Journal of Applied Physiology Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 82: 1637-1643, 1997;
8750-7587/97 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zinkovska, S.
Right arrow Articles by Kirby, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zinkovska, S.
Right arrow Articles by Kirby, D. A.

Journal of Applied Physiology
Vol. 82, No. 5, pp. 1637-1643, May 1997
CONTROL OF BREATHING, CIRCULATION, AND TEMPERATURE

Intracerebroventricular propranolol prevented vascular resistance increases on arousal from sleep apnea

Sophia Zinkovska and Debra A. Kirby

Children's Hospital, Harvard Medical School, Boston 02115; and Veterans Affairs Medical Center, West Roxbury, Massachusetts 02132

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Zinkovska, Sophia, and Debra A. Kirby. Intracerebroventricular propranolol prevented vascular resistance increases on arousal from sleep apnea. J. Appl. Physiol. 82(5): 1637-1643, 1997.---Despite the increased risk of sudden cardiac death associated with sleep apnea, little is known about mechanisms controlling cardiovascular responses to sleep apnea and arousal. Chronically instrumented pigs were used to investigate the effects of airway obstruction (AO) during rapid-eye-movement (REM) and non-REM (NREM) sleep and arousal on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). A stainless steel cannula was implanted in the lateral cerebral ventricle. During REM sleep, HR was 133 ± 10 beats/min, MAP was 65 ± 3 mmHg, CO was 1,435 ± 69 ml/min, and TPR was 0.046 ± 0.004 mmHg · ml-1 · min. During AO, CO decreased by 90 ± 17 ml/min (P < 0.05). On arousal from AO, MAP increased by 15 ± 3 mmHg, HR increased by 10 ± 3 beats/min, and TPR increased by 0.008 ± 0.001 mmHg · ml-1 · min (all P < 0.05). Changes during NREM were similar but were more modest during AO. After the intracerebroventricular administration of propranolol (50 µg/kg; a beta -adrenoreceptor blocking agent), decreases in CO during AO and increases in HR during arousal were intact, but increases in MAP and TPR were no longer significant. These data suggest that vascular responses to AO during sleep may be regulated in part by beta -adrenergic receptors in the central nervous system.

brain; beta -adrenoreceptor; pig

INTRODUCTION

CHRONIC OBSTRUCTIVE SLEEP APNEA is associated with increased mortality, hypertension, and arrhythmia (5, 11-13, 15, 17-19). Patients with obstructive sleep apnea experience repetitive upper airway obstructions (AOs) during sleep. These episodes last 10 s or more and are terminated on arousal, with attendant increases in upper airway dilator muscle activity leading to restoration of airway patency. Apnea termination in patients with sleep apnea is associated with an increase in mean arterial pressure (MAP) and heart rate (HR). This increase in MAP occurs against a background of changes in intrathoracic pressure, O2 saturation, lung volume, and sleep state (11, 30, 33). In individuals with reduced and compromised myocardial circulation, hemodynamic changes at apnea termination may tip the balance of myocardial O2 supply and demand, setting the stage for ischemia and dysrhythmia. Little is known about changes in cardiac function or systemic resistance during apnea and arousal or about how these changes are mediated.

Specific brain regions may be involved in vasoconstriction that occurs in response to sleep apnea and arousal. Intracerebroventricular (icv) injection of adrenergic agonists and antagonists has been shown to have substantial effects on HR and blood pressure (6, 27, 28, 32) and to alter left ventricular function and latency to ventricular fibrillation (25), as well as incidence of ventricular fibrillation during ischemia (21). This study was designed to test the hypothesis that beta -receptor activation in the central nervous system may be involved in hemodynamic responses to obstructive sleep apnea.

METHODS

Cardiac instrumentation. A total of nine Yorkshire pigs weighing 12 kg were studied. For instrumentation, pigs were tranquilized with sodium xylazine (1 mg/kg im, Rompun) and ketamine (10 mg/kg, Ketaset) and anesthetized with sodium pentobarbital (15 mg/kg iv, Sigma Chemical) and ketamine. Through a left thoracotomy in the third intercostal space, tygon catheters were implanted in the aorta for measurement of arterial blood pressure and in the pulmonary artery for intravenous drug administration. An ultrasonic flow probe (Transonics) was placed around the ascending aorta to measure aortic blood flow (minus coronary artery blood flow). Antibiotics were given prophylactically.

Sleep electrode instrumentation. One week after completion of the thoracotomy, an incision was made in the scalp, and two 1.5-cm openings were made into the frontal sinuses. Stainless steel electrodes were placed behind each eye and on the surface of the frontal lobe of the brain through 1.0-mm-diameter holes in the lateral and posterior walls of the sinus for the recording of the electrooculogram (EOG) and the electroencephalogram (EEG), respectively. Additional electrodes were inserted 2 cm into the splenius muscle on the dorsal side of the neck to record the electromyogram (EMG). All electrodes were attached to a small nine-pin electrical connector (model 223-1609, Amphenol, Oak Brook, IL), which, in turn, was attached to the skull with methyl methacrylate bone cement (Surgical Simplex P, Howmedica, Rutherford, NJ).

The icv cannula. In addition, with use of stereotaxic techniques, an 18-gauge stainless steel cannula was placed such that the tip rested 2 mm above the lateral cerebral ventricle on one side. The location was typically 13 mm anterior to bregma. Confirmation of proper placement of the cannula was accomplished by the lowering of a sterile 25-gauge needle through the cannula into the lateral ventricle, recording a pressure decrease of 5-10 mmHg and phasic pressure changes, and withdrawing 0.1 ml of cerebrospinal fluid (CSF). To fix the cannula in place, two stainless steel screws were placed in the skull, and the screws and cannula were surrounded by methyl methacrylate. Animals were treated with prophylactic antibiotics and allowed to recover for 7 days before experimentation. During that time, the animals were adapted to lie quietly in a padded fabric sling by three trials of 3-h practice sessions. Animal care and experimental protocols were approved by the Children's Hospital Animal Management Program.

Endotracheal occluder. Two days before the sleep studies began, a double-lumen endotracheal balloon occluder was placed in the trachea [by using sterile techniques and a short-acting anesthetic agent, sodium thiamylal (0.5 mg/kg iv)] via a 1-cm incision made immediately distal to the larynx. This apparatus occupied 20% of the trachea and was held in place by skin sutures. During the experiments, the balloon portion of the tube was inflated from the observation room several feet away without the animal being awakened. The lumen of the catheter was used to measure intratracheal pressure and was attached to a fluid-filled pressure transducer (Statham P50, Gould).

Experimental protocol. During sleep sessions, recordings were made of a lead II surface electrocardiogram (ECG), arterial blood pressure via transducer (Statham P50), and aortic blood flow as an indicator of cardiac output (CO). Resistance-capacitance circuits with 2- and 8-s time constants provided mean values for arterial pressure and aortic blood flow, respectively. Total peripheral resistance (TPR) was calculated as the quotient of MAP and CO. A cardiotachometer provided a continuous assessment of mean HR from the ECG signal. Hemodynamic signals were displayed on an oscilloscope and polygraph. Line of best fit was used to assess MAP, HR, and CO over the data-collection intervals. EMG, EOG, and EEG were processed via high-sensitivity amplifiers (model 7P511, Grass Instruments, Quincy, MA). Data obtained while the pigs were in the sleep chamber and sling were classified as occurring when the pigs were either awake, in non-rapid-eye-movement (NREM) sleep, or in rapid-eye-movement (REM) sleep, on the basis of contrasts between distinctive frequency and voltage characteristics as described previously (35).

Two to three min into a NREM or REM sleep cycle, the balloon of the endotracheal catheter was inflated over a 5-s period with a predetermined amount of air. A video monitor in the sleep chamber and the EMG and EOG signals were used to determine the latency to arousal after the obstruction of the airway was complete. MAP, HR, and CO were measured before and during episodes of AO, and immediately after arousal, by using 20-s epochs at each data-collection point (except during AO episodes, when each period between obstruction and arousal constituted a data-collection epoch). Measurements of tracheal pressure were used only to confirm tracheal occlusion and release and were not quantified as data. Studies were conducted under two experimental conditions presented on randomly assigned different days: 1) no-drug control condition (vehicle injection 300 µl of artificial CSF) and 2) after beta 1- and beta 2-adrenoreceptor blockade via DL-propranolol (50 µg/kg icv in 300 µl of artificial CSF). Sterile artificial CSF had the following composition (in mM): 147 Na+, 3.5 K+, 1.0 Ca2+, 1.2 Mg2+, 129 Cl-, 1 phosphate, and 25 HCO-3, with a pH of 7.4 (7). In two pigs, AO trials were conducted after icv injection of D-propranolol (50 µg/kg; Sigma Chemical), a dextrorotary isomer of propranolol that has 1-2% of the beta -adrenoreceptor-blocking capacity of DL-propranolol.

In addition, arterial blood was sampled from the aortic catheter during quiet awake periods and immediately before and during the AO episodes, as late in the AO period as possible. Most episodes lasted 10-15 s, and samples were drawn at least 7 s after the onset of AO. A blood-gas analyzer (NOVA Biochemical) was used to measure pH, PO2, PCO2, and O2 saturation.

Data from multiple AO episodes obtained from each animal were averaged, and mean values for each pig were entered into group data, which are presented as means ± SE. The average number of AO episodes per animal was three in NREM and two in REM sleep. Group values before, during, and after AO were compared by using analysis of variance for repeated measures, followed by Neuman-Keuls test for differences. Differences in baseline parameters among awake, NREM sleep, and REM sleep were evaluated similarly, by using the groups of six animals studied in the three conditions (31).

RESULTS

Hemodynamic changes during sleep. To examine hemodynamic changes as a function of sleep stage, baseline (pre-AO) data from a group of six animals were compared in the awake state, NREM sleep, and REM sleep. HR values in the awake state, NREM sleep stage, and REM sleep stage were 135 ± 9, 128 ± 8, and 127 ± 7 beats/min, respectively. MAP in the same sequence was 75 ± 5, 73 ± 5 and 61 ± 2 mmHg. CO was 1,550 ± 90, 1,477 ± 121, and 1,472 ± 86 mmHg, and TPR was 0.049 ± 0.004, 0.050 ± 0.030, and 0.043 ± 0.004 mmHg · ml-1 · min in the awake state, during NREM sleep, and during REM sleep, respectively. During REM sleep, MAP and TPR were significantly reduced (P < 0.05) compared with during NREM sleep and in the awake state. These results are in agreement with previous studies of hemodynamic changes during sleep in this model (26, 35).

Effects of AO during REM sleep. Eight animals were studied: six reported in the sleep stage hemodynamic data, plus two others not included previously. Polygraph tracings for a typical animal are shown in Fig. 1. During the AO, CO decreased by 90 ± 17 ml/min from 1,435 ± 69 ml/min, and TPR increased by 0.006 ± 0.002 from 0.046 ± 0.004 mmHg · ml-1 · min (both P < 0.05; Table 1). During arousal from AO, HR was increased by 10 ± 3 beats/min compared with control and MAP was increased by 15 ± 3 mmHg; TPR increased by 0.008 ± 0.001 mmHg · ml-1 · min (all P < 0.05, Fig. 2). Duration of AO before spontaneous arousal followed by immediate release of the balloon was 13 ± 2 s.
Fig. 1. Effects of sleep stage and apnea, followed by arousal, on electrooculogram (EOG), EEG, tracheal pressure, heart rate, mean arterial pressure, and cardiac output. Depicted is obstructive airway episode (AO) beginning during rapid-eye-movement (REM) sleep. AO was associated with a reduction in cardiac output and increases in total peripheral resistance; arousal was associated with increase in heart rate, mean arterial pressure, and total peripheral resistance. NREM, non-REM.
[View Larger Version of this Image (67K GIF file)]

Table 1. Hemodynamic response to AO during REM sleep before and after icv propranolol

n Pre-AO Pre-AO to During AO (Change From Pre-AO) Pre-AO to Arousal (Change From Pre-AO)
Control 8
  Mean arterial pressure, mmHg 65 ± 3  3 ± 2  15 ± 3*
  Heart rate, beats/min 133 ± 9  1 ± 3  10 ± 3*
  Cardiac output, ml/min 1,435 ± 69   -90 ± 17* 25 ± 50 
  Total peripheral resistance, mmHg · ml-1 · min 0.046 ± 0.004  0.006 ± 0.002* 0.008 ± 0.001*
icv Propranolol 8
  Mean arterial pressure, mmHg 71 ± 5  0 ± 2  5 ± 4 
  Heart rate, beats/min 125 ± 7   -4 ± 2  9 ± 2*
  Cardiac output, ml/min 1,353 ± 65   -87 ± 41* 82 ± 47 
  Total peripheral resistance, mmHg · ml-1 · min 0.054 ± 0.005  0.004 ± 0.002  0.000 ± 0.002
Values are means ± SE; n, no. of pigs. AO, airway obstruction; REM, rapid eye movement; icv, intracerebroventricular. AO duration: 13 ± 2 s during control; 18 ± 3 s during icv propranolol. * Significantly different from pre-AO baseline, P < 0.05.

Fig. 2. Changes in heart rate, mean arterial pressure, cardiac output, and total peripheral resistance occurring in REM sleep during AO followed by arousal in control conditions. Baseline values from awake state are at bases of Pre AO to During AO bars. * Significant decrease in cardiac output and increase in total peripheral resistance during AO and increases in heart rate, mean arterial pressure, and total peripheral resistance on arousal, P < 0.05.
[View Larger Version of this Image (30K GIF file)]

Values for PO2 in baseline were lower during REM sleep compared with awake and NREM sleep values (77 ± 6 Torr in REM sleep, 89 ± 2 Torr in NREM sleep; P < 0.05) but decreased to a comparable level during AO. All other blood-gas parameters and changes during AO were comparable to those occurring in NREM sleep (Table 2, Fig. 3).

Table 2. Blood gases during AO before and after icv propranolol

n PO2, Torr PCO2, Torr pH %Saturation
NREM 8
    Pre-AO 89 ± 2  35 ± 1  7.480 ± 0.014  97.5 ± 0 
    During AO 65 ± 3* 42 ± 2* 7.437 ± 0.014* 91.3 ± 1*
REM 8
    Pre-AO 77 ± 6dagger 37 ± 2  7.483 ± 0.009  95.6 ± 1 
    During AO 62 ± 5* 42 ± 2* 7.458 ± 0.020  90.6 ± 2*
NREM icv   propranolol 3
    Pre-AO 84 ± 4  35 ± 1  7.483 ± 0.003  95.6 ± 2 
    During AO 66 ± 2  42 ± 2  7.433 ± 0.020  93.3 ± 1 
REM icv   propranolol 3
    Pre-AO 69 ± 13  36 ± 2  7.476 ± 0.014  94.0 ± 3 
    During AO 59 ± 6  43 ± 1  7.428 ± 0.008  90.0 ± 2 
Awake values 90 ± 3  35 ± 2  7.483 ± 0.015  97.5 ± 0
Values are means ± SE; n, no. of pigs. NREM, non-REM. * Significantly different from pre-AO value, P < 0.05.  dagger Significantly different from awake control and NREM control, P < 0.05.

Fig. 3. Change in PO2 and PCO2 during AO in NREM and REM sleep. Baseline values are at bases of bars. Duration of AO ranged from 10 to 18 s. * All changes significant at P < 0.05.
[View Larger Version of this Image (21K GIF file)]

Effects of AO during NREM sleep. Seven animals were studied during AO in NREM sleep (6 reported in the baseline comparison above plus 1 animal not included elsewhere). During baseline conditions, before AO, HR was 130 ± 7 beats/min, MAP was 76 ± 6 mmHg, CO was 1,423 ± 115 ml/min, and TPR was 0.055 ± 0.006 mmHg · ml-1 · min (Table 3). The AO lasted 10 ± 1 s before spontaneous arousal followed by immediate release of the balloon. During AO, CO decreased by 71 ± 13 ml/min and TPR increased by 0.006 ± 0.002 mmHg · ml-1 · min (both P < 0.05). During arousal from AO, HR increased by 9 ± 2 beats/min and MAP increased by 6 ± 2 mmHg (P < 0.05). The PO2 before AO was 89 ± 2 Torr, and it decreased during AO to 65 ± 3 Torr. The PCO2 increased during AO from 35 ± 1 to 42 ± 2 Torr (both P < 0.05; Fig. 3, Table 2). Percent O2 saturation decreased during AO from 97.5 ± 0 to 91.3 ± 1%, and pH decreased from 7.480 ± 0.014 to 7.437 ± 0.014 (both P < 0.05).

Table 3. Hemodynamic response to AO during NREM sleep before and after icv propranolol

n Pre-AO Pre-AO to During AO (Change From Pre-AO) Pre-AO to Arousal (Change From Pre-AO)
Control 7
  Mean arterial pressure, mmHg 76 ± 6  3 ± 2  6 ± 2*
  Heart rate, beats/min 130 ± 7  0 ± 2  9 ± 2*
  Cardiac output, ml/min 1,423 ± 115   -71 ± 13* 34 ± 26 
  Total peripheral resistance, mmHg · ml-1 · min 0.055 ± 0.006  0.006 ± 0.002* 0.002 ± 0.002 
icv Propranolol 5
  Mean arterial pressure, mmHg 87 ± 7  1 ± 1  1 ± 1 
  Heart rate, beats/min 126 ± 7   -3 ± 2  9 ± 3*
  Cardiac output, ml/min 1,460 ± 124   -60 ± 21  2 ± 48 
  Total peripheral resistance, mmHg · ml-1 · min 0.061 ± 0.005  0.004 ± 0.001  0.001 ± 0.003
Values are means ± SE; n, no. of pigs. AO duration: 10 ± 1 s during control; 15 ± 4 s during icv propranolol. * Significantly different from pre-AO baseline, P < 0.05.

Effects of AO during REM sleep after icv propranolol (Tables 1 and 2, Fig. 4). Baseline values in REM sleep were not altered by icv propranolol treatment. However, after icv propranolol, arousal from AO was not accompanied by significant increases in MAP or TPR (Fig. 4). Blood-gas parameters, measured in three pigs, did not differ from data gathered in vehicle-treated control trials. Duration of AO was 18 ± 3 s.
Fig. 4. Change in heart rate, mean arterial pressure, cardiac output, and total peripheral resistance in REM sleep during AO after central beta -adrenoreceptor blockade via intracerebroventricular propranolol (50 µg/kg). Baseline values for awake state are at bases of bars. Note that mean arterial pressure and total peripheral resistance increases on arousal from AO were minimal. * P < 0.05.
[View Larger Version of this Image (27K GIF file)]

Effects of AO during NREM after icv propranolol (Tables 2 and 3). Baseline values in NREM sleep were not altered significantly by icv propranolol. The increases in TPR that occurred during AO without icv propranolol were no longer significant. The modest increase in MAP that occurred on arousal from AO did not occur after icv propranolol. Duration of AO was 15 ± 4 s. The HR increase was similar to that which occurred previously, but a CO decrease during AO that had been observed after vehicle treatment was suggested but not statistically significant in the icv propranolol group data. PO2, PCO2, O2 saturation, and pH were tested in three pigs during AO after icv propranolol and did not differ from vehicle-treated control trials without propranolol.

Two animals were studied after icv administration of D-propranolol. In these animals, in REM sleep, CO decreased during AO by 125 ml/min from 1,600 ml/min, MAP increased during arousal from AO from 79 to 91 mmHg, and TPR increased from 0.060 to 0.064 ± 0.038 mmHg · ml-1 · min. Each of these changes was comparable to the main effects observed in the study without blockade, suggesting that beta -adrenoreceptor blockade, rather than nonspecific properties of propranolol, was a mechanism responsible for the changes observed after icv propranolol.

DISCUSSION

In the present study, significant decreases in MAP and TPR occurred during REM sleep. These results were expected on the basis of previous work (23, 26, 35). During AO in REM sleep, decreases in CO and increases in TPR were observed. On arousal from AO during REM sleep, TPR, MAP, and HR increased significantly. Changes occurring during AO in NREM sleep were similar; however, TPR increased during AO but not during arousal in NREM. After the administration of propranolol into the cerebral ventricular system, baseline values of TPR, MAP, HR, and CO were not significantly altered. In REM sleep, the CO decrease during AO and the HR increase during arousal remained intact. However, the increases in MAP and TPR that occurred during AO in REM and NREM and on arousal from AO during REM sleep were greatly reduced. This study is the first attempt to examine the role of central beta -adrenoreceptors in cardiovascular resistance responses to AO. The main finding was that beta -adrenoreceptors in the central nervous system appear to play a role in vascular resistance increases during arousal from AO.

Clinical evidence of cardiovascular dysfunction associated with sleep apnea has been increasingly apparent. Hypertension (17, 19), cardiac arrhythmia (12, 18), cerebroventricular dysfunction (22), and sudden death (15) have been associated with obstructive sleep apnea. There is also evidence that the syndrome is more prevalent and problematic than is currently documented or diagnosed (5, 34). Human patterns of hemodynamics during sleep in normal individuals generally show a decrease in MAP during NREM sleep, with a return toward awake levels during REM sleep. In the normal pig, the lowest values for MAP occur during REM sleep, with a return toward normal values in NREM sleep. Both show a decrease in blood pressure during sleep. Few studies using animal models of apnea during sleep exist, and fewer still incorporate cardiovascular data. Baker and Fewell (1) and Fewell (8) studied upper AO during sleep in 11- to 24-day-old lambs. Hendricks and co-workers (16) studied the English bulldog, in which spontaneous sleep-disordered breathing occurs. Canine models of obstructive apnea (20) and rat (29) and pig models (9) of apnea have been studied. However, aside from the studies of Baker and Fewell and of Fewell, little vascular resistance data are available. In the studies of Baker and Fewell and of Fewell, no cardiovascular data were available for the period immediately after arousal from apnea. To our knowledge, there are no studies available of the central mechanisms controlling vascular resistance changes that occur in response to sleep apnea. An intratracheal obstruction model such as this does not perfectly mimic human sleep apnea, which may originate in the central nervous system or be caused by obstruction from collapse of soft tissue of the throat. However, the hemodynamic response patterns in HR and MAP appear to be similar, and mechanisms are not yet understood (10, 11, 13, 30, 34).

Evidence from varied sources supports the contention that specific brain regions accessible via the cerebral ventricles may be involved in vasoconstriction responses to specific sleep events, such as sleep apnea and arousal. Classic work by Bonham and colleagues (2, 3) and by Gutterman and colleagues (14) in the cat identified sites in the paraventricular nucleus that projected to the lateral hypothalamus. These sites produced coronary vasoconstriction when stimulated (2, 3, 14). The periventricular nuclei may be involved in regulation of sleep apnea and in cardiovascular responses to behavioral stimuli. Exposure of the periventricular nuclei to ouabain can aggravate central sleep apneas (29), and intravenous beta -blockade (presumed to cross the blood-brain barrier) has been reported to aggravate sleep apnea in patients (4).

The icv injection of adrenergic agonists and antagonists has significant hemodynamic consequences in a number of species (6, 23, 27, 28). The icv administration of propranolol altered left ventricular function and latency to ventricular fibrillation in pigs stressed by placement in an unfamiliar laboratory setting during ischemia (25). There were no significant changes in baseline parameters in the present study after icv propranolol. This may be due to the effort made in the present study to adapt the pigs to the laboratory setting. Also, the present study measured CO, whereas left ventricular function was measured in the study of Parker et al. (25). In our laboratory (21), we have demonstrated that the combination of tyrosine and propranolol injected into the lateral ventricle prevented the occurrence of ventricular fibrillation after acute coronary arterial occlusion.

The data from the present study indicate that injection of a beta -adrenoreceptor antagonist into the lateral ventricle of sleeping pigs greatly reduced increases in TPR and MAP that occurred during and after sleep apnea and arousal. It is possible that spillover of propranolol from the CSF into plasma altered hemodynamic responses to AO. We did not measure levels of propranolol in plasma. However, Parker et al. (25), who used similar doses of propranolol icv, also in pigs, found modest increases that were below levels needed for effective systemic beta -adrenoreceptor blockade. In a previous study in our laboratory (21), hemodynamic responses to intravenous isoproterenol were intact after icv propranolol (50 µg/kg), indicating that peripheral beta -receptors were not blocked by the icv injection of propranolol. Specificity of the beta -adrenergic effects in the central nervous system was suggested by studies using the dextrorotary isomer D-propranolol, also administered icv. In a previous study of AO, peripheral beta -blockade did not alter MAP increases on arousal but did prevent increases in HR (22).

The decrease in CO during AO and the increase in HR observed during arousal from AO in the control study remained intact after icv beta -blockade. The decrease in CO may have been because of impaired venous return during repeated respiration attempts against a closed airway. The HR increase may have been secondary to lung inflation on arousal and termination of apnea. Baker and Fewell (1) reached this conclusion in studies in the lamb.

The data generated in this study support the hypothesis that shifts in autonomic tone in the peripheral nervous system and beta -receptor activation in the central nervous system may be involved in controlling the vascular resistance component of the hemodynamic responses to sleep apnea. More studies are needed that will identify specific brain nuclei and efferent pathways. Studies of coronary blood flow in this model would also be valuable. Such studies may help to determine whether chronic sleep apnea or acute apneic episodes could be a factor in cardiovascular morbidity and mortality and what role the central nervous system plays in these events.

ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-49829.

FOOTNOTES

Address for reprint requests: D. A. Kirby, Cardiology Sect., Dept. of Veterans Affairs Medical Center, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132.

Received 19 July 1995; accepted in final form 19 November 1996.

REFERENCES

1. Baker, S. B., and J. E. Fewell. Effects of hyperoxia on the arousal response to upper airway obstruction in lambs. Pediatr. Res. 21: 116-120, 1987 [Medline] .
2. Bonham, A. C., D. D. Gutterman, J. M. Arthur, M. L. Marcus, G. F. Gebhart, and M. J. Brody. Electrical stimulation in perifornical lateral hypothalamus decreases coronary blood flow in cats. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H474-H484, 1987 [Abstract/Free Full Text] .
3. Bonham, A. C., D. D. Gutterman, J. M. Arthur, M. L. Marcus, G. F. Gebhart, and M. J. Brody. Neurogenic regulation of coronary blood flow: evidence for a central nervous system pathway. Circ. Res. 61, Suppl. II: II-42-II-46, 1987.
4. Boudoulas, H., H. Schmidt, P. Geleris, R. W. Clark, and R. P. Lewis. Case reports on deterioration of sleep apnea during therapy with propranolol---preliminary studies. Res. Commun. Chem. Pathol. Pharmacol. 39: 3-10, 1983 [Medline] .
5. Cherniack, N. S. Sleep apnea and its causes. J. Clin. Invest. 73: 1501-1506, 1984 .
6. Day, M. D., and A. G. Roach. Central alpha - and beta -adrenoreceptors modifying arterial blood pressure and heart rate in conscious cats. Br. J. Pharmacol. 51: 325-333, 1974 [Medline] .
7. During, M. J., I. N. Ackworth, and R. J. Wurtman. Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens. Brain Res. 452: 378-380, 1988 [Medline] .
8. Fewell, J. E. Influence of sleep on systemic and coronary hemodynamics in lambs. J. Dev. Physiol. 19: 71-76, 1993 [Medline] .
9. Galland, B. C., D. P. G. Bolton, and B. J. Taylor. Apnea and rapid eye movement sleep excess in the piglet during recovery from hyperthermia. Pediatr. Res. 34: 518-524, 1993 [Medline] .
10. Garpestad, E., H. Katayama, J. A. Parker, J. Ringler, J. Lilly, T. Yashuda, R. H. Moore, H. W. Strauss, and J. W. Weiss. Stroke volume and cardiac output decrease at termination of obstructive apneas. J. Appl. Physiol. 73: 1743-1748, 1992 [Abstract/Free Full Text] .
11. Gastaut, H., C. A. Tassinari, and B. Duron. Polygraphic study of the episodic diurnal and nocturnal (apneic and respiratory) manifestations of the "Pickwick Syndrome." Brain Res. 2: 167-186, 1966.
12. Gillis, A. M., R. Stoohs, and C. Guilleminault. Changes in the QT interval during obstructive sleep apnea. Sleep 14: 346-350, 1991 [Medline] .
13. Guilleminault, C. Obstructive sleep apnea: the clinical syndrome and historical perspective. Med. Clin. N. Am. 69: 1187-1203, 1985 [Medline] .
14. Gutterman, D. D., A. C. Bonham, J. M. Arthur, G. F. Gebhart, M. L. Marcus, and J. Brody. Characterization of coronary vasoconstriction site in medullary reticular formation. Am. J. Physiol. 256 (Heart Circ. Physiol. 25): H1218-H1227, 1989 [Abstract/Free Full Text] .
15. He, J., M. H. Kryger, F. J. Zorick, W. Conway, and T. Roth. Mortality and apnea index in obstructive sleep apnea. Chest 94: 9-14, 1988 [Abstract/Free Full Text] .
16. Hendricks, J. C., L. R. Kline, R. J. Kovalski, J. A. O'Brien, A. R. Morrison, and A. I. Pack. The English bulldog: a natural model of sleep-disordered breathing. J. Appl. Physiol. 63: 1344-1350, 1987 [Abstract/Free Full Text] .
17. Hla, K. M., T. B. Young, T. Bidwell, M. Palta, J. B. Skatrud, and J. Dempsey. Sleep apnea and hypertension. Ann. Intern. Med. 120: 382-388, 1994 [Abstract/Free Full Text] .
18. Imaizumi, T. Arrhythmias in sleep apnea. Am. Heart J. 100: 513-516, 1980 [Medline] .
19. Jeong, D., and J. E. Dimsdale. Sleep apnea and essential hypertension, a critical review of the epidemiological evidence for co-morbidity. Clin. Exp. Hypertens. Part A Theory Pract. A11: 1301-1323, 1989.
20. Kimoff, R. J., H. Makino, R. L. Horner, L. F. Kozar, F. Lue, A. S. Slutsky, and E. A. Phillipson. Canine model of obstructive sleep apnea: model description and preliminary application. J. Appl. Physiol. 76: 1810-1817, 1994 [Abstract/Free Full Text] .
21. Kirby, D. A., D. A. Johnson, J. M. B. Pinto, S. Zhao, and B. Lown. Control of ventricular fibrillation after coronary artery occlusion via intracerebroventricular injections. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H479-H483, 1992 [Abstract/Free Full Text] .
22. Kirby, D. A., J. M. B. Pinto, J. W. Weiss, E. Garpestad, and S. Zinkovska. Effects of beta adrenergic receptor blockade on hemodynamic changes associated with obstructive sleep apnea. Physiol. Behav. 58: 919-923, 1995 [Medline] .
23. Kirby, D. A., A. Zinkovska, and K. Saupe. Peripheral resistance increases upon arousal from obstructive sleep apnea were absent following intracerebroventricular blockade. Circulation 90: I-268, 1994.
24. Loeppky, J. A., W. F. Voyles, M. W. Eldridge, and C. W. Sikes. Sleep apnea and autonomic cerebrovascular dysfunction. Sleep 10: 25-34, 1987 [Medline] .
25. Parker, G. W., L. H. Michael, C. J. Hartley, J. E. Skinner, and M. L. Entman. Central beta -adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs. Circ. Res. 66: 259-270, 1990 [Abstract/Free Full Text] .
26. Pinto, J. M. B., E. Garpestad, J. W. Weiss, D. M. Bergau, and D. A. Kirby. Hemodynamic changes associated with obstructive sleep apnea followed by arousal in a porcine model. J. Appl. Physiol. 75: 1439-1443, 1993. [Abstract/Free Full Text]
27. Privitera, P. J., J. G. Webb, and T. Walle. Effects of centrally administered propranolol on plasma renin activity, plasma norepinephrine and arterial pressure. Eur. J. Pharmacol. 54: 51-60, 1979 [Medline] .
28. Reid, J. L., P. J. Lewis, M. G. Myers, and C. T. Dollery. Cardiovascular effects of intracerebroventricular D-, L- and DL-propranolol in the conscious rabbit. J. Pharmacol. Exp. Ther. 188: 394-399, 1974 [Abstract/Free Full Text] .
29. Sato, T., M. Tadokoro, H. Kaba, H. Saito, K. Seto, and H. Takatsuji. Centrally administered ouabain aggravates central sleep apneas. J. Appl. Physiol. 74: 545-548, 1993 [Abstract/Free Full Text] .
30. Shepard, J. W. Gas exchange and hemodynamics in sleep apnea. Med. Clin. N. Am. 69: 1243-1264, 1985 [Medline] .
31. Snedecor, G. W., and W. G. Cochran. Analysis of frequencies in one-way and two-way classifications. In: Statistical Methods (7th ed.). Ames: Iowa State Univ. Press, 1980, p. 194-210.
32. Tackett, R. L., J. G. Webb, and P. J. Privitera. Cerebroventricular propranolol elevates cerebrospinal fluid norepinephrine and lowers blood pressure. Science 213: 911-913, 1981 [Abstract/Free Full Text] .
33. Tilkian, A. G., C. Guilleminault, J. S. Schroeder, K. L. Lehrman, F. B. Simmons, and W. C. Dement. Hemodynamics in sleep induced apnea. Ann. Intern. Med. 85: 714-719, 1976 .
34. Young, T., M. Palta, J. Dempsey, J. Skatrud, S. Weber, and S. Badr. The occurrence of sleep-disordered breathing among middle-aged adults. N. Engl. J. Med. 328: 1230-1235, 1993 [Abstract/Free Full Text] .
35. Zinkovska, S., K. Rodriguez, and D. A. Kirby. Coronary and total peripheral resistance changes during sleep in a porcine model. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H723-H729, 1996 [Abstract/Free Full Text] .
0161-7567/97 $5.00 Copyright © 1997 the American Physiological Society


This article has been cited by other articles:


Home page
 Eur Respir JHome page
K. Dingli, T. Assimakopoulos, P.K. Wraith, I. Fietze, C. Witt, and N.J. Douglas
Spectral oscillations of RR intervals in sleep apnoea/hypopnoea syndrome patients
Eur. Respir. J., December 1, 2003; 22(6): 943 - 950.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
H. Schneider, C. D. Schaub, C. A. Chen, K. A. Andreoni, A. R. Schwartz, P. L. Smith, J. L. Robotham, and C. P. O'Donnell
Effects of arousal and sleep state on systemic and pulmonary hemodynamics in obstructive apnea
J Appl Physiol, March 1, 2000; 88(3): 1084 - 1092.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. P. Lonergan III, J. C. Ware, R. L. Atkinson, W. C. Winter, and P. M. Suratt
Sleep apnea in obese miniature pigs
J Appl Physiol, February 1, 1998; 84(2): 531 - 536.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zinkovska, S.
Right arrow Articles by Kirby, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zinkovska, S.
Right arrow Articles by Kirby, D. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online