Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans
Introduction
Sympathetic nerve activity and arterial pressure are frequently elevated in patients with obstructive sleep apnea (OSA) (Fletcher et al., 1987, Kales et al., 1984, Carlson et al., 1994) and are thought to contribute to cardiovascular complications. Large cross-sectional and prospective studies suggest that OSA may cause hypertension (Bixler et al., 2000, Nieto et al., 2000, Peppard et al., 2000). However, the mechanisms responsible for sympathetic activation and hypertension in OSA are not known.
Several studies reported elevated discharge rates of sympathetic vasoconstrictor nerves in patients with OSA (Somers et al., 1995, Hedner et al., 1988, Leuenberger et al., 1995) and raise the possibility that hypertension in OSA is linked to heightened sympathetic tone. Because treatment with nasal continuous positive airway pressure (CPAP) or tracheostomy reduces sympathetic nerve activity (Waravdekar et al., 1996, Hedner et al., 1995, Fletcher et al., 1987) and blood pressure (Pepperell et al., 2002, Becker et al., 2003), physiological stress resulting from acute obstructive apneas is likely responsible for chronic sympathetic activation and hypertension in OSA.
Acute obstructive apnea is associated with transient surges of sympathetic activity and vasoconstriction that appear to be triggered by hypoxia and/or arousal from sleep (Morgan et al., 1996, Leuenberger et al., 1995, Imadojemu et al., 2002). It has been suggested that the acute sympathoexcitatory stimuli evoked by obstructive apnea may over time contribute to chronic (long-term) sympathetic activation. In support of this concept, Fletcher et al. reported that rats exposed to intermittent hypoxia develop hypertension (Fletcher et al., 1992c). This effect appeared to be mediated via the sympathetic nervous system and activation of peripheral chemoreceptors (Fletcher et al., 1992b, Fletcher et al., 1992a). Recent studies in humans suggest that short-term (20 min) exposure to combined hypoxia and hypercapnia (Morgan et al., 1995) and intermittent asphyxia (Xie et al., 2000) during spontaneous breathing result in sustained sympathetic activation but no change of blood pressure following exposure to these stimuli. However, these studies did not specifically address the role of intermittent cessation of breathing (apnea). Apnea is known to enhance chemoreflex-induced sympathetic activation and transient peripheral vasoconstriction (Leuenberger et al., 2001).
The purpose of this study was to test whether a series of repetitive voluntary apneas would result in sympathetic activation and blood pressure elevation that persist following this intervention. We hypothesized that if intermittent hypoxia due to intermittent airway occlusion is responsible for chronic sympathoexcitation and hypertension in OSA, sympathetic nerve activity and blood pressure would be elevated in healthy humans after an exposure to a series of repetitive voluntary apnea maneuvers.
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Subjects
Eighteen healthy men and 8 women, age 27.3 ± 1.3 yrs (mean ± SE; range 21–48 yrs) with a body-mass-index of 23.3 ± 0.6 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 in
Effects of repetitive room air apneas (n = 8)
Repetitive apnea maneuvers during exposure to room air (RA) were associated with a decrease of SaO2 from 97.7 ± 0.3% to a nadir of 95.1 ± 0.8% (P < 0.05) and a rise of CO2ET from 40.4 ± 0.9 mm Hg at baseline to an end-apnea peak of 46.5 ± 1.3 mm Hg (P < 0.01). The effects of repetitive RA apneas on hemodynamic and ventilatory parameters and on MSNA are shown in Table 1.
Effects of repetitive hypoxic apneas (n = 11)
Repetitive apnea maneuvers during intermittent administration of hypoxic gas were associated with a decrease of SaO2 from 97.1 ± 0.5% to a
Discussion
In this report we examined the sympathetic and blood pressure responses to a series of 30 repetitive voluntary apnea maneuvers in humans. The principal findings are that repetitive apnea associated with hypoxia (hypoxic apneas) induced an increase of sympathetic nerve activity and blood pressure that persisted beyond the duration of the apnea trials. In contrast, no increase of sympathetic nerve activity or of blood pressure was observed after room air apneas, where the apnea-induced hypoxia
Acknowledgements
The authors are grateful to Jennie Stoner for her excellent secretarial assistance. This work was supported in part by National Institutes of Health grants R01 HL068699 (Leuenberger), K23 HL004190 (Imadojemu), M01 RR010732, and C06 RR016499.
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