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

Penn State Heart and Vascular Institute, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 9 January 2007 ; accepted in final form 1 June 2007

	ABSTRACT

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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; O₂ 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 O₂ (FI_O2) 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_O2 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.

sleep apnea; hypertension; sympathetic nerve activity; hypoxia; chemoreflex sensitivity

Several approaches have been used to mimic the neurocirculatory events associated with sleep apnea in the laboratory. For example, in animal models, intermittent hypoxia applied over days to weeks has been found to lead to hypertension (4, 10) that appears to be mediated by the sympathetic nervous system (9). Furthermore, studies in healthy humans reported that relatively short bouts (20–30 min) of intermittent hypoxia raise muscle sympathetic nerve activity (7, 18, 39) and blood pressure (18). Moreover, there is evidence that chronic intermittent hypoxia enhances chemoreflex responses to hypoxia in rodents (11), and a recent report suggests that the sympathetic responses to hypoxic apnea are altered following intermittent hypoxia in humans (6). The stimulus examined in the latter report (6) before and after intermittent hypoxia (i.e., apnea) is complex because apart from chemoreceptor stimulation, sympathetic outflow is modified by apnea-induced cessation of breathing (lung inflation reflex) and transient changes in blood pressure (arterial baroreflex).

Therefore, the purpose of this study was to test whether intermittent hypoxia would alter the sympathetic reflex responses to brief exposures to continuous nonapneic hypoxia. We hypothesized that if intermittent hypoxia enhances the sympathetic reflex responses to continuous hypoxia, this mechanism might contribute to the altered sympathetic chemoreflex control observed in patients with sleep apnea. Our findings support this hypothesis and suggest that a 30-min bout of intermittent hypoxia is capable of sensitizing hypoxic chemoreflex responses in awake healthy humans.

	METHODS

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Subjects.   Thirteen healthy men and six women, age 29 ± 2 yr (mean ± SE) with a body mass index of 25 ± 1 kg/m², who had no significant medical history and were on no medications, participated in the studies. The study protocol was approved by the Institutional Review Board of The Milton S. Hershey Medical Center, and informed written consent was obtained. All studies were performed in the General Clinical Research Center at Penn State University's College of Medicine with the subjects awake and in the supine position.

Before instrumentation, the subjects were instructed to perform 20-s voluntary end-expiratory apnea maneuvers at functional residual capacity. Care was taken to avoid straining that might result in a Müller or a Valsalva maneuver. For precise timing of the apnea-breathing cycle, a clock was positioned within the subject's visual field. Markers were placed at the 0- and 20-s positions to indicate the beginning and the end of voluntary apnea.

Blood pressure and heart rate measurements.   Beat-by-beat blood pressure and mean arterial pressure (MAP) were determined with a finger photoplethysmographic device (Finapres, Ohmeda, CO) that has been shown to reliably register blood pressure changes induced by physiological maneuvers (27). To prevent finger edema, the Finapres device was turned off for 2 min in the middle of the 30-min repetitive apnea series. Baseline blood pressure was validated with an automated sphygmomanometer (Dinamap, Critikon, FL). A two-lead electrocardiogram was monitored to determine heart rate (HR).

Microneurography.   Muscle sympathetic nerve activity (MSNA), the sympathetic efferent vasoconstrictor signal directed to skeletal muscle, was determined via peroneal microneurography as described previously (12, 17). Briefly, a tungsten microelectrode was inserted into the peroneal nerve below the fibular head to record activity in efferent sympathetic fascicles carrying skeletal muscle vasoconstrictor nerve traffic to the distal lower extremity. The nerve traffic signal was filtered, amplified, rectified, and integrated and recorded on a Gould TA 4000 recorder (Gould, Valley View, OH). Standard techniques were used to demonstrate that the nerve signal in fact represented MSNA (12, 17). The recordings were analyzed by inspection, and MSNA was expressed as burst incidence (bursts/min) and total amplitude per minute (units/min).

Ventilatory parameters.   To determine minute ventilation (l/min) and end-tidal CO₂ (%), a tight-sealing facemask was positioned and was connected to an Ohmeda respiratory gas monitor (Ohmeda RGM 5200, Ohmeda, Colorado). Arterial O₂ saturation (Sa_O2, %) was determined via an ear oximeter (Ohmeda, CO). Respiration was monitored with a strain-gauge pneumograph.

Protocol 1: Reflex responses to acute hypoxia (FI_O2 0.1) before and after repetitive hypoxic apnea.   In an initial group of subjects, we examined the effects of acute continuous hypoxia (FI_O2 0.1; for 5 min) before and after a repetitive hypoxic apnea protocol. Following instrumentation and a 10-min period of acclimatization to the facemask, baseline parameters were determined over 5 min. The subjects were then exposed to acute hypoxia (FI_O2 0.1) for 5 min, and MAP, HR, ventilatory measurements, and MSNA were recorded (trial 1). After a recovery period of 15 min and reestablishment of basal MSNA, baseline measurements were again obtained, and a 30-min paradigm of repetitive hypoxic apnea was performed as described previously (18, 23). Briefly, spontaneous breathing was interrupted every min by a 20-s voluntary apnea at functional residual capacity. To produce significant transient O₂ desaturation, before each apnea, the subjects breathed a hypoxic gas (FI_O2 0.1) for 20–25 s. At the end of apnea, the subjects exhaled for 1 s before resuming spontaneous breathing, thus allowing sampling of end-tidal CO₂ at end apnea. Thirty such maneuvers were performed over 30 min (one per min). One minute following the last apnea, hemodynamic, sympathetic nerve, and ventilatory parameters were again recorded for 5 min, and the exposure to acute hypoxia (FI_O2 0.1, for 5 min) was repeated (trial 2). A schematic of the experimental protocol is shown in Fig. 1.

View larger version (5K): [in this window] [in a new window]   Fig. 1. Schematic outline of the experimental protocol.

Data analysis and statistics.   All hemodynamic, MSNA, and ventilatory data were arranged in 1-min bins. To assess the effects of the repetitive hypoxic apnea paradigm on MAP, HR, MSNA, and minute ventilation, baseline data preceding this intervention were averaged over 5 min and were compared with a 5-min average obtained following repetitive apnea by paired two-tailed t-test. To assess the effects of acute continuous hypoxia or hyperoxia on MSNA, hemodynamic parameters, and ventilatory parameters before and after the repetitive apnea paradigm, two-way ANOVA for repeated measures was performed. If significant F values were found, post hoc testing at individual time points was performed with the simple effects method. All data are expressed as means ± SE. A P value of <0.05 was considered statistically significant.

	RESULTS

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Chemical stimuli during repetitive hypoxia apnea.   Repetitive hypoxic apnea was associated with a decrease of Sa_O2 from a baseline (during regular breathing) of 96.9 ± 0.3% to a nadir of 81.4 ± 0.9% at end apnea (P < 0.001). Correspondingly, in nine subjects in whom end-tidal CO₂ at end apnea was measured, it was 40.4 ± 0.9 mmHg during quiet breathing at baseline and was elevated to 43.3 ± 1.0 mmHg at end apnea (P = 0.005). Thus our repetitive apnea paradigm resulted in intermittent moderate hypoxia and mild hypercapnia.

Effects of repetitive hypoxic apneas on hemodynamic and ventilatory parameters and on MSNA (n = 19).   Compared with baseline, in the recovery following 30 repetitive hypoxic apnea maneuvers, MSNA (units/min) increased by 35 ± 6% (P = 0.001) and mean MAP rose by 3.5 ± 1.2 mmHg (P < 0.01). When men (n = 13) and women (n = 6) were analyzed separately, the percent increase of MSNA amplitude (+38 ± 8 vs. +29 ± 11%; P = 0.49) and the rise of MAP (3.2 ± 1.7 vs. 4.2 ± 1.3 mmHg; P = 0.63) were similar. Repetitive hypoxic apnea was associated with small but statistically significant decreases of HR, minute ventilation, end-tidal CO₂, and Sa_O2 (P < 0.05 for all). These results are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Effects of intermittent hypoxia on MAP, HR, MSNA, E, end-tidal CO2, and SaO2

View this table: [in this window] [in a new window]   Table 2. Effects of continuous hypoxia (FIO2 0.1, for 5 min) on MSNA, MAP, HR, E, end-tidal CO2, and SaO2

View larger version (11K): [in this window] [in a new window]   Fig. 2. Effects of acute hypoxia [fraction of inspired O2 (FIO2) 0.1] on muscle sympathetic nerve activity (MSNA) and minute ventilation (E) before (pre) and after (post) intermittent hypoxia (n = 11). ns, Not significant.

View larger version (12K): [in this window] [in a new window]   Fig. 3. Representative recordings (20 s) of MSNA during room air breathing (baseline) and hypoxia from 1 male subject pre- and post-intermittent hypoxia. MAP, mean arterial pressure; SaO2, arterial oxygen saturation.

View this table: [in this window] [in a new window]   Table 3. Effects of continuous hyperoxia (FIO2 0.5, for 5 min) on MSNA, MAP, HR, E, end-tidal CO2, and SaO2

View larger version (11K): [in this window] [in a new window]   Fig. 4. Effects of acute hyperoxia (FIO2 0.5) on MSNA and E before and after intermittent hypoxia (n = 8).

	DISCUSSION

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In agreement with several recent reports (7, 18, 39), we found that our repetitive hypoxic apnea protocol resulted in sympathetic activation that persisted on resumption of normoxic breathing. In contrast to the reports by Xie et al. (39) and by Cutler et al. (7), who examined shorter exposures to intermittent hypoxia (i.e., 20 min vs. 30 min in our studies), but in agreement with our prior reports (18, 23), we also found a small but statistically significant increase in MAP by 3–4 mmHg. Taken together, our prior and present reports strongly suggest that the sympathetic activation induced by intermittent hypoxia in our model is associated with a small rise in mean blood pressure that outlasts the period of this intervention. Because neither intermittent hypercapnia (7, 39) nor intermittent apnea alone (18) produce this effect, it is likely that the sustained sympathetic activation and blood pressure elevation are the result of intermittent stimulation of arterial chemoreceptors.

The present data extend our prior work (18) and suggest that the state of increased sympathetic activity induced by intermittent hypoxia is associated with heightened sensitivity to acute hypoxic chemoreflex stimulation. This finding is particularly relevant because enhanced chemoreflex sensitivity to hypoxia has been reported in patients with obstructive sleep apnea (14, 24). Because blood pressure is elevated in normal individuals following intermittent hypoxia and in subjects with sleep apnea (14), and in light of the known interaction between the baroreflex and arterial chemoreflex (i.e., greater sympathetic stimulation by hypoxia during hypotension) (36), the enhanced responses to arterial chemoreflex stimulation cannot be due to relative hypotension and engagement of the arterial baroreflex. Instead, as reported previously, elevated sympathetic activity and blood pressure following intermittent hypoxic apnea are consistent with resetting of the arterial baroreflex (23).

The responses to acute hypoxia before the intermittent hypoxia protocol observed in this study agree with findings from prior publications. Acute hypocapnic hypoxia of short duration leads to an increase in MSNA with a lag time of 2–3 min (16, 32, 37). In extension of these findings, our data demonstrate that the sympathetic response to the second exposure to acute hypoxia (i.e., following the intermittent hypoxic apnea protocol) was markedly enhanced. It should be noted that the O₂ desaturation induced by exposure to hypoxia was slightly more prominent post-intermittent hypoxia and may have resulted from slightly lower minute ventilation. However, end-tidal CO₂, a major codeterminant of peripheral chemoreceptor activity (1), was also slightly but significantly lower on repeat exposure to hypoxia. Thus, despite mild hypocapnia and higher blood pressure, which would be expected to counteract peripheral chemoreceptor activation (1, 36, 37), following intermittent hypoxia the sympathetic response to hypoxia was markedly enhanced. However, the response of minute ventilation on repeat exposure to hypoxia was not statistically different, suggesting that sympathetic activity and ventilatory drive in response to chemoreceptor stimulation may be controlled separately.

Our study extends a recent publication that reported altered chemoreflex control following compared with before a 20-min exposure to intermittent hypoxic apnea (6). Whereas in that report (6) chemoreflex control was assessed by examining the responses to apnea, a complex physiological maneuver that evokes hypoxia- and hypercapnia-mediated chemoreceptor stimulation that is modified by transient changes in blood pressure and the absence of afferent nerve traffic from lung inflation receptors (12), our data more closely represent the effects of chemoreflex stimulation alone.

Our finding of mild hypocapnia following intermittent hypoxia agree with a report by Mateika et al. (21), who employed an alternating hypoxia-hyperoxia protocol to induce eight separate bouts of hypoxia over 1 h to examine its effects on peripheral chemoreflex responsiveness. These investigators speculated that the hypocapnia observed immediately following intermittent hypoxia was responsible for the failure to demonstrate ventilatory long-term facilitation in their study (21). Whether we would have observed greater sympathetic and ventilatory responses to continuous hypoxia after intermittent hypoxia if the hypocapnia had been corrected remains to be determined.

The mechanism underlying the enhanced sympathetic chemoreflex responses following intermittent hypoxia is not clear. Two main possibilities should be considered and likely represent neural plasticity. First, intermittent hypoxia may lead to altered activity of neurochemical circuits at the level of the brain stem. In this regard, it has been demonstrated in a variety of animal models that (prolonged) intermittent hypoxia may activate serotonin-dependent pathways that act to induce respiratory long-term facilitation (22). Alternatively, such an effect could be due to functional alterations in arterial chemoreceptors secondary to reactive oxygen species generated as a result of repetitive hypoxia-reoxygenation (28). Future studies on the effects of anti-oxidant interventions and/or of the effects of modulators of serotonin pathways in the brain might provide insight into these issues.

The discrepancy between the rise in sympathetic activity and blood pressure following intermittent hypoxia on the one hand and the rise in sympathetic activity without change of blood pressure during continuous hypoxia on the other hand deserves a comment. Because we determined the sympathetic vasoconstrictor signal but not the metabolic vasodilators released in various tissues, or the cardiac output response to hypoxia, we can only speculate about the potential mechanisms. It has been established that during systemic hypoxia, vasoactive metabolites such as adenosine (20) and nitric oxide (3) are released and lead to vasodilation in skeletal muscle (19) that is matched by an increase in cardiac output (31). Thus the failure of blood pressure to rise during systemic hypoxia despite increased sympathetic activity is due to peripheral vasodilation. In contrast, the increased blood pressure following intermittent hypoxia (i.e., when the subjects are again normoxic) is likely due to persistently increased sympathetic vasoconstrictor nerve activity once tissue hypoxia and the consequent release of metabolic vasodilators have resolved. However, confirmation of this hypothesis requires further investigation.

Neither before nor following intermittent hypoxia did we observe an attenuation of sympathetic nerve activity on exposure to hyperoxia. In contrast, following intermittent hypoxia, we noted a trend for a transient and paradoxical increase in sympathetic activity. While O₂ administration is expected to inactivate peripheral chemoreceptors, it decreased sympathetic nerve activity only in some (12, 34) but not all prior studies in healthy humans (25). Why the sympathetic responses to hypoxia are enhanced but those to hyperoxia are not altered correspondingly by intermittent hypoxia remains unclear. In contrast to baroreceptors that are thought to transduce a pressure signal over a wide range of pressures in a direct fashion (33), the relationship between chemoreflex activity and its determinants may be more complex (1) and involves peripheral and central receptor sites. For example, while hypoxia may increase peripheral chemoreceptor discharge, hyperoxia, by raising O₂ partial pressure, may exert direct vascular effects and could promote the formation of reactive oxygen species that are capable of stimulating chemoreceptor afferents (30). Thus, particularly following intermittent hypoxia, counteractive inhibitory (high O₂ partial pressure) and excitatory (reactive oxygen species) effects could prevent a decrease of sympathetic nerve activity in response to hyperoxia.

Several limitations of our study should be addressed. The repetitive hypoxic apnea intervention represents a complex stimulus to the autonomic nervous system consisting of intermittent hypoxia, mild hypercapnia, and cessation of afferent nerve traffic from lung inflation receptors that are all known to lead to sympathoexcitation. Because we were careful to avoid inadvertent Müller or Valsalva maneuvers, we believe it is unlikely that changes of intrathoracic pressure (which was not measured) affected arterial and/or cardiopulmonary baroreceptor activity that could be responsible for our observations. We should also note that our data do not allow us to assess the time course of chemoreflex sensitization, i.e., we cannot comment on whether the enhanced chemoreflex responses would have exhibited a time-dependent attenuation. Because of the exquisite difficulty of maintaining and interpreting extended nerve recordings over the course of several hours, we intentionally limited the duration of our study. Moreover, patients with obstructive sleep apnea experience repetitive cycles of hypoxia-reoxygenation for many hours each night, i.e., they are exposed to intermittent chemoreflex stimulation for much longer periods than the short-term exposure achieved in our model. We should also acknowledge that we did not perform time-control experiments nor did we examine whether intermittent hypoxia alters chemoreflex sensitivity to CO₂, a process that is thought to be predominantly mediated by central chemoreceptors (37). In a recent animal study, Greenberg et al. (11) have shown enhanced chemoreflex sensitivity to hypoxia and hypercapnia in rats following intermittent exposure to hypoxia. However, we believe the findings reported here are important because they highlight that repetitive chemoreflex stimulation even of short duration exerts sustained effects on blood pressure and autonomic neural control in healthy humans.

In conclusion, our data demonstrate that intermittent hypoxia applied over a 30-min period increases basal sympathetic activity and blood pressure and accentuates the sympathetic chemoreflex responses to hypoxia in healthy awake humans. These findings support the notion that intermittent hypoxia may contribute to the chronic sympathetic activation, hypertension, and enhanced chemoreflex activity noted in patients with obstructive sleep apnea. Therefore, these findings strengthen the rationale that preventing intermittent hypoxia, a goal that is presently best achieved with continuous positive airway pressure therapy, is crucial to prevent the adverse neurocirculatory and cardiovascular consequences of sleep apnea.

	GRANTS

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This work was supported in part by National Institutes of Health Grants R01-HL-068699 (U. A. Leuenberger), P01-HL-077670, and M01-RR-010732.

	ACKNOWLEDGMENTS

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We are grateful to Jennie Stoner for excellent secretarial assistance. We express sincere thanks to our study participants and to the staff of the GCRC.

	FOOTNOTES

 

Address for reprint requests and other correspondence: U. A. Leuenberger, Div. of Cardiology, MC H047, Heart & Vascular Institute, The Pennsylvania State Univ. College of Medicine, The Milton S. Hershey Medical Center, P.O. Box 850, Hershey, PA 17033 (e-mail: uleuenberger{at}psu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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