Cardiovascular response to arousal from sleep under controlled conditions of central and peripheral chemoreceptor stimulation in humans.

The cardiovascular response to an arousal occurring at the termination of an obstructive apnea is almost double that to a spontaneous arousal. We investigated the hypothesis that central plus peripheral chemoreceptor stimulation, induced by hypercapnic hypoxia (HH), augments the cardiovascular response to arousal from sleep. Auditory-induced arousals during normoxia and HH (>10-s duration) were analyzed in 13 healthy men [age 24 +/- 1 (SE) yr]. Subjects breathed on a respiratory circuit that held arterial blood gases constant, despite the increased ventilation associated with arousal. Arousals were associated with a significant increase in mean arterial blood pressure at 5 s (P < 0.001) and with a significant decrease in the R-R interval at 3 s (P < 0.001); however, the magnitude of the changes was not significantly different during normoxia compared with HH (mean arterial blood pressure: normoxia, 91 +/- 4 to 106 +/- 4 mmHg; HH, 91 +/- 4 to 109 +/- 5 mmHg; P = 0.32; R-R interval: normoxia, 1.12 +/- 0.04 to 0.90 +/- 0.05 s; HH, 1.09 +/- 0.05 to 0.82 +/- 0.03 [corrected] s; P = 0.78). Mean ventilation increased significantly at the second breath postarousal for both conditions (P < 0.001), but the increase was not significantly different between the two conditions (normoxia, 5.35 +/- 0.40 to 9.57 +/- 1.69 l/min; HH, 8.57 +/- 0.63 to 11.98 +/- 0.70 l/min; P = 0.71). We conclude that combined central and peripheral chemoreceptor stimulation with the use of HH does not interact with the autonomic outflow associated with arousal from sleep to augment the cardiovascular response.     

Response to inspiratory resistive loading during sleep in normal children and children with obstructive apnea.

The response to inspiratory resistance loading (IRL) of the upper airway during sleep in children is not known. We, therefore, evaluated the arousal responses to IRL during sleep in children with the obstructive sleep apnea syndrome (OSAS) compared with controls. Children with OSAS aroused at a higher load than did controls (23 +/- 8 vs. 15 +/- 7 cmH(2)O. l(-1). s; P < 0.05). Patients with OSAS had higher arousal thresholds during rapid eye movement (REM) vs. non-REM sleep (P < 0.001), whereas normal subjects had lower arousal thresholds during REM (P < 0.005). Ventilatory responses to IRL were evaluated in the controls. There was a marked decrease in tidal volume both immediately (56 +/- 17% of baseline at an IRL of 15 cmH(2)O. l(-1). min; P < 0.001) and after 3 min of IRL (67 +/- 23%, P < 0.005). The duty cycle increased. We conclude that children with OSAS have impaired arousal responses to IRL. Despite compensatory changes in respiratory timing, normal children have a decrease in minute ventilation in response to IRL during sleep. However, arousal occurs before gas-exchange abnormalities.     

Hypoxemia alone does not explain blood pressure elevations after obstructive apneas

In patients with obstructive sleep apnea (OSA), substantial elevations of systemic blood pressure (BP) and depressions of oxyhemoglobin saturation (SaO2) accompany apnea termination. The causes of the BP elevations, which contribute significantly to nocturnal hypertension in OSA, have not been defined precisely. To assess the relative contribution of arterial hypoxemia, we observed mean arterial pressure (MAP) changes following obstructive apneas in 11 OSA patients during non-rapid-eye-movement (NREM) sleep and then under three experimental conditions: 1) apnea with O2 supplementation; 2) hypoxemia (SaO2 80%) without apnea; and 3) arousal from sleep with neither hypoxemia nor apnea. We found that apneas recorded during O2 supplementation (SaO2 nadir 93.6% +/- 2.4; mean +/- SD) in six subjects were associated with equivalent postapneic MAP elevations compared with unsupplemented apneas (SaO2 nadir 79-82%): 18.8 +/- 7.1 vs. 21.3 +/- 9.2 mmHg (mean change MAP +/- SD); in the absence of respiratory and sleep disruption in eight subjects, hypoxemia was not associated with the BP elevations observed following apneas: -5.4 +/- 19 vs. 19.1 +/- 7.8 mmHg (P less than 0.01); and in five subjects, auditory arousal alone was associated with MAP elevation similar to that observed following apneas: 24.0 +/- 8.1 vs. 22.0 +/- 6.9 mmHg. We conclude that in NREM sleep postapneic BP elevations are not primarily attributable to arterial hypoxemia. Other factors associated with apnea termination, including arousal from sleep, reinflation of the lungs, and changes of intrathoracic pressure, may be responsible for these elevations.     

Comparison of arousal responses to tracheal and face mask occlusions in sleeping newborn piglets.

The arousal responses after occlusion of the airway at the mid-trachea were compared with the responses after occlusion of the airway in a face mask in chronically instrumented 3- to 5-day-old piglets. For each site of occlusion arousal latency was significantly longer from active sleep than from quiet sleep. There was a significant increase in the frequency of early arousals after face mask occlusions compared with tracheal occlusions in both sleep states. During quiet sleep the frequency of arousal by 1 s after occlusion was 0.55 with face mask occlusions compared with 0.28 with tracheal occlusion (P less than 0.01). During active sleep the frequency of arousal by 3 s after a face mask occlusion was 0.32 compared with 0.08 after tracheal occlusion (P less than 0.05). Arousal from quiet sleep occurred before changes in arterial oxygen saturation. During active sleep mean saturation at arousal was not different between face mask and tracheal occlusions. Exposure of the upper airway to the pressures generated during airway occlusions results in earlier arousal in both quiet and active sleep, indicating a potential role for upper airway mechanoreceptors in initiating arousal in the newborn piglet.     

Cerebral blood flow response to isocapnic hypoxia during slow-wave sleep and wakefulness.

Nocturnal hypoxia is a major pathological factor associated with cardiorespiratory disease. During wakefulness, a decrease in arterial O2 tension results in a decrease in cerebral vascular tone and a consequent increase in cerebral blood flow; however, the cerebral vascular response to hypoxia during sleep is unknown. In the present study, we determined the cerebral vascular reactivity to isocapnic hypoxia during wakefulness and during stage 3/4 non-rapid eye movement (NREM) sleep. In 13 healthy individuals, left middle cerebral artery velocity (MCAV) was measured with the use of transcranial Doppler ultrasound as an index of cerebral blood flow. During wakefulness, in response to isocapnic hypoxia (arterial O2 saturation -10%), the mean (+/-SE) MCAV increased by 12.9 +/- 2.2% (P < 0.001); during NREM sleep, isocapnic hypoxia was associated with a -7.4 +/- 1.6% reduction in MCAV (P <0.001). Mean arterial blood pressure was unaffected by isocapnic hypoxia (P >0.05); R-R interval decreased similarly in response to isocapnic hypoxia during wakefulness (-21.9 +/- 10.4%; P <0.001) and sleep (-20.5 +/- 8.5%; P <0.001). The failure of the cerebral vasculature to react to hypoxia during sleep suggests a major state-dependent vulnerability associated with the control of the cerebral circulation and may contribute to the pathophysiologies of stroke and sleep apnea.     

Arousal responses to airway occlusion in sleeping dogs: comparison of nasal and tracheal occlusions

Previous studies have shown that the arousal threshold to hypoxia, hypercapnia, and tracheal occlusions is greatly depressed in rapid-eye-movement (REM) sleep compared with slow-wave sleep (SWS). The aim of this study was to compare the arousal thresholds in SWS and REM sleep in response to an upper airway pressure stimulus. We compared the waking responses to tracheal (T) vs. nasal (N) occlusion in four unanesthetized, naturally sleeping dogs. The dogs either breathed through a tracheal fistula or through the snout using a fiberglass mask. A total of 295 T and 160 N occlusion tests were performed in SWS and REM sleep. The mean time to arousal during N and T tests was variable in the same dog and among the dogs. The mean time to arousal in SWS-tracheal occlusion was longer than that in N tests in only two of the four dogs. The total number of tests inducing arousal within the first 15 s of SWS-nasal occlusion tests was significantly more than that of T tests (N: 47%; T: 27%). There was a marked depression of arousal within the initial 15 s of REM sleep in T tests compared with N tests (N: 21%; T: 0%). The frequency of early arousals in REM tests was less than that of SWS for both N and T tests. The early arousal in N occlusion is in sharp contrast to the well-described depressed arousal responses to hypoxia, hypercapnia, and asphyxia. This pattern of arousal suggests that the upper airway mechanoreceptors may play an important role in the induction of an early arousal from nasal occlusion.     

Effect of bilateral vagotomy on oxygenation, arousal, and breathing movements in fetal sheep.

To investigate the effects of bilateral cervical vagotomy on arousal and breathing responses, we studied eight sham-operated and eight chronically instrumented unanesthetized vagotomized sheep fetuses between 136 and 144 days of gestation (term approximately 147 days). Each fetus was instrumented to record sleep states, diaphragmatic electromyogram, blood pressure, pH, and blood gas tensions. In a randomized order, fetal lungs were distended with four different O2 concentrations: 0 (100% N2), 21, 50, and 100% at a continuous positive airway pressure of 30 cmH2O via an in situ Y-endotracheal tube. Under control conditions, inspiratory time and the duration of the single longest breathing episode decreased from 598 +/- 99 (SD) ms and 24 +/- 10 min in sham group to 393 +/- 162 ms and 11.0 +/- 3.0 min in vagotomized group (P = 0.04 and 0.033), respectively. In response to lung distension with 100% N2, breathing time decreased from 44 +/- 17 to 20 +/- 18% (P = 0.045) in sham-operated fetuses, whereas it remained unchanged in the vagotomized group. In response to 100% O2, fetal arterial PO2 increased in five of eight fetuses sham-operated from 18.2 +/- 5.1 to 227 +/- 45 Torr (P = 0.0001) and in six of eight vagotomized fetuses from 18.5 +/- 4.4 to 172 +/- 39 Torr (P < 0.001). Although arousal was observed in all oxygenated fetuses at the onset of breathing, the duration of arousal was markedly attenuated in vagotomized fetuses (14 +/- 10 vs. 46 +/- 29 min in sham group; P = 0.024). Frequency and amplitude of breathing and respiratory output (frequency x amplitude) increased only in sham group (P = 0.02, 0.004, and 0.0002, respectively). We conclude that in response to lung distension and oxygenation, arousal and stimulation of breathing during active and quite sleep are critically dependent on intact vagal nerves.     

Patients with obstructive sleep apnea have an abnormal peripheral vascular response to hypoxia.

Patients with obstructive sleep apnea (OSA) have been reported to have an augmented pressor response to hypoxic rebreathing. To assess the contribution of the peripheral vasculature to this hemodynamic response, we measured heart rate, mean arterial pressure (MAP), and forearm blood flow by venous occlusion plethysmography in 13 patients with OSA and in 6 nonapneic control subjects at arterial oxygen saturations (Sa(O(2))) of 90, 85, and 80% during progressive isocapnic hypoxia. Measurements were also performed during recovery from 5 min of forearm ischemia induced with cuff occlusion. MAP increased similarly in both groups during hypoxia (mean increase at 80% Sa(O(2)): OSA patients, 9 +/- 11 mmHg; controls, 12 +/- 7 mmHg). Forearm vascular resistance, calculated from forearm blood flow and MAP, decreased in controls (mean change -37 +/- 19% at Sa(O(2)) 80%) but not in patients (mean change -4 +/- 16% at 80% Sa(O(2))). Both groups decreased forearm vascular resistance similarly after forearm ischemia (maximum change from baseline -85%). We conclude that OSA patients have an abnormal peripheral vascular response to isocapnic hypoxia.     

Cardiovascular autonomic function correlates with the response to aerobic training in healthy sedentary subjects

Individual responses to aerobic training vary from almost none to a 40% increase in aerobic fitness in sedentary subjects. The reasons for these differences in the training response are not well known. We hypothesized that baseline cardiovascular autonomic function may influence the training response. The study population included sedentary male subjects (n = 39, 35 +/- 9 yr). The training period was 8 wk, including 6 sessions/wk at an intensity of 70-80% of the maximum heart rate for 30-60 min/session. Cardiovascular autonomic function was assessed by measuring the power spectral indexes of heart rate variability from 24-h R-R interval recordings before the training period. Mean peak O2 uptake increased by 11 +/- 5% during the training period (range 2-19%). The training response correlated with age (r = -0.39, P = 0.007) and with the values of the high-frequency (HF) spectral component of R-R intervals (HF power) analyzed over the 24-h recording (r = 0.46, P = 0.002) or separately during the daytime hours (r = 0.35, P = 0.028) and most strongly during the nighttime hours (r = 0.52, P = 0.001). After adjustment for age, HF power was still associated with the training response (e.g., P = 0.001 analyzed during nighttime hours). These data show that cardiovascular autonomic function is an important determinant of the response to aerobic training among sedentary men. High vagal activity at baseline is associated with the improvement in aerobic power caused by aerobic exercise training in healthy sedentary subjects.     

Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep.

Six healthy subjects (5 males and 1 female, 26-40 yr old) were studied during non-rapid-eye-movement (NREM) sleep to assess the role of upper airway (UA) afferents in the arousal response to induced airway occlusion. Subjects wore an airtight face mask attached to a low-resistance one-way valve. A valve in the inspiratory circuit allowed instantaneous inspiratory airway occlusion and release; the expiratory circuit remained unoccluded at all times. Each subject was studied during two nights. On one night, occlusions were created during stable stage 2 NREM sleep before and after application of 4% lidocaine to the oral and nasal mucosa. On the other night, the protocol was duplicated with saline ("sham anesthesia") rather than lidocaine. The order of nights was randomized. Occlusions were sustained until electroencephalographic arousal. Three to 12 occlusions were performed in each subject for each of the four parts of the protocol (pre- and post-lidocaine, pre- and post-saline). The auditory threshold for arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after UA lidocaine. For the group, arousal time after UA anesthesia was prolonged compared with preanesthesia arousal time (P less than 0.001); arousal time after sham anesthesia did not significantly increase from before sham anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was greater than the increase with sham anesthesia (P less than 0.001). The auditory arousal threshold did not increase after UA anesthesia. Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and end-tidal PCO2 during occlusions were similar before and after UA anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodepressor reaction induced by inferior vena caval occlusion and isoproterenol.

Testing for the susceptibility for vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol. To explore the basis of the vasodepressor test in humans, the present experiment examined whether a reduced cardiac volume coupled with adrenergic stimulation causes a vasodepressor reaction in rats. Vasodepressor reaction was defined as paradoxical heart rate slowing in conjunction with hypotension during inferior vena caval occlusion. Inferior vena caval occlusion was performed for 60 s and the maximum changes in R-R were measured during seven states as follows. (A) Under control conditions inferior vena caval occlusion alone accelerated the rate in 32 of 32 rats (delta R-R, -13.9 +/- 1.7 ms, p less than 0.001). (B) When inferior vena caval occlusion was performed during an infusion of isoproterenol (0.5-1.0 micrograms.min-1), a vasodepressor reaction was observed in all rats as the heart rate slowed (delta R-R, +138.1 +/- 14.8 ms, p less than 0.001). The vasodepressor reaction was further examined during isoproterenol and inferior vena caval occlusion under five additional states. (C) After atropine the vasodepressor reaction was unchanged (delta R-R, +132.7 +/- 24.8 ms, p less than 0.001). (D) After bilateral vagotomy the paradoxical slowing was eliminated. (E) After intrapericardial lidocaine the paradoxic slowing was eliminated. (F) After bilateral stellectomy nonsignificant slowing was still present, but this was markedly reduced when compared with B (p less than 0.001). (G) Following chronic chemical sympathetic denervation with 6-hydroxydopamine the paradoxic bradycardia was eliminated. Conclusions: (1) Reduced cardiac volume combined with adrenergic stimulation can stimulate a vasodepressor reaction; (2) the vasodepressor reaction requires signalling by the afferent but not efferent vagal fibers; (3) the bradycardia is mainly due to withdrawal of sympathetic efferent tone.     

Cardiac changes during arousals from non-REM sleep in healthy volunteers

Our aim was to evaluate cardiac changes evoked by spontaneous and sound-induced arousals from sleep. Cardiac responses to spontaneous and auditory-induced arousals were recorded during overnight sleep studies in 28 young healthy subjects (14 males, 14 females) during non-rapid eye movement sleep. Computerized analysis was applied to assess beat-to-beat changes in heart rate, atrio-ventricular conductance, and ventricular repolarization from 30 s before to 60 s after the auditory tone. During both types of arousals, the most consistent change was the increase in the heart rate (in 62% of spontaneous and in 89% of sound-induced arousals). This was accompanied by an increase or no change in PR interval and by a decrease or no change in QT interval. The magnitude of all cardiac changes was significantly higher for tone-induced vs. spontaneous arousals (mean +/- SD for heart rate: +9 +/- 8 vs. +13 +/- 9 beats per min; for PR prolongation: 14 +/- 16 vs. 24 +/- 22 ms; for QT shortening: -12 +/- 6 vs. -20 +/- 9 ms). The prevalence of transient tachycardia and PR prolongation was also significantly higher for tone-induced vs. spontaneous arousals (tachycardia: 85% vs. 57% of arousals, P < 0.001; PR prolongation: 51% vs. 25% of arousals, P < 0.001). All cardiac responses were short-lasting (10-15 s). We conclude that cardiac pacemaker region, conducting system, and ventricular myocardium may be under independent neural control. Prolongation of atrio-ventricular delay may serve to increase ventricular filling during arousal from sleep. Whether prolonged atrio-ventricular conductance associated with increased sympathetic outflow to the ventricular myocardium contributes to arrhythmogenesis during sudden arousal from sleep remains to be evaluated.     

nCPAP improves abnormal autonomic function in at-risk-for-SIDS infants with OSA.

We evaluated cardiovascular autonomic control and arousability during sleep in infants with obstructive sleep apnea (OSA) before and after 10 +/- 4 (mean +/- SD) days of treatment with nasal continuous positive airway pressure (nCPAP). Six OSA infants and 12 age-matched control infants were studied with polygraphic sleep studies at the age of 13 +/- 4 wk. During the study, 45 degrees head-up tilt tests were performed in slow-wave and rapid eye movement sleep. Blood pressure (BP) and heart rate (HR) were continuously monitored. All OSA infants had decreased initial BP and HR responses, followed by hypotension in two and hypertension in two. OSA infants displayed higher arousal thresholds in response to the tilt in rapid eye movement sleep (P < 0.005) and higher baseline HR (P < 0.05) than controls. nCPAP treatment normalized BP and HR responses as well as arousal thresholds to tilting and stabilized HR levels. OSA in infants may be linked with cardiovascular autonomic control disturbances and decreased arousability during sleep. These defects are improved by control of OSA with nCPAP.     

Influence of sleep state on frequency of swallowing, apnea, and arousal in human infants.

Apnea and arousal are modulated with sleep stage, and swallowing may interfere with respiratory rhythm in infants. We hypothesized that swallowing itself would display interaction with sleep state. Concurrent polysomnography and measurement of swallowing allowed time-matched analysis of 3,092 swallows, 482 apneas, and 771 arousals in 17 infants aged 1-34 wk. The mean rates of swallowing, apnea, and arousal were significantly different, being 23.3 +/- 8.5, 9.4 +/- 8.8, and 15.5 +/- 10.6 h(-1), respectively (P < 0.001 ANOVA). Swallows occurred before 25.2 +/- 7.9% and during 74.8 +/- 6.3% of apneas and before 39.8 +/- 6.0% and during 60.2 +/- 6.0% of arousals. The frequencies of apneas and arousals were both strongly influenced by sleep state (active sleep > indeterminate > quiet sleep, P < 0.001), whether or not the events coincided with swallowing, but swallowing rate showed minimal independent interaction with sleep state. Interactions between swallowing and sleep state were predominantly influenced by the coincidence of swallowing with apnea or arousal.     

Effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnea.

During obstructive sleep apnea (OSA), systemic (Psa) and pulmonary (Ppa) arterial pressures acutely increase after apnea termination, whereas left and right ventricular stroke volumes (SV) reach a nadir. In a canine model (n = 6), we examined the effects of arousal, parasympathetic blockade (atropine 1 mg/kg iv), and sleep state on cardiovascular responses to OSA. In the absence of arousal, SV remained constant after apnea termination, compared with a 4.4 +/- 1.7% decrease after apnea with arousal (P < 0.025). The rise in transmural Ppa was independent of arousal (4.5 +/- 1.0 vs. 4.1 +/- 1.2 mmHg with and without arousal, respectively), whereas Psa increased more after apnea termination in apneas with arousal compared with apneas without arousal. Parasympathetic blockade abolished the arousal-induced increase in Psa, indicating that arousal is associated with a vagal withdrawal of the parasympathetic tone to the heart. Rapid-eye-movement (REM) sleep blunted the increase in Psa (pre- to end-apnea: 5.6 +/- 2.3 mmHg vs. 10.3 +/- 1.6 mmHg, REM vs. non-REM, respectively, P < 0.025), but not transmural Ppa, during an obstructive apnea. We conclude that arousal and sleep state both have differential effects on the systemic and pulmonary circulation in OSA, indicating that, in patients with underlying cardiovascular disease, the hemodynamic consequences of OSA may be different for the right or the left side of the circulation.     

Oxygen-conserving effects of apnea in exercising men.

We sought to determine whether apnea-induced cardiovascular responses resulted in a biologically significant temporary O(2) conservation during exercise. Nine healthy men performing steady-state leg exercise carried out repeated apnea (A) and rebreathing (R) maneuvers starting with residual volume +3.5 liters of air. Heart rate (HR), mean arterial pressure (MAP), and arterial O(2) saturation (Sa(O(2)); pulse oximetry) were recorded continuously. Responses (DeltaHR, DeltaMAP) were determined as differences between HR and MAP at baseline before the maneuver and the average of values recorded between 25 and 30 s into each maneuver. The rate of O(2) desaturation (DeltaSa(O(2))/Deltat) was determined during the same time interval. During apnea, DeltaSaO(2)/Deltat had a significant negative correlation to the amplitudes of DeltaHR and DeltaMAP (r(2) = 0.88, P < 0.001); i.e., individuals with the most prominent cardiovascular responses had the slowest DeltaSa(O(2))/Deltat. DeltaHR and DeltaMAP were much larger during A (-44 +/- 8 beats/min, +49 +/- 4 mmHg, respectively) than during R maneuver (+3 +/- 3 beats/min, +30 +/- 5 mmHg, respectively). DeltaSa(O(2))/Deltat during A and R maneuvers was -1.1 +/- 0.1 and -2.2 +/- 0.2% units/s, respectively, and nadir Sa(O(2)) values were 58 +/- 4 and 42 +/- 3% units, respectively. We conclude that bradycardia and hypertension during apnea are associated with a significant temporary O(2) conservation and that respiratory arrest, rather than the associated hypoxia, is essential for these responses.     

Temperature modulates P2X receptor-mediated cardiovascular responses to muscle afferent activation

Static muscle contraction increases ATP release into the muscle interstitial space. Elevated ATP in muscle stimulates thin fiber muscle afferents and increases blood pressure via engagement of purinergic P2X receptors. In addition, ATP activates P2X receptors and enhances cardiovascular responses induced by stimulation of muscle mechanoreceptors. In this study, we examined whether elevated muscle temperature would attenuate and whether reduced temperature would potentiate P2X effects on reflex muscle responses. alpha,beta-Methylene ATP (alpha,beta-MeATP) was injected into the arterial blood supply of hindlimb muscle to stimulate P2X receptors, and muscle stretch was induced to activate mechanically sensitive muscle afferents as alpha,beta-MeATP was injected in 10 anesthetized cats. Femoral arterial injection of alpha,beta-MeATP (1.0 mM) increased mean arterial pressure (MAP) by 35+/-5 (35 degrees C), 26+/-3 (37 degrees C), and 19+/-3 mmHg (39 degrees C; P<0.05 vs. 35 degrees C), respectively. Muscle stretch (2 kg) elevated MAP. The MAP response was significantly enhanced 34% and 36% when alpha,beta-MeATP (0.2 mM) was arterially infused 5 min before muscle stretch at 35 degrees and 37 degrees C, respectively. However, as muscle temperature reached 39 degrees C, the stretch-evoked response was augmented only 6% by alpha,beta-MeATP injection, and the response was significantly attenuated compared with the response with muscle temperature of 35 degrees and 37 degrees C. In addition, we also examined effects of muscle temperature on alpha,beta-MeATP enhancement of the cardiovascular responses to static muscle contraction while the muscles were freely perfused and the circulation to the muscles was occluded. Because muscle temperature was 37 degrees C, arterial injections of alpha,beta-MeATP significantly augmented contraction-evoked MAP response by 49% (freely perfused) and 53% (ischemic condition), respectively. It is noted that this effect was significantly attenuated at a muscle temperature of 39 degrees C. These data indicate that the effect of P2X receptor on reflex muscle response is sensitive to alternations of muscle temperature and that elevated temperature attenuates the response.     

A model of sleep-disordered breathing in the C57BL/6J mouse.

To investigate the pathophysiological sequelae of sleep-disordered breathing (SDB), we have developed a mouse model in which hypoxia was induced during periods of sleep and was removed in response to arousal or wakefulness. An on-line sleep-wake detection system, based on the frequency and amplitude of electroencephalograph and electromyograph recordings, served to trigger intermittent hypoxia during periods of sleep. In adult male C57BL/6J mice (n = 5), the sleep-wake detection system accurately assessed wakefulness (97.2 +/- 1.1%), non-rapid eye movement (NREM) sleep (96.0 +/- 0.9%) and rapid eye movement (REM) sleep (85.6 +/- 5.0%). After 5 consecutive days of SDB, 554 +/- 29 (SE) hypoxic events were recorded over a 24-h period at a rate of 63.6 +/- 2.6 events/h of sleep and with a duration of 28.2 +/- 0.7 s. The mean nadir of fraction of inspired O(2) (FI(O(2))) on day 5 was 13.2 +/- 0.1%, and 137.1 +/- 13.2 of the events had a nadir FI(O(2)) <10% O(2). Arterial blood gases confirmed that hypoxia of this magnitude lead to a significant degree of hypoxemia. Furthermore, 5 days of SDB were associated with decreases in both NREM and REM sleep during the light phase compared with the 24-h postintervention period. We conclude that our murine model of SDB mimics the rate and magnitude of sleep-induced hypoxia, sleep fragmentation, and reduction in total sleep time found in patients with moderate to severe SDB in the clinical setting.     

Inspiratory-resistive loading increases the ventilatory response to arousal but does not reduce genioglossus muscle activity on the return to sleep

Arousals from sleep are thought to predispose to obstructive sleep apnea by causing hyperventilation and hypocapnia, which reduce airway dilator muscle activity on the return to sleep. However, prior studies of auditory arousals have not resulted in reduced genioglossus muscle activity [GG-electromyogram (EMG)], potentially because airway resistance prior to arousal was low, leading to a small ventilatory response to arousal and minimal hypocapnia. Thus we aimed to increase the ventilatory response to arousal by resistive loading prior to auditory arousal and determine whether reduced GG-EMG occurred on the return to sleep. Eighteen healthy young men and women were recruited. Subjects were instrumented with a nasal mask with a pneumotachograph, an epiglottic pressure catheter, and intramuscular GG-EMG electrodes. Mask CO(2) levels were monitored. Three- to 15-s arousals from sleep were induced with auditory tones after resting breathing (No-Load) or inspiratory-resistive loading (Load; average 8.4 cmH(2)O·l(-1)·s(-1)). Peak minute ventilation following arousal was greater after Load than No-Load (mean ± SE; 8.0 ± 0.6 vs. 7.4 ± 0.6 l/min, respectively). However, the nadir end tidal partial pressure of CO(2) did not differ between Load conditions (43.1 ± 0.6 and 42.8 ± 0.5 mmHg, respectively), and no period of reduced GG activity occurred following the return to sleep (GG-EMG baseline, minimum after Load and No-Load = 2.9 ± 1.2%, 3.1 ± 1.3%, and 3.0 ± 1.3% max, respectively). These findings indicate that the hyperventilation, which occurs following tone-induced arousal, is appropriate for the prevailing level of respiratory drive, because loading did not induce marked hypocapnia or lower GG muscle activity on the return to sleep. Whether similar findings occur following obstructive events in patients remains to be determined.     

Hemodynamic responses to static and dynamic muscle contractions at equivalent workloads

We tested the hypothesis that static contraction causes greater reflex cardiovascular responses than dynamic contraction at equivalent workloads [i.e., same tension-time index (TTI), holding either contraction time or peak tension constant] in chloralose-anesthetized cats. When time was held constant and tension was allowed to vary, dynamic contraction of the hindlimb muscles evoked greater increases (means +/- SE) in mean arterial pressure (MAP; 50 +/- 7 vs. 30 +/- 5 mmHg), popliteal blood velocity (15 +/- 3 vs. 5 +/- 1 cm/s), popliteal venous PCO(2) (15 +/- 3 vs. 3 +/- 1 mmHg), and a greater decrease in popliteal venous pH (0.07 +/- 0.01 vs. 0.03 +/- 0.01), suggesting greater metabolic stimulation during dynamic contraction. Similarly, when peak tension was held constant and time was allowed to vary, dynamic contraction evoked a greater increase in blood velocity (13 +/- 1 vs. -1 +/- 1 cm/s) without causing any differences in other variables. To investigate the reflex contribution of mechanoreceptors, we stretched the hindlimb dynamically and statically at the same TTI. A larger reflex increase in MAP during dynamic stretch (32 +/- 8 vs. 24 +/- 6 mmHg) was observed when time was held constant, indicating greater mechanoreceptor stimulation. However, when peak tension was held constant, there were no differences in the reflex cardiovascular response to static and dynamic stretch. In conclusion, at comparable TTI, when peak tension is variable, dynamic muscle contraction causes larger cardiovascular responses than static contraction because of greater chemical and mechanical stimulation. However, when peak tensions are equivalent, static and dynamic contraction or stretch produce similar cardiovascular responses.