Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans

Abstract

Sympathetic nerve activity and arterial pressure are frequently elevated in patients with obstructive sleep apnea (OSA). The mechanisms responsible for chronic sympathetic activation and hypertension in OSA are unknown. To determine whether repetitive apneas raise sympathetic nerve activity and/or arterial pressure, awake and healthy young subjects performed voluntary end-expiratory apneas for 20 s per min for 30 min (room air apneas). To accentuate intermittent hypoxia, in a separate group of subjects, hypoxic gas (inspired O₂ 10%) was added to the inspiratory port for 20 s before each apnea (hypoxic apneas). Mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA, peroneal microneurography) were determined before and up to 30 min following the repetitive apneas. Following 30 hypoxic apneas (O₂ saturation nadir 83.1 ± 1.2%), MSNA increased from 17.4 ± 2.7 to 23.4 ± 2.5 bursts/min and from 164 ± 28 to 240 ± 35 arbitrary units respectively (P < 0.01 for both; n = 10) and remained elevated while MAP increased transiently from 80.5 ± 3.7 to 83.1 ± 3.9 mm Hg (P < 0.05; n = 11). In contrast, in the subjects who performed repetitive apneas during room air exposure (O₂ saturation nadir 95.1 ± 0.8%), MAP and MSNA did not change (n = 8). End-tidal CO₂ post-apnea, an index of apnea-induced hypercapnia, was similar in the 2 groups. In a separate control group, no effect of time on MAP or MSNA was noted (n = 7). Thus, repetitive hypoxic apneas result in sustained sympathetic activation and a transient elevation of blood pressure. These effects appear to be due to intermittent hypoxia and may play a role in the sympathetic activation and hypertension in OSA.

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.