Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans

We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 +/- 4.2 yr, mean +/- SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (Vp) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH (P < 0.01) and PH (P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, Vp was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of approximately 0.34 cm x s(-1).%desaturation(-1) (P < 0.05). The Vp response to PH was biphasic with an initial decrease from baseline occurring at 79 +/- 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of -0.24 cm x s(-1) x % desaturation(-1). When expressed in relation to end-tidal Pco2, a sensitivity of -1.08 cm x s(-1).Torr(-1) was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.     

Interactive effect of hypoxia and otolith organ engagement on cardiovascular regulation in humans.

We determined the interaction between the vestibulosympathetic reflex and the arterial chemoreflex in 12 healthy subjects. Subjects performed three trials in which continuous recordings of muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), heart rate (HR), and arterial oxygen saturation were obtained. First, in prone subjects the otolith organs were engaged by use of head-down rotation (HDR). Second, the arterial chemoreflex was activated by inspiration of hypoxic gas (10% O2 and 90% N2) for 7 min with HDR being performed during minute 6. Third, hypoxia was repeated (15 min) with HDR being performed during minute 14. HDR [means +/- SE; increase (Delta)7 +/- 1 bursts/min and Delta50 +/- 11% for burst frequency and total MSNA, respectively; P < 0.05] and hypoxia (Delta6 +/- 2 bursts/min and Delta62 +/- 29%; P < 0.05) increased MSNA. Additionally, MSNA increased when HDR was performed during hypoxia (Delta11 +/- 2 bursts/min and Delta127 +/- 57% change from normoxia; P < 0.05). These increases in MSNA were similar to the algebraic sum of the individual increase in MSNA elicited by HDR and hypoxia (Delta13 +/- 1 bursts/min and Delta115 +/- 36%). Increases in MAP (Delta3 +/- 1 mmHg) and HR (Delta19 +/- 1 beats/min) during combined HDR and hypoxia generally were smaller (P < 0.05) than the algebraic sum of the individual responses (Delta5 +/- 1 mmHg and Delta24 +/- 2 beats/min for MAP and HR, respectively; P < 0.05). These findings indicate an additive interaction between the vestibulosympathetic reflex and arterial chemoreflex for MSNA. Therefore, it appears that MSNA outputs between the vestibulosympathetic reflex and arterial chemoreflex are independent of one another in humans.     

Cerebral hypoperfusion during hypoxic exercise following two different hypoxic exposures: independence from changes in dynamic autoregulation and reactivity

We examined the effects of exposure to 10-12 days intermittent hypercapnia [IHC: 5:5-min hypercapnia (inspired fraction of CO(2) 0.05)-to-normoxia for 90 min (n = 10)], intermittent hypoxia [IH: 5:5-min hypoxia-to-normoxia for 90 min (n = 11)] or 12 days of continuous hypoxia [CH: 1,560 m (n = 7)], or both IH followed by CH on cardiorespiratory and cerebrovascular function during steady-state cycling exercise with and without hypoxia (inspired fraction of oxygen, 0.14). Cerebrovascular reactivity to CO(2) was also monitored. During all procedures, ventilation, end-tidal gases, blood pressure, muscle and cerebral oxygenation (near-infrared spectroscopy), and middle cerebral artery blood flow velocity (MCAv) were measured continuously. Dynamic cerebral autoregulation (CA) was assessed using transfer-function analysis. Hypoxic exercise resulted in increases in ventilation, hypocapnia, heart rate, and cardiac output when compared with normoxic exercise (P < 0.05); these responses were unchanged following IHC but were elevated following the IH and CH exposure (P < 0.05) with no between-intervention differences. Following IH and/or CH exposure, the greater hypocapnia during hypoxic exercise provoked a decrease in MCAv (P < 0.05 vs. preexposure) that was related to lowered cerebral oxygenation (r = 0.54; P < 0.05). Following any intervention, during hypoxic exercise, the apparent impairment in CA, reflected in lowered low-frequency phase between MCAv and BP, and MCAv-CO(2) reactivity, were unaltered. Conversely, during hypoxic exercise following both IH and/or CH, there was less of a decrease in muscle oxygenation (P < 0.05 vs. preexposure). Thus IH or CH induces some adaptation at the muscle level and lowers MCAv and cerebral oxygenation during hypoxic exercise, potentially mediated by the greater hypocapnia, rather than a compromise in CA or MCAv reactivity.     

Ventilatory chemosensitivity of the 1-day-old chicken hatchling after embryonic hypoxia

We investigated the effects of sustained embryonic hypoxia on the neonatal ventilatory chemosensitivity. White Leghorn chicken eggs were incubated at 38 degrees C either in 21% O(2) throughout incubation (normoxia, Nx) or in 15% O(2) from embryonic day 5 (hypoxia, Hx), hatching time included. Hx embryos hatched approximately 11 h later than Nx, with similar body weights. Measurements of gaseous metabolism (oxygen consumption, Vo(2)) and pulmonary ventilation (Ve) were conducted either within the first 8 h (early) or later hours (late) of the first posthatching day. In resting conditions, Hx had similar Vo(2) and body temperature (Tb) and slightly higher Ve and ventilatory equivalent (Ve/Vo(2)) than Nx. Ventilatory chemosensitivity was evaluated from the degree of hyperpnea (increase in Ve) and of hyperventilation (increase in Ve/Vo(2)) during acute hypoxia (15 and 10% O(2), 20 min each) and acute hypercapnia (2 and 4% CO(2), 20 min each). The chemosensitivity differed between the early and late hours, and at either time the responses to hypoxia and hypercapnia were less in Hx than in Nx because of a lower increase in Ve and a lower hypoxic hypometabolism. In a second group of Nx and Hx hatchlings, the Ve response to 10% O(2) was tested in the same hatchlings at the early and late hours. The results confirmed the lower hypoxic chemosensitivity of Hx. We conclude that hypoxic incubation affected the development of respiratory control, resulting in a blunted ventilatory chemosensitivity.     

Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans.

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.     

Oxygen cost of exercise hyperpnea: measurement.

To quantitate the O2 cost of maximal exercise hyperpnea, we required eight healthy adult subjects to mimic, at rest, the important mechanical components of submaximal and maximal exercise hyperpnea. Expired minute ventilation (VE), transpulmonary and transdiaphragmatic (Pdi) pressures, and end-expiratory lung volume (EELV) were measured during exercise at 70 and 100% of maximal O2 uptake. At rest, subjects were given visual feedback of their exercise transpulmonary pressure-tidal volume loop (WV), breathing frequency, and EELV, which they mimicked repeatedly for 5 min per trial over several trials, while hypocapnia was prevented. The change in total body O2 uptake (VO2) was measured and presumed to represent the O2 cost of the hyperpnea. In 61 mimicking trials with VE of 115-167 l/min and WV of 124-544 J/min, VE, WV, duty cycle of the breath, and expiratory gastric pressure (Pga) integrated with respect to time (integral of Pga.dt/min) were not different from those observed during maximum exercise. integral of Pdi.dt/min was 14% less and EELV was 6% greater during maximum exercise than during mimicking. The O2 cost measurements within a subject were reproducible over 3-12 trials (coefficient of variation +/- 10% range 5-16%). The O2 costs of hyperpnea correlated highly and positively with VE and WV and less, but significantly, with integral of Pdi.dt and integral of Pga.dt. The O2 cost of VE rose out of proportion to the increasing hyperpnea, so that between 70 and 100% of maximal VO2 delta VO2/delta VE increased 40-60% (1.8 +/- 0.2 to 2.9 +/- 0.1 ml O2/l VE) as VE doubled.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential responses of expiratory muscles to chemical stimuli in awake dogs

We assessed respiratory muscle response patterns to chemoreceptor stimuli (hypercapnia, hypoxia, normocapnic hypoxia, almitrine, and almitrine + CO2) in six awake dogs. Mean electromyogram (EMG) activities were measured in the crural (CR) diaphragm, triangularis sterni (TS), and transversus abdominis (TA). Hypercapnia and normocapnic hypoxia caused mild to marked hyperpnea [2-5 times control inspiratory flow (VI)] and increased activity in CR diaphragm, TS, and TA. When hypocapnia was permitted to develop during hypoxia and almitrine-induced moderate hyperpnea, CR diaphragm activity increased, whereas TS and TA activities usually did not change or were reduced below control. Over time in hypercapnia, CR diaphragm, TS, and TA were augmented and maintained at these levels over many minutes; with hypoxic hyperventilation CR diaphragm, TS, and TA were first augmented but then CR diaphragm remained augmented while TS and, less consistently, TA were inhibited over time. Marked hyperpnea (4-5 times control) due to carotid body stimulation increased TA and TS EMG activity despite an accompanying hypocapnia. We conclude that in the intact awake dog 1) carotid body stimulation augments the activity of both inspiratory and expiratory muscles; 2) hypocapnia overrides the augmenting effect of carotid body stimulation on expiratory muscles during moderate hyperpnea, usually resulting in either no change or inhibition; 3) at higher levels of hyperpnea both chemoreceptor stimulation and stimulatory effects secondary to a high ventilatory output favor expiratory muscle activation; these effects override any inhibitory effects of a coincident hypocapnia; and 4) expiratory muscles of the rib cage/abdomen may be augmented/inhibited independently of one another.     

Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin.

Respiratory long-term facilitation (LTF) is a long-lasting (>1 h) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and is thought to prevent sleep-disordered breathing such as sleep apnea. Raphe nuclei, which modulate several physiological functions through serotonin, receive dense projections from orexin-containing neurons in the hypothalamus. We examined possible contributions of orexin to ventilatory LTF by measuring respiration in freely moving prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates before, during, and after exposure to intermittent hypoxia (IH; 5 x 5 min at 10% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Respiratory data during quiet wakefulness (QW), slow wave sleep (SWS), and rapid-eye-movement sleep were separately calculated. Baseline ventilation before hypoxic stimulation and acute responses during stimulation did not differ between the ORX-KO and WT mice, although ventilation depended on vigilance state. Whereas the WT showed augmented minute ventilation (by 20.0 +/- 4.5% during QW and 26.5 +/- 5.3% during SWS; n = 8) for 2 h following IH, ORX-KO showed no significant increase (by -3.1 +/- 4.6% during QW and 0.3 +/- 5.2% during SWS; n = 8). Both genotypes showed no LTF after SH or sham stimulation. Sleep apnea indexes did not change following IH, even when LTF appeared in the WT mice. We conclude that LTF occurs during both sleep and wake periods, that orexin is necessary for eliciting LTF, and that LTF cannot prevent sleep apnea, at least in mice.     

Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.

This study tested the effects of inhaled nitric oxide [NO; 20 parts per million (ppm)] during normoxic and hypoxic (fraction of inspired O(2) = 14%) exercise on gas exchange in athletes with exercise-induced hypoxemia. Trained male cyclists (n = 7) performed two cycle tests to exhaustion to determine maximal O(2) consumption (VO(2 max)) and arterial oxyhemoglobin saturation (Sa(O(2)), Ohmeda Biox ear oximeter) under normoxic (VO(2 max) = 4.88 +/- 0.43 l/min and Sa(O(2)) = 90.2 +/- 0.9, means +/- SD) and hypoxic (VO(2 max) = 4.24 +/- 0.49 l/min and Sa(O(2)) = 75.5 +/- 4.5) conditions. On a third occasion, subjects performed four 5-min cycle tests, each separated by 1 h at their respective VO(2 max), under randomly assigned conditions: normoxia (N), normoxia + NO (N/NO), hypoxia (H), and hypoxia + NO (H/NO). Gas exchange, heart rate, and metabolic parameters were determined during each condition. Arterial blood was drawn at rest and at each minute of the 5-min test. Arterial PO(2) (Pa(O(2))), arterial PCO(2), and Sa(O(2)) were determined, and the alveolar-arterial difference for PO(2) (A-aDO(2)) was calculated. Measurements of Pa(O(2)) and Sa(O(2)) were significantly lower and A-aDO(2) was widened during exercise compared with rest for all conditions (P < 0.05). No significant differences were detected between N and N/NO or between H and H/NO for Pa(O(2)), Sa(O(2)) and A-aDO(2) (P > 0.05). We conclude that inhalation of 20 ppm NO during normoxic and hypoxic exercise has no effect on gas exchange in highly trained cyclists.     

Effect of brain blood flow on hypoxic ventilatory response in humans

To assess the effect of brain blood flow on hypoxic ventilatory response, we measured arterial and internal jugular venous blood gases and ventilation simultaneously and repeatedly in eight healthy male humans in two settings: 1) progressive and subsequent sustained hypoxia, and 2) stepwise and progressive hypercapnia. Ventilatory response to progressive isocapnic hypoxia [arterial O2 partial pressure 155.9 +/- 4.0 (SE) to 46.7 +/- 1.5 Torr] was expressed as change in minute ventilation per change in arterial O2 saturation and varied from -0.16 to -1.88 [0.67 +/- 0.19 (SE)] l/min per % among subjects. In the meanwhile, jugular venous PCO2 (PjCO2) decreased significantly from 51.0 +/- 1.1 to 47.3 +/- 1.0 Torr (P less than 0.01), probably due to the increase in brain blood flow, and stayed at the same level during 15 min of sustained hypoxia. Based on the assumption that PjCO2 reflects the brain tissue PCO2, we evaluated the depressant effect of fall in PjCO2 on hypoxic ventilatory response, using a slope for ventilation-PjCO2 line which was determined in the second set of experiments. Hypoxic ventilatory response corrected with this factor was -1.31 +/- 0.33 l/min per %, indicating that this factor modulated hypoxic ventilatory response in humans. The ventilatory response to progressive isocapnic hypoxia did not correlate with this factor but significantly correlated with the withdrawal test (modified transient O2 test), which was performed on a separate day. Accordingly we conclude that an increase in brain blood flow during exposure to moderate hypoxia may substantially attenuate the ventilatory response but that it is unlikely to be the major factor of the interindividual variation of progressive isocapnic hypoxic ventilatory response in humans.     

Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans.

Nitric oxide (NO) plays a pivotal role in the regulation of peripheral vascular tone. Its role in the regulation of cerebral vascular tone in humans remains to be elucidated. This study investigates the role of NO in hypoxia-induced cerebral vasodilatation in young healthy volunteers. The effect of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on the cerebral blood flow (CBF) was assessed during normoxia and during hypoxia (peripheral O(2) saturation 97 and 80%, respectively). Subjects were positioned in a magnetic resonance scanner, breathing normal air (normoxia) or a N(2)-O(2) mixture (hypoxia). The CBF was measured before and after administration of L-NMMA (3 mg/kg) by use of phase-contrast magnetic resonance imaging techniques. Administration of L-NMMA during normoxia did not affect CBF. Hypoxia increased CBF from 1,049 +/- 113 to 1,209 +/- 143 ml/min (P < 0.05). After L-NMMA administration, the augmented CBF returned to baseline (1,050 +/- 161 ml/min; P < 0.05). Similarly, cerebral vascular resistance declined during hypoxia and returned to baseline after administration of L-NMMA (P < 0.05 for both). Use of phase-contrast magnetic resonance imaging shows that hypoxia-induced cerebral vasodilatation in humans is mediated by NO.     

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).     

Decline in peripheral chemoreceptor excitatory stimulation during acute hypoxia in the lamb

Chemoreceptor function was studied in eight 2- to 3-day-old unanesthetized lambs to sequentially assess hypoxic chemoreflex strength during an 18-min exposure to hypoxia [inspired O2 fraction (FIO2) = 0.08]. The immediate ventilatory (VE) drop in response to five breaths of pure O2 was measured at 3, 7, and 15 min during hypoxia. Each lamb was studied again at 10-11 days of age. At 2-3 days of age VE increased, with the onset of hypoxia, from 658 +/- 133 (SD) ml.min-1 X kg-1 to a peak of 1,124 +/- 177 ml.min-1 X kg-1. A dampening of the VE response then occurred, with a mean decline in VE of 319 ml.min-1 X kg-1 over the 18-min hypoxia period. Each pure O2 test (Dejours test) resulted in an abrupt fall in VE (delta VEDejours). This VE drop was 937 +/- 163, 868 +/- 244, and 707 +/- 120 ml.min-1 X kg-1 at 3, 7, and 15 min of hypoxia, respectively. Comparing the three O2 tests, delta VEDejours was significantly decreased by 15 min, indicating a loss of about one-fourth of the O2 chemoreflex drive during hypoxia. Testing at 10-11 days of age revealed a smaller VE decline during hypoxia. O2 tests at the beginning and end of the hypoxic period were not significantly different, indicating a smaller loss of hypoxic chemoreflex drive in the more mature animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise

We examined the relationship between changes in cardiorespiratory and cerebrovascular function in 14 healthy volunteers with and without hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 80%] at rest and during 60-70% maximal oxygen uptake steady-state cycling exercise. During all procedures, ventilation, end-tidal gases, heart rate (HR), arterial blood pressure (BP; Finometer) cardiac output (Modelflow), muscle and cerebral oxygenation (near-infrared spectroscopy), and middle cerebral artery blood flow velocity (MCAV; transcranial Doppler ultrasound) were measured continuously. The effect of hypoxia on dynamic cerebral autoregulation was assessed with transfer function gain and phase shift in mean BP and MCAV. At rest, hypoxia resulted in increases in ventilation, progressive hypocapnia, and general sympathoexcitation (i.e., elevated HR and cardiac output); these responses were more marked during hypoxic exercise (P < 0.05 vs. rest) and were also reflected in elevation of the slopes of the linear regressions of ventilation, HR, and cardiac output with Sa(O(2)) (P < 0.05 vs. rest). MCAV was maintained during hypoxic exercise, despite marked hypocapnia (44.1 +/- 2.9 to 36.3 +/- 4.2 Torr; P < 0.05). Conversely, hypoxia both at rest and during exercise decreased cerebral oxygenation compared with muscle. The low-frequency phase between MCAV and mean BP was lowered during hypoxic exercise, indicating impairment in cerebral autoregulation. These data indicate that increases in cerebral neurogenic activity and/or sympathoexcitation during hypoxic exercise can potentially outbalance the hypocapnia-induced lowering of MCAV. Despite maintaining MCAV, such hypoxic exercise can potentially compromise cerebral autoregulation and oxygenation.     

Arterial pressure and muscle sympathetic nerve activity are increased after two hours of sustained but not cyclic hypoxia in healthy humans.

Sustained and episodic hypoxic exposures lead, by two different mechanisms, to an increase in ventilation after the exposure is terminated. Our aim was to investigate whether the pattern of hypoxia, cyclic or sustained, influences sympathetic activity and hemodynamics in the postexposure period. We measured sympathetic activity (peroneal microneurography), hemodynamics [plethysmographic forearm blood flow (FBF), arterial pressure, heart rate], and peripheral chemosensitivity in normal volunteers on two occasions during and after 2 h of either exposure. By design, mean arterial oxygen saturation was lower during sustained relative to cyclic hypoxia. Baseline to recovery muscle sympathetic nerve activity and blood pressure went from 15.7 +/- 1.2 to 22.6 +/- 1.9 bursts/min (P < 0.01) and from 85.6 +/- 3.2 to 96.1 +/- 3.3 mmHg (P < 0.05) after sustained hypoxia, respectively, but did not exhibit significant change from 13.6 +/- 1.5 to 17.3 +/- 2.5 bursts/min and 84.9 +/- 2.8 to 89.8 +/- 2.5 mmHg after cyclic hypoxia. A significant increase in FBF occurred after sustained, but not cyclic, hypoxia, from 2.3 +/- 0.2 to 3.29 +/- 0.4 and from 2.2 +/- 0.1 to 3.1 +/- 0.5 ml.min(-1).100 g of tissue(-1), respectively. Neither exposure altered the ventilatory response to progressive isocapnic hypoxia. Two hours of sustained hypoxia increased not only muscle sympathetic nerve activity but also arterial blood pressure. In contrast, cyclic hypoxia produced slight but not significant changes in hemodynamics and sympathetic activity. These findings suggest the cardiovascular response to acute hypoxia may depend on the intensity, rather than the pattern, of the hypoxic exposure.     

Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle.

Exercise blunts sympathetic alpha-adrenergic vasoconstriction (functional sympatholysis). We hypothesized that sympatholysis would be augmented during hypoxic exercise compared with exercise alone. Fourteen subjects were monitored with ECG and pulse oximetry. Brachial artery and antecubital vein catheters were placed in the nondominant (exercising) arm. Subjects breathed hypoxic gas to titrate arterial O2 saturation to 80% while remaining normocapnic via a rebreath system. Baseline and two 8-min bouts of rhythmic forearm exercise (10 and 20% of maximum) were performed during normoxia and hypoxia. Forearm blood flow, blood pressure, heart rate, minute ventilation, and end-tidal CO2 were measured at rest and during exercise. Vasoconstrictor responsiveness was determined by responses to intra-arterial tyramine during the final 3 min of rest and each exercise bout. Heart rate was higher during hypoxia (P < 0.01), whereas blood pressure was similar (P = 0.84). Hypoxic exercise potentiated minute ventilation compared with normoxic exercise (P < 0.01). Forearm blood flow was higher during hypoxia compared with normoxia at rest (85 +/- 9 vs. 66 +/- 7 ml/min), at 10% exercise (276 +/- 33 vs. 217 +/- 27 ml/min), and at 20% exercise (464 +/- 32 vs. 386 +/- 28 ml/min; P < 0.01). Arterial epinephrine was higher during hypoxia (P < 0.01); however, venoarterial norepinephrine difference was similar between hypoxia and normoxia before (P = 0.47) and during tyramine administration (P = 0.14). Vasoconstriction to tyramine (%decrease from pretyramine values) was blunted in a dose-dependent manner with increasing exercise intensity (P < 0.01). Interestingly, vasoconstrictor responsiveness tended to be greater (P = 0.06) at rest (-37 +/- 6% vs. -33 +/- 6%), at 10% exercise (-27 +/- 5 vs. -22 +/- 4%), and at 20% exercise (-22 +/- 5 vs. -14 +/- 4%) between hypoxia and normoxia, respectively. Thus sympatholysis is not augmented by moderate hypoxia nor does it contribute to the increased blood flow during hypoxic exercise.     

Dobutamine potentiates arterial chemoreflex sensitivity in healthy normal humans

beta-Adrenergic agonists may increase chemosensitivity in humans. We tested the hypothesis that the beta1-agonist dobutamine increases peripheral chemosensitivity in a double-blind placebo-controlled randomized and crossover study. In 15 healthy subjects, we examined the effects of dobutamine on breathing, hemodynamics, and sympathetic nerve activity (measured using microneurography) during normoxia, isocapnic hypoxia (10% O2), posthypoxic maximal voluntary end-expiratory apnea, hyperoxic hypercapnia, and cold pressor test (CPT). Dobutamine increased ventilation (7.5 +/- 0.3 vs. 6.7 +/- 0.2 l/min, P = 0.0004) during normoxia, markedly enhanced the ventilatory (16.1 +/- 1.6 vs. 11.4 +/- 0.7 l/min, P < 0.0001) and sympathetic (+403 +/- 94 vs. +222 +/- 5%, P < 0.03) responses at the fifth minute of isocapnic hypoxia, and enhanced the sympathetic response to the apnea performed after hypoxia (+501 +/- 107% vs. +291 +/- 38%, P < 0.05). No differences were observed between dobutamine and placebo on the responses to hyperoxic hypercapnia and CPT. Dobutamine increases ventilation during normoxia and potentiates the ventilatory and sympathetic responses to hypoxia in healthy subjects. Dobutamine does not affect the responses to hyperoxic hypercapnia and CPT. We conclude that dobutamine enhances peripheral chemosensitivity.     

Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups.

Carotid bodies are functionally immature at birth and exhibit poor sensitivity to hypoxia. Previous studies have shown that continuous hypoxia at birth impairs hypoxic sensing at the carotid body. Intermittent hypoxia (IH) is more frequently experienced in neonatal life. Previous studies on adult animals have shown that IH facilitates hypoxic sensing at the carotid bodies. On the basis of these studies, in the present study we tested the hypothesis that neonatal IH facilitates hypoxic sensing of the carotid body and augments ventilatory response to hypoxia. Experiments were performed on 2-day-old rat pups that were exposed to 16 h of IH soon after the birth. The IH paradigm consisted of 15 s of 5% O2 (nadir) followed by 5 min of 21% O2 (9 episodes/h). In one group of experiments (IH and control, n = 6 pups each), sensory activity was recorded from ex vivo carotid bodies, and in the other (IH and control, n = 7 pups each) ventilation was monitored in unanesthetized pups by plethysmography. In control pups, sensory response of the carotid body was weak and was slow in onset (approximately 100 s). In contrast, carotid body sensory response to hypoxia was greater and the time course of the response was faster (approximately 30 s) in IH compared with control pups. The magnitude of the hypoxic ventilatory response was greater in IH compared with control pups, whereas changes in O2 consumption and CO2 production during hypoxia were comparable between both groups. The magnitude of ventilatory stimulation by hyperoxic hypercapnia (7% CO2-balance O2), however, was the same between both groups of pups. These results demonstrate that neonatal IH facilitates carotid body sensory response to hypoxia and augments hypoxic ventilatory chemoreflex.     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O? fraction (Fi(O?)) 21-5%, 60/h], IH 12 times/h (Fi(O?) 5% for 15 s, 12/h), sustained hypoxia (SH; Fi(O?) 10%), or normoxia while fasting. Tissue oxygen partial pressure (Pti(O?)) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of Pti(O?) were attenuated in muscle and abolished in fat. In obese mice, baseline liver Pti(O?) was lower than in lean mice, whereas muscle and fat Pti(O?) did not differ. During IH, Pti(O?) was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens.