14) hypoxia, or room air (21% FiO 2 and 0.03% FiCO 2, n = 15). Norepinephrine, dopamine, serotonin, and their metabolites in the jypothalamus, hippocampus, and adrenal glands were measured by high-performance liquid chromatography (HPLC). Spontaneous behavioral activity was assessed for 30 min by automated activity monitors. Episodic hypocapnic hypoxia produced a decrease in dopamine turnover and eucapnic hypoxia increased norepinephrine levels in the hypothalamus. Animals exposed to hypocapnic hypoxia also exhibited a consistent increase in horizontal (walking) and vertical (rearing) activity, as well as in total activity time. From these results, it is concluded that episodic eucapnic and hypocapnic hypoxia may affect metabolism of different neurotransmitters in the CNS.

Role of K+ in regulating hypoxic cerebral blood flow in the rat: effect of glibenclamide and ouabain.

We assessed the role of extracellular potassium ([K+]e) on the increase in cerebral blood flow (CBF) during hypoxia, and we tested whether it was affected by glibenclamide or ouabain. Cortical CBF was measured using the hydrogen clearance technique in enflurane-anesthetized rats, and local [K+]e was measured with K+ microelectrodes adjacent to the hydrogen electrode. Eucapnic hypoxia (arterial Po2 approximately 35-40 Torr) increased CBF twofold and caused a modest rise in [K+]e (from 2.9 +/- 0.2 to 3.7 +/- 0.2 mM; mean arterial blood pressure, ABP, 86 +/- 5 mmHg). If ABP fell < 70 mmHg during hypoxia, no increase in CBF was seen, whereas [K+]e increased to > 20 mM. Glibenclamide (10-100 microM intracortically) attenuated [K+]e and CBF during hypoxia (ABP approximately 75 mmHg, P < 0.01). Ouabain (20-1,000 microM) increased [K+]e; however, it did not remove the hypoxic-induced rise in [K+]e. We conclude that glibenclamide-sensitive potassium channels contribute to the accumulation of [K+]e during hypoxia, although an increase in CBF during hypoxia can occur without a marked rise in [K+]e. Furthermore, if ABP falls below the lower limit of autoregulation during hypoxia, there is no increase in CBF, yet there is a large increase in [K+]e.

An animal model of the relationship between systemic hypertension and repetitive episodic hypoxia as seen in sleep apnoea.

Multiple factors may be responsible for acute and chronic blood pressure changes during obstructive sleep apnoea. A popular hypothesis is that recurrent episodic hypoxia stimulates chemoreceptors which, in turn, cause sympathetically mediated vasoconstriction and perhaps long-term vascular remodelling. Disruption of sleep architecture secondary to frequent arousals may also cause chronic stress which may contribute to diurnal hypertension. A less likely factor elevating blood pressure is the effect of abrupt intra-thoracic pressure changes on venous return and cardiac output. The rat responds to chronic, recurrent episodic hypocapnic hypoxia (12-s bursts of nitrogen followed by air into Plexiglas chambers, every 30 s, 7 h d-1, 2-4% nadir ambient oxygen) with sustained increase in diurnal blood pressure 11-14 mmHg). Subsequent studies reveal that carotid sinus nerve section (chemodenervation) and chemically induced peripheral sympathetic denervation with the neurotoxin 6-OH dopamine both eliminate this blood pressure-elevating effect of chronic episodic hypoxaemia. Using this model, Sprague-Dawley rats have been challenged with both eucapnic hypoxia and asphyxia and failed to show an additional blood pressure elevation above that caused by hypoxia (hypocapnic) alone. It appears that hypocapnic hypoxia creates a maximal stimulus to the sympathetic nervous system to which the addition of hypercarbia does not increase the blood pressure response. An alternative explanation is that the rat has protective mechanisms that limit the diurnal blood pressure response from further increase.

Ventilatory response to oxygen after eucapnic hypoxia in conscious dogs

In humans the ventilatory [minute ventilation (VI)] response to sustained hypoxia is biphasic: an initial brisk increase followed by a decline is usually seen. However, in adult dogs, the ventilatory response to a similar stimulus shows no decline. To evaluate if central ventilatory drive is altered by sustained hypoxia, we measured the lowest ventilation (nadir) as the lowest moving average of seven sequential breaths within 200 s after transition to hyperoxia (100% O2) after 3 different exposures: room air, 4-min (brief) eucapnic hypoxia (arterial O2 saturation = approximately 80%), and 12-min (prolonged) eucapnic hypoxia. The nadir hyperoxic VI after brief hypoxia (2.7 +/- 0.2 l/min) was similar to that after room air (2.6 +/- 0.2 l/min; P > 0.05), with both less than prior room air mean VI (P < 0.05). The nadir after prolonged hypoxia (3.5 +/- 0.3 l/min) was significantly greater than that after brief hypoxia (P < 0.05). This suggests that central ventilatory drive increases in conscious dogs after sustained eucapnic hypoxia. The reason for the difference in central ventilatory response to hypoxia between conscious dogs and adult humans is unexplained.

A specific and potent pressor effect of hypoxia in patients with sleep apnea.

A hypoxic ramp test (to 75% arterial oxygen saturation) during the awake state was performed in 17 patients with obstructive sleep apnea (OSA). Blood pressure was monitored with an indwelling arterial line (radial artery), and the ventilatory response to eucapnic hypoxia was determined. Eight of the patients were normotensive. The remaining nine hypertensive patients were studied after a 3-wk washout of antihypertensive medication. Compared with a nonmatched group of normotensive nonsnoring control subjects in whom hypoxemia did not affect blood pressure, all OSA patients showed various degrees of pressor responses during hypoxia. The pressor response was of similar magnitude in normotensive and hypertensive patients with OSA. There was a significant relationship between the ventilatory and the pressor responses to hypoxia (p = 0.03) that was similar in both normotensive and hypertensive patients. Although disease severity expressed as apnea index (number of apneas per hour of sleep) or minimum arterial oxygen saturation reached during the overnight recording correlated with the magnitude of the pressor response (p = 0.03 and 0.045, respectively), the ventilatory response to hypoxia was unrelated to disease severity. Hypoxemia induced a similar increase in heart rate in controls and in normotensive patients, but an attenuated heart rate response was seen at the nadir of oxygen saturation in hypertensive subjects (p < 0.05). These data demonstrate that patients with obstructive sleep apneas have a pressor response to hypoxia. This response is likely to be involved in the blood pressure swings seen during apnea in patients with OSA.(ABSTRACT TRUNCATED AT 250 WORDS)