Several epidemiological studies have identified obstructive sleep apnea (OSA) as a risk factor for systemic hypertension, but a direct etiologic link between the two disorders has not been established definitively. Furthermore, the specific physiological mechanisms underlying the association between OSA and systemic hypertension have not been identified. The purpose of this study was to systematically examine the effects of OSA on daytime and nighttime blood pressure (BP). We induced OSA in four dogs by intermittent airway occlusion during nocturnal sleep. Daytime and nighttime BP were measured before, during, and after a 1-3-mo long period of OSA. OSA resulted in acute transient increases in nighttime BP to a maximum of 13.0 Ϯ 2.0 mmHg (mean Ϯ SEM), and eventually produced sustained daytime hypertension to a maximum of 15.7 Ϯ 4.3 mmHg. In a subsequent protocol, recurrent arousal from sleep without airway occlusion did not result in daytime hypertension. The demonstration that OSA can lead to the development of sustained hypertension has considerable importance, given the high prevalence of both disorders in the population. ( J. Clin. Invest. 1997. 99:106-109.)

The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of the neurons mediating this depression are unknown. By locally manipulating neurotransmission in the adult rat, we identify the critical site of the medulla, the preBötzinger complex, that mediates opioid-induced respiratory depression in vivo. Here we show that opioids at the preBötzinger complex cause respiratory depression or fatal apnea, with anesthesia and deep-sleep being particularly vulnerable states for opioid-induced respiratory depression. Importantly, we establish that the preBötzinger complex is fully responsible for respiratory rate suppression following systemic administration of opioid analgesics. The site in the medulla most sensitive to opioids corresponds to a region expressing neurokinin-1 receptors, and we show in rhythmically active brainstem section in vitro that neurokinin-1 receptor-expressing preBötz-inger complex neurons are selectively inhibited by opioids. In summary, neurokinin-1 receptor-expressing preBötzinger complex neurons constitute the critical site mediating opioid-induced respiratory rate depression, and the key therapeutic target for its prevention or reversal.

SUMMARY1. To determine if negative upper airway pressure causes reflex pharyngeal dilator muscle activation, we used intra-oral bipolar surface electrodes to record genioglossus electromyogram (EMG) activity in response to 500 ms duration pressure stimuli of 0. -25.-5.-15, -25 and -35 cmH2O (0-90 % rise time < 30 ms) in ten normal, conscious, supine subjects.2. WN&ith the subjects relaxed at end-expiration, stimuli were applied in each of three conditions: (i) glottis open (GO), (ii) glottis closed (GC) and (iii) controls with the mouth and nose closed.3. Six rectified and integrated EMG responses were bin averaged for each pressure in each experimental condition. Response latency was defined as the time when the EMG activity significantly increased above pre-stimulus levels. Response magnitude was quantified as the ratio of the EMG activity for 80 ms post-stimulus to 80 ms prestimulus; data from after the subject's voluntary reaction time (for tongue protrusion) were not analysed.4. Negative airway pressure activated the genioglossus. The median latency of activation (34 ms) was much faster than the time for voluntary activation (184 ms) indicating a reflex response.5. Significant activation, compared to 0 cmH20 controls and controls with mouth and nose closed, occurred with pressures of at least -5 cmH2O (GC) and -15 cmH2O (GO). , responses with GO were significantly greater than with GC.6. The magnitude ('strength') of the responses differed between subjects; these differences were repeatable.7. WTe conclude that negative airway pressure causes reflex pharyngeal dilator muscle activation in man. Responses with GC suggest that upper airway receptors can mediate the response but larger responses with GO indicate a contribution from subglottal receptors.

Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.

The genioglossus (GG) muscle of the tongue contributes to effective lung ventilation by maintaining an open pharyngeal airway. Decreased GG activity in sleep, especially REM sleep (Sauerland & Harper, 1976) can lead to airway narrowing, increased upper airway resistance and hypoventilation (Henke et al. 1992). In individuals with already anatomically narrow upper airways, such GG suppression can produce airway occlusion and obstructive sleep apnoea (Remmers et al. 1978), a serious sleep-related breathing disorder affecting approximately 4 % of adults (Young et al. 1993). However, despite increased knowledge of the major effects of sleep on GG activity, it is still not known which brainstem neural circuits and neurotransmitters modulate hypoglossal (XII) motor output to GG muscle in wakefulness and natural sleep.In vitro studies using neonatal tissue slices have shown that 5-HT depolarizes and increases the excitability of XII motoneurons (Berger et al. 1992). 5-HT also facilitates XII motoneurons in decerebrate cats (Kubin et al. 1992;Douse & White, 1996). Medullary raphe neurons provide the 5-HT inputs to XII motor nucleus (Manaker & Tischler, 1993) and show decreasing discharge from wakefulness to non-REM and REM sleep (Jacobs & Azmitia, 1992). There is also decreased discharge of medullary raphe neurons projecting to XII motor nucleus in a pharmacological model of REM sleep evoked by carbachol microinjection into the pontine reticular formation of decerebrate cats (Woch et al. 1996). This pharmacological REM-like state in decerebrate cats is also associated with reduced 5-HT at the XII motor nucleus (Kubin et al. 1994). 1. Serotonin (5-hydroxytryptamine, 5-HT) excites hypoglossal (XII) motoneurons in reduced preparations, and it has been suggested that withdrawal of 5-HT may underlie reduced genioglossus (GG) muscle activity in sleep. However, systemic administration of 5-HT agents in humans has limited effects on GG activity. Whether 5-HT applied directly to the XII motor nucleus increases GG activity in an intact preparation either awake or asleep has not been tested.2. The aim of this study was to develop a novel freely behaving animal model for in vivo microdialysis of the XII motor nucleus across sleep-wake states, and test the hypothesis that 5-HT application will increase GG activity.3. Eighteen rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the XII motor nucleus and perfused with artificial cerebrospinal fluid (ACSF) or 10 mM 5-HT.4. Normal decreases in GG activity occurred from wakefulness to non-rapid eye movement (non-REM) and REM sleep with ACSF (P < 0.01). Compared to ACSF, 5-HT caused marked GG activation across all sleep-wake states (increases of 91-251 %, P < 0.015). Importantly, 5-HT increased sleeping GG activity to normal waking levels for as long as 5-HT was applied (3-5 h). Despite tonic stimulation by 5-HT, periods of phasic GG ...