help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1544-1549, (2002)
© 2002 American Thoracic Society

Original Article

Prenatal Nicotine Exposure Blunts the Cardiorespiratory Response to Hypoxia in Lambs

Ola Hafström, Joseph Milerad and Håkan W. Sundell

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Håkan W. Sundell, M.D., Vanderbilt University School of Medicine, A-0126, Medical Center North, Nashville, TN 37232-2585. E-mail: hakan.sundell{at}mcmail.vanderbilt.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Because smoking during pregnancy is a major risk factor for late fetal death and the sudden infant death syndrome, we investigated cardiorespiratory defense mechanisms to hypoxia in 7 prenatally nicotine-exposed (N) lambs (approximate maternal dose: 0.5 mg/kg/day) and 11 control (C) lambs all at an average age of 5 days. The ventilatory response to 10% oxygen (hyperpnea) was significantly attenuated during quiet sleep in N lambs compared with C lambs and in N lambs aroused from sleep later compared with C lambs (161 ± 90 versus 75 ± 66 seconds, p < 0.05). The ventilatory response to hypoxia was similar in the two groups during wakefulness (W), whereas the heart rate response (tachycardia) was significantly lower in N lambs compared with C lambs during both activity states. The ventilatory response to hyperoxia was significantly lower in N lambs compared with C lambs during both activity states. Transition from W to quiet sleep was associated with a significant decrease in ventilation in C lambs but not in N lambs. In conclusion, prenatal nicotine exposure, at a dose comparable with moderate smoking, blunts major elements of the cardiorespiratory defense to hypoxia, i.e., the heart rate and ventilatory and arousal responses, and abolishes the normal decrease in ventilation during sleep compared with W.

Key Words: chemoreceptors • prenatal nicotine exposure delayed effects • respiration • sudden infant death • smoking


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increases in ventilation and heart rate (HR) followed by arousal are the first line of defense to sleep-related hypoxemia. Other adaptive strategies, such as a decrease in metabolic rate, are of importance, particularly in immature subjects (1), but a brisk cardiorespiratory activation is the immediate response of mammals that are more mature at birth (e.g., newborn sheep) (2).

Infants and young children with chronic lung disease (3), Arnold-Chiari malformation (4), or apparent life-threatening episodes (5) are at risk of apneic spells during sleep. Studies have shown that ventilatory responses to acute hypoxia or hyperoxia are attenuated, and that hypoxic arousal responses are often altered in these infants, and there is circumstantial evidence that the common underlying abnormality in these infants and children may be a decreased sensitivity of carotid body chemoreceptors (6–8). It has been proposed that a similar deficiency is also a contributing factor for the sudden infant death syndrome (9) and that its origin is exposure to tobacco smoke or nicotine (10).

We have previously shown in young lambs that acute postnatal exposure to nicotine attenuates cardiorespiratory activation and delays arousal in response to mild hypoxia during sleep (11). Delayed hypoxic awakening has been reported in infants of smoking mothers (12), whereas rat pups exposed to nicotine during fetal life have a lower ability to sustain or cope with severe acute hypoxia or anoxia (10, 13).

To further elucidate the link between prenatal nicotine exposure and postnatal defense to hypoxia, we tested the hypothesis that nicotine exposure during the last trimester impairs the acute cardiorespiratory and arousal responses to mild hypoxia after birth. Last trimester exposure was chosen to avoid possible teratogenic effects of nicotine during early embryonic development. The low nicotine dosage employed was selected to minimize the effects on fetal growth because its retardation has been shown to be an important confounder in studies of postnatal regulation of breathing (14). Although there are numerous chemicals present in tobacco smoke, nicotine was chosen to further evaluate the potential of nicotine substitution as a safe alternative to smoking during pregnancy. All experiments were performed during wakefulness (W) and natural quiet sleep (QS) in chronically instrumented lambs without the use of sedation or anesthesia.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Eleven lambs were exposed to nicotine bitartrate during the last trimester of fetal development (approximate maternal dose: 0.5 mg/kg/day resulting in a maternal nicotine concentration of 7 ± 1 ng/ml, mean ± SD) (15). Four of the prenatally nicotine-exposed (N) lambs and one unexposed control (C) lamb were not used because of respiratory illness or technical problems. Thus, 7 N and 11 C lambs were studied at a mean age of 5.4 ± 2.5 and 5.1 ± 1.6 days, respectively (not a significant difference). Mean body weight at the time of the studies was 5.6 ± 1.5 kg (N) and 6.1 ± 1.4 kg (C) (not a significant difference). Some data during W were included in a previous report (15).

Prenatal Nicotine Exposure
Osmotic pumps (Alzet, Model 2ML4; Durect Corp., Cupertino, CA) were implanted subcutaneously in the ewe on approximately the 98th day of the 147-day gestation. The pumps delivered nicotine bitartrate continuously at 40 mg/day or approximately 0.5 mg/kg/day. The pumps were replaced after 28 days and removed after delivery of the lamb. Plasma concentrations of nicotine and cotinine were determined at 120 ± 15 days of gestation (16).

Instrumentation
The lambs were instrumented, using combined ketamine and halothane anesthesia, with the placement of a tracheal window and arterial and venous catheters (11, 15, 17) and electrodes for electroencephalogram, nuchal electromyogram, and electrooculogram at an age of 2 to 3 days (18). At least 48 hours postoperative recovery was allowed before the first study.

The research protocol was approved by the Vanderbilt University Animal Care Committee.

Study Protocol and Equipment
We used a computerized system, which allowed us to measure inspiratory flows and volumes, end-tidal carbon dioxide (PETCO2) and airway occlusion pressure (P0.1) on a breath-by-breath basis with minimal or no effects on ventilation and breathing pattern (19). The lambs were breathing spontaneously through a cuffed endotracheal tube connected to the horizontal leg of a T-shaped valve assembly. The inspiratory side consisted of a pneumotachometer (Model #3700; Hans Rudolph, Inc., Kansas City, MO) and a pneumatic occlusion valve set to open at a preset negative airway pressure. The expiratory side consisted of a low-resistance expiratory valve and a flap valve, acting as a variable expiratory resistance similar to normal laryngeal expiratory braking activity. Airway pressure was measured by means of a Validyne 45-1 differential pressure transducer (Validyne Engineering Corp., Northridge, CA) in the endotracheal tube. P0.1 (a noninvasive estimate of central inspiratory activity) (20) was measured as the change in airway pressure over time (dP/dt). Because only linear dP/dt curves were used for this analysis, the numeric data were equivalent to extrapolated negative airway pressure at 100 milliseconds, i.e., P0.1 (19). PETCO2 was analyzed by a Beckman LB2 infrared capnograph (Beckman Instruments Inc., Anaheim, CA) on gas sampled from the T-joint. Mean arterial blood pressure (Model P23 ID; Gould-Statham, Oxnard, CA), HR (HR) (H-P Model 211376A rate computer), transcutaneous hemoglobin oxygen saturation (SaO2) (Ohmeda model 3700 pulse oximeter; Ohmeda Inc., Louisville, CO), electroencephalogram, electromyogram, and electrooculogram were continuously monitored during the experiments, and determinations of activity state and arousal were performed using criteria described previously (11). The analog flow and pressure signals were digitized, stored, and used for calculation of tidal volume (VT), respiratory rate (RR), inspiratory minute ventilation (I), and mean inspiratory flow (VT/inspiratory time). The lambs were studied slightly restrained in a sling (Alice King Chatham, Medical Arts, Los Angeles, CA) during W and QS. No sedation or anesthesia was used during the experiments.

Room Air Breathing
When the unsedated lambs had been resting quietly for several minutes, ventilatory and cardiovascular variables were recorded for 1 minute in each activity state and used for baseline calculations.

Hypoxia Test
The ventilatory, PETCO2, HR, and blood pressure responses to 10% oxygen in nitrogen were determined in each activity state and were expressed as percent increase from baseline during each minute of hypoxia (11).

Hyperoxia Test
The ventilatory response to 100% oxygen was used as an estimate of resting peripheral chemoreceptor activity (21) and was expressed as percent change in ventilation during the first 10 seconds (or the first five breaths whichever came first) poststimulation (11).

Statistical Methods
Unpaired t tests were used to assess differences between the groups regarding resting baseline variables, time to arousal, and the hyperoxia response. Paired t tests were used to detect differences within the groups regarding the effect of activity state on the baseline variables and the response to hyperoxia. Two-factor analysis of variance, repeated measures design, was used to compare ventilatory and cardiovascular variables during hypoxia between C and N lambs and to compare the same variables within each group during W and QS. Thus, one factor in the analysis was the change in cardiorespiratory variables over time and the second factor was nicotine treatment or activity state. Significant differences were accepted for p values less than 0.05. Data are presented as mean ± SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Nicotine Plasma Concentrations
Mean plasma concentrations of nicotine and cotinine in the ewes were 7 ± 1 and 18 ± 5 ng/ml, respectively. The sampled ewes were the same as reported previously (15).

Effects of Nicotine on Baseline Cardiorespiratory Variables
Nicotine exposure had no significant effect on resting I while breathing room air during either activity state (Table 1) . However, N lambs had a significantly higher RR, lower VT, and lower PETCO2 compared with C lambs during both W and QS (Table 1). The N lambs had higher resting P0.1 compared with the C lambs, but the difference was statistically significant only during QS (Table 1). Resting HR was significantly higher in N lambs compared with C lambs during both W and QS (Table 2) . Resting mean arterial blood pressure was similar in the two groups during both activity states (Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Baseline ventilatory variables during room air breathing

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Baseline cardiovascular variables

 
Effects of Activity State on Baseline Cardiorespiratory Variables
The C lambs had significantly lower resting I while breathing room air during QS than during W, and this difference was mainly due to a lower RR, whereas VT remained about the same (Table 1). The C lambs had significantly higher PETCO2 and a lower P0.1 during QS than during W (Table 1). In contrast, these variables were similar in N lambs during both activity states (Table 1). HR, mean arterial pressure and SaO2 were essentially the same during W and QS in both groups of lambs (Table 1 and 2).

Effects of Nicotine on the Ventilatory Response to Hypoxia
There was a similar increase in I (Figure 1 , left upper panel), RR, and VT during the first 4 minutes of hypoxia in both experimental groups during W. However, I increased significantly less in the N lambs than in the C lambs during QS (Figure 1, right upper panel). A smaller RR increment in the N lambs was the main contribution to this difference. The increase in RR during the fourth minute of the test was 26 ± 17% in N lambs and 64 ± 22% in C lambs (p < 0.01). VT increased about the same in both groups. Changes in PETCO2 during the hypoxic challenge followed the changes in ventilation during both W and QS, i.e., PETCO2 decreased more in the C lambs compared with the N lambs during QS (Figure 1, lower panels). P0.1 increased to a similar degree during both activity states in the two groups of lambs. The decrease in SaO2 was comparable during hypoxia in the two groups during both W and QS. At the end of 4 minutes of hypoxia during W, SaO2 was 63.0 ± 10.5% in the C lambs and 60.6 ± 12.0% in the N lambs; during QS, SaO2 was 64.6 ± 7.5% and 61.0 ± 13.5%, respectively.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. Ventilatory (I) and end-tidal CO2 (PETCO2) responses to hypoxia (0.1 fraction of inspired oxygen) in 7 nicotine-exposed and 11 control lambs studied during wakefulness (W) and quiet sleep (QS). Values are mean ± SD. Statistically significant difference between groups: *p values less than 0.05; **p values less than 0.01; NS, no statistically significant difference between groups.

 
Effect of Activity State on the Ventilatory Response to Hypoxia
The ventilatory response to hypoxia was significantly lower during W compared with QS in C lambs, whereas there was no such difference in N lambs (Figure 2) .



View larger version (14K):
[in this window]
[in a new window]
  		Figure 2. Ventilatory response (I) to hypoxia (0.1 fraction of inspired oxygen) in 11 control and 7 nicotine-exposed lambs studied during wakefulness (W) and quiet sleep (QS). Values are mean ± SD. Statistically significant difference between activity states: *p values less than 0.05; NS, no statistically significant difference between activity states.

 
Arousal
Time from start of hypoxia to arousal from QS was significantly longer in N lambs compared with C lambs: 161 ± 90 seconds and 75 ± 66 seconds, respectively (Figure 3 , left panel). SaO2 at arousal was 68 ± 15% in N lambs and 80 ± 12% in C lambs. This difference did not achieve statistical significance (p = 0.06) (Figure 3, right panel).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 3. Time to arousal from quiet sleep and transcutaneuous hemoglobin oxygen saturation (SaO2) at time of arousal in 7 nicotine-exposed and 11 control lambs. Values are mean ± SD. Statistically significant difference between groups: *p values less than 0.05.

 
Cardiovascular Response to Hypoxia
The HR response to hypoxia was lower in N lambs compared with C lambs during both W and QS (Figure 4 , upper panels). The mean arterial pressure response to hypoxia was similar in the two groups during both activity states (Figure 4, lower panels).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 4. Heart rate (HR) and mean arterial blood pressure (BP) responses to hypoxia (0.1 fraction of inspired oxygen) in 6 nicotine-exposed and 10 control lambs studied during wakefulness (W) and quiet sleep (QS). Values are mean ± SD. Statistically significant difference between groups: *p values less than 0.05; NS, no statistically significant difference between groups.

 
Hyperoxia
The ventilatory response to hyperoxia was significantly lower in N lambs compared with C lambs during both activity states (Figure 5) . Activity states had no significant effect on the ventilatory response to hyperoxia. (Figure 5).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 5. Ventilatory response (I) to hyperoxia (1.0 fraction of inspired oxygen) in 7 nicotine-exposed (N) and 11 control (C) lambs studied during wakefulness and quiet sleep. Values are mean ± SD. Statistically significant difference between groups: *p values less than 0.05; ***p values less than 0.001.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study showed that young lambs exposed to nicotine during fetal life but not thereafter have delayed arousal and reduced ventilatory and HR responses to hypoxia. In addition, we observed that the normal decrease in ventilation after the change from W to QS was absent in lambs exposed to nicotine in utero.

Previous investigations assessing the effects of exposure to nicotine or maternal cigarette smoke on arousal and the ventilatory response to hypoxia or hyperoxia have yielded inconsistent results. As in the present study, prenatal nicotine exposure decreased the ventilatory response to hypoxia in rat pups in a study by St.-John and Leiter (22), whereas no such effect was detected in two studies by Bamford and coworkers and Bamford and Carroll (23, 24). Three-day-old N rat pups in the latter study, showed no significant response to 100% oxygen, indicating an altered level of baseline carotid body chemoreceptor activity. Robinson and coworkers recently reported a higher frequency of apnea in response to hypoxia in newborn mice (25).

A blunted ventilatory response to hypoxia was found in infants of smokers compared with C infants by Ueda and coworkers (26) but not by Sovik and coworkers (27) or Lewis and Bosue (12). However, the latter authors demonstrated that infants of smoking mothers have a deficient hypoxia awakening response from QS (12). Protective responses (combined ventilatory and awakening responses) to rebreathing during quiet or active sleep were found to be similar in a large study of smoke-exposed and nonexposed infants by Campbell and coworkers (28). It should be noted that these infants were studied during a combined hypoxia and hypercapnia challenge. Possibly, a stimulatory effect of CO2 may have masked a blunted response to hypoxia.

Cardiorespiratory Activation by Hypoxemia
Arousal from sleep is part of the "defense-alerting reaction," an integrated behavioral and cardiorespiratory response that is elicited from hypothalamic areas in response to a variety of potentially harmful stimuli (29). When hypoxemia acts as a trigger of the defense-alerting reaction, the response is elicited by stimulation of carotid body chemoreceptors, i.e., by the same sensory pathway that mediates the hyperventilatory response (30, 31). Several autonomic cardiorespiratory effects that accompany hypoxic arousal can be reproduced experimentally by chemoreceptor stimulation (32), and conversely, denervation of carotid body chemoreceptors can delay or abolish arousal in response to hypoxemia (30, 31). Therefore, the concomitant attenuation of the hyperventilatory response and delayed arousal seen in our experiments are consistent with a decreased sensitivity of carotid body oxygen chemoreceptors or an altered central processing of their sensory discharge. The lower ventilatory response to hyperoxia further supports the involvement of carotid body oxygen chemoreceptors (21). Inhaling 100% oxygen briefly "silences" peripheral chemoreceptors, and the accompanying decrease in ventilation represents a noninvasive estimate of resting peripheral chemoreceptor activity.

Potential Mechanism of Action
Nicotine has a potential to affect different components of the oxygen chemosensory pathway. Nicotinic acetylcholine receptors have been identified on carotid body chemoreceptor cells of rat and cat (33, 34) as well as in the cat carotid body afferent system (35). Nicotine is known to promote release of dopamine from the carotid body (36) as well as centrally, notably in sites involved in regulation of arousal (37) and autonomic functions (38). Dopamine acts as an inhibitory neuromodulator in the carotid body (39). Such dopaminergic inhibitory modulation in either location may lead to diminished oxygen sensitivity (40, 41). In agreement with the notion of an inhibitory dopaminergic mechanism, we demonstrated that the N animals, which had delayed arousal and reduced ventilatory responses to both hypoxia and hyperoxia, could be normalized by blockade of the central dopamine D1-receptors by SCH 23390 or the peripheral D2-receptors by domperidone (42, 43).

Effects of Prenatal Nicotine Exposure on Cardiovascular Autonomic Control
A common observation in all studies across species and age groups has been that nicotine exposure increases resting sympathetic tone, while responsiveness to sympathetic stress is decreased. In adult habitual smokers, these changes in sympathetic activity lead to elevated HR and mean arterial pressure and decreased baroreceptor sensitivity (44). Rat pups exposed to nicotine before birth have reduced ß-adrenergic receptor binding capabilities in the myocardium and a reduced cardiac response to adrenergic stimulation (45). Consistent with the notion of an elevated resting sympathetic tone, resting HR was higher in N lambs in our study, but HR during hypoxia increased significantly less compared with C lambs. N lambs had similar mean arterial pressure as C lambs, suggesting that no resetting of baroreceptor sensitivity had occurred as a consequence of nicotine exposure.

Activity States and Respiratory Control
In the experiments reported here, QS was accompanied by a lowering of resting I in the C lambs, as expected. In contrast, resting I did not decrease during QS in the N animals. The underlying mechanism for this finding is unclear. There is an anatomic proximity between brain stem respiratory nuclei and neurons of the reticular formation involved in the regulation of sleep-W states. Respiratory-related neurons have been observed to have either a decreased rate of discharge or a complete cessation of firing during sleep, with a concomitant decrease in resting I (46). Because ventilation during QS is closely linked to metabolic rate, prenatal nicotine exposure may lead to dissociation between onset of sleep and downregulation of metabolic activity. Prenatal nicotine exposure was recently shown to interfere directly with sleep/wake ontogenesis in neonatal rats and also led to an upregulation of nicotinic and muscarinic cholinergic receptor messenger RNA in brain regions involved in regulation of the vigilance state (47).

Nicotine Dose
In contrast to earlier studies in rats where the fetus was exposed to comparatively high nicotine levels during the entire pregnancy, we used a nicotine dosage that produced maternal plasma concentrations of nicotine that were lower than those observed in pregnant habitual smokers (48, 49). Also, fetal exposure in the present study was limited to the last trimester of pregnancy. Previous experiments performed on rodents have shown that continuous infusion of nicotine at a higher dose than the one employed here does not affect uteroplacental circulation and fetal growth (50). Although a low dose was given during a limited period of intrauterine development, we still could document effects on defense mechanisms to hypoxia.

Confounding Factors
The magnitude of HR and I responses to hypoxemia increases with increased carotid body oxygen sensitivity, CO2 levels, and sympathetic tone, whereas hypocapnia and a lack of adrenergic stimulation leads to an attenuation of the response (for a detailed review, see [29]). A potential confounder when evaluating the hypoxic ventilatory and arousal responses in the present work was the fact that resting PETCO2 levels in N lambs were lower. The attenuated hypoxic ventilatory response may be due to relative hypocapnia (51), i.e., the animals had a lower hypoxic ventilatory response secondary to a decreased CO2 drive. What makes this explanation less likely is that the lower PETCO2 levels in N lambs at baseline were not a consequence of an acute hyperventilation but represented a physiologic resting state to which the animals were adapted.

Resting I of the two animal groups was similar, but the N lambs had a different breathing pattern with smaller VT and higher RR suggesting altered lung mechanics (15). To what extent changes in pulmonary mechanics may have affected the ventilatory response to hypoxia (52) cannot be deduced with certainty from the present results.

In conclusion, our data indicate that exposure to a low dose of nicotine during the last trimester of pregnancy blunts major elements of the cardiorespiratory defense to hypoxia, i.e., ventilatory, HR, and arousal responses. Taken together with the blunted ventilatory response to hyperoxia, these findings indicate altered oxygen sensitivity. Nicotine substitution often used as an aid to quit smoking may not be a safe alternative during pregnancy.


   Acknowledgments
 
The authors thank Patricia A. Minton, R.N., Rao Gaddipati, M.S., and Stanley D. Poole, M.S. for their skilled technical assistance and Donna Staed for typing the manuscript.


   FOOTNOTES
 
Supported by grants from the National Institute of Health (HD 28916 and HL 14214). J.M. and O.H. were supported in part by Swedish Medical Research Council grant number k98-27x-11265-04a.

Presented in part at the annual meetings of the American Pediatric Society/Society for Pediatric Research in 1997 and 1998 and the American Thoracic Society in 1998.

Received in original form April 5, 2002; accepted in final form August 26, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Mortola JP, Rezzonico R, Lanthier C. Ventilation and oxygen consumption during acute hypoxia in newborn mammals: a comparative analysis. Respir Physiol 1989;78:31–43.[CrossRef][Medline]
  2. Bureau MA, Zinman R, Foulon P, Begin R. Diphasic ventilatory response to hypoxia in newborn lambs. J Appl Physiol 1984;56:84–90.[Abstract/Free Full Text]
  3. Sekar KC, Duke JC. Sleep apnea and hypoxemia in recently weaned premature infants with and without bronchopulmonary dysplasia. Pediatr Pulmonol 1991;10:112–116.[Medline]
  4. Waters KA, Forbes P, Morielli A, Hum C, O'Gorman AM, Vernet O, Davis GM, Tewfik TL, Ducharme FM, Brouillette RT. Sleep-disordered breathing in children with myelomeningocele. J Pediatr 1998;132:672–681.[CrossRef][Medline]
  5. Guilleminault C, Stoohs R. From apnea of infancy to obstructive sleep apnea syndrome in the young child. Chest 1992;102:1065–1071.[Abstract/Free Full Text]
  6. Katz-Salamon M, Jonsson B, Lagercrantz H. Blunted peripheral chemoreceptor response to hyperoxia in a group of infants with bronchopulmonary dysplasia. Pediatr Pulmonol 1995;20:101–106.[Medline]
  7. Gozal D, Arens R, Omlin KJ, Jacobs RA, Keens TG. Peripheral chemoreceptor function in children with myelomeningocele and Arnold-Chiari malformation type 2. Chest 1995;108:425–431.[Abstract/Free Full Text]
  8. van der Hal AL, Rodriguez AM, Sargent CW, Platzker AC, Keens TG. Hypoxic and hypercapneic arousal responses and prediction of subsequent apnea in apnea of infancy. Pediatrics 1985;75:848–854.[Abstract/Free Full Text]
  9. Hunt CE, Brouillette RT. Sudden infant death syndrome: 1987 perspective. J Pediatr 1987;110:669–678.[CrossRef][Medline]
  10. Slotkin TA, Lappi SE, McCook EC, Lorber BA, Seidler FJ. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syndrome. Brain Res Bull 1995;38:69–75.[CrossRef][Medline]
  11. Hafstrom O, Milerad J, Asokan N, Poole SD, Sundell HW. Nicotine delays arousal during hypoxemia in lambs. Pediatr Res 2000;47:646–652.[Medline]
  12. Lewis KW, Bosque EM. Deficient hypoxia awakening response in infants of smoking mothers: possible relationship to sudden infant death syndrome. J Pediatr 1995;127:691–699.[CrossRef][Medline]
  13. Fewell JE, Smith FG, Ng VK. Prenatal exposure to nicotine impairs protective responses of rat pups to hypoxia in an age-dependent manner. Respir Physiol 2001;127:61–73.[CrossRef][Medline]
  14. Harding R, Tester ML, Moss TJ, Davey MG, Louey S, Joyce B. Effects of intra-uterine growth restriction on the control of breathing and lung development after birth. Clin Exp Pharmacol Physiol 2000;27:114–119.[CrossRef][Medline]
  15. Hafstrom O, Milerad J, Sundell HW. Altered breathing pattern after prenatal nicotine exposure in the young lamb. Am J Respir Crit Care Med 2002;166:92–97.[Abstract/Free Full Text]
  16. Hariharan M, VanNoord T, Greden JF. A high-performance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem 1988;34:724–729.[Abstract/Free Full Text]
  17. Milerad J, Larsson H, Lin J, Sundell HW. Nicotine attenuates the ventilatory response to hypoxia in the developing lamb. Pediatr Res 1995;37:652–660.[Medline]
  18. Lindgren C, Lin J, Graham BS, Gray ME, Parker RA, Sundell HW. Respiratory syncytial virus infection enhances the response to laryngeal chemostimulation and inhibits arousal from sleep in young lambs. Acta Paediatr 1996;85:789–797.[Medline]
  19. Milerad J, Larsson H, Lin J, Lindstrom DP, Sundell HW. Breath-by-breath determinations of airway occlusion pressure in the developing lamb. Eur J Appl Physiol 1996;74:44–51.[CrossRef]
  20. Whitelaw WA, Derenne JP. Airway occlusion pressure. J Appl Physiol 1993;74:1475–1483.[Abstract/Free Full Text]
  21. Girard F, Lacaisse A, Dejours P. Le stimulus O2 ventilatoire a la période néonatal chez l'omme. J Physiol (Paris) 1960;52:108–109.
  22. St.-John WM, Leiter JC. Maternal nicotine depresses eupneic ventilation of neonatal rats. Neurosci Lett 1999;267:206–208.[CrossRef][Medline]
  23. Bamford OS, Schuen JN, Carroll JL. Effect of nicotine exposure on postnatal ventilatory responses to hypoxia and hypercapnia. Respir Physiol 1996;106:1–11.[CrossRef][Medline]
  24. Bamford OS, Carroll JL. Dynamic ventilatory responses in rats: normal development and effects of prenatal nicotine exposure. Respir Physiol 1999;117:29–40.[CrossRef][Medline]
  25. Robinson DM, Peebles KC, Kwok H, Adams BM, Clarke LL, Woollard GA, Funk GD. Prenatal nicotine exposure increases apnoea and reduces nicotinic potentiation of hypoglossal inspiratory output in mice. J Physiol (Lond) 2002;538:957–973.[Abstract/Free Full Text]
  26. Ueda Y, Stick SM, Hall G, Sly PD. Control of breathing in infants born to smoking mothers. J Pediatr 1999;135:226–232.[CrossRef][Medline]
  27. Sovik S, Lossius K, Eriksen M, Grogaard J, Walloe L. Development of oxygen sensitivity in infants of smoking and non-smoking mothers. Early Hum Dev 1999;56:217–232.[CrossRef][Medline]
  28. Campbell AJ, Galland BC, Bolton DP, Taylor BJ, Sayers RM, Williams SM. Ventilatory responses to rebreathing in infants exposed to maternal smoking. Acta Paediatr 2001;90:793–800.[Medline]
  29. Hilton SM. The defence-arousal system and its relevance for circulatory and respiratory control. J Exp Biol 1982;100:159–174.[Abstract/Free Full Text]
  30. Bowes G, Townsend ER, Kozar LF, Bromley SM, Phillipson EA. Effect of carotid body denervation on arousal response to hypoxia in sleeping dogs. J Appl Physiol 1981;51:40–45.[Abstract/Free Full Text]
  31. Fewell JE, Kondo CS, Dascalu V, Filyk SC. Influence of carotid denervation on the arousal and cardiopulmonary response to rapidly developing hypoxemia in lambs. Pediatr Res 1989;25:473–477.[Medline]
  32. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev 1994;74:543–594.[Free Full Text]
  33. Wyatt CN, Peers C. Nicotinic acetylcholine receptors in isolated type I cells of the neonatal rat carotid body. Neuroscience 1993;54:275–281.[CrossRef][Medline]
  34. Obeso A, Gomez-Nino MA, Almaraz L, Dinger B, Fidone S, Gonzalez C. Evidence for two types of nicotinic receptors in the cat carotid body chemoreceptor cells. Brain Res 1997;754:298–302.[CrossRef][Medline]
  35. Shirahata M, Ishizawa Y, Rudisill M, Schofield B, Fitzgerald RS. Presence of nicotinic acetylcholine receptors in cat carotid body afferent system. Brain Res 1998;814:213–217.[CrossRef][Medline]
  36. Gomez-Nino A, Dinger B, Gonzalez C, Fidone SJ. Differential stimulus coupling to dopamine and norepinephrine stores in rabbit carotid body type I cells. Brain Res 1990;525:160–164.[CrossRef][Medline]
  37. Svensson TH, Engberg G. Effect of nicotine on single cell activity in the noradrenergic nucleus locus coeruleus. Acta Physiol Scand Suppl 1980;479:31–34.
  38. Andersson K, Eneroth P, Fuxe K, Mascagni F, Agnati LF. Effects of chronic exposure to cigarette smoke on amine levels and turnover in various hypothalamic catecholamine nerve terminal systems and on the secretion of pituitary hormones in the male rat. Neuroendocrinology 1985;41:462–466.[Medline]
  39. Hertzberg T, Hellstrom S, Lagercrantz H, Pequignot JM. Development of the arterial chemoreflex and turnover of carotid body catecholamines in the newborn rat. J Physiol (Lond) 1990;425:211–225.[Abstract/Free Full Text]
  40. Llados F, Zapata P. Effects of dopamine analogues and antagonists on carotid body chemosensors in situ. J Physiol (Lond) 1978;274:487–499.[Abstract/Free Full Text]
  41. Goiny M, Lagercrantz H, Srinivasan M, Ungerstedt U, Yamamoto Y. Hypoxia-mediated in vivo release of dopamine in nucleus tractus solitarii of rabbits. J Appl Physiol 1991;70:2395–2400.[Abstract/Free Full Text]
  42. Hafstrom O, Poole SD, Milerad J, Sundell HW. Dopaminergic mediation of delayed arousal from quiet sleep in young lambs exposed to nicotine in utero. Pediatr Res 1998;43:332A.
  43. Hafstrom O, Poole SD, Milerad J, Sundell HW. The impaired ventilatory response to acute hypoxemia in sleeping lambs exposed to nicotine prenatally is mediated by a dopaminergic mechanism. Pediatr Res 1998;43:332A.
  44. Niedermaier ON, Smith ML, Beightol LA, Zukowska-Grojec Z, Goldstein DS, Eckberg DL. Influence of cigarette smoking on human autonomic function. Circulation 1993;88:562–571.[Medline]
  45. Navarro HA, Mills E, Seidler FJ, Baker FE, Lappi SE, Tayyeb MI, Spencer JR, Slotkin TA. Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding. Brain Res Bull 1990;25:233–237.[CrossRef][Medline]
  46. Phillipson EA, Bower G. Control of breathing during sleep. In: Cherniack NS, Widdicome JG, editors. Handbook of physiology. The respiratory system. Control of breathing, Part 2: American Physiological Society; 1986. p. 649–689.
  47. Frank MG, Srere H, Ledezma C, O'Hara B, Heller HC. Prenatal nicotine alters vigilance states and AchR gene expression in the neonatal rat: implications for SIDS. Am J Physiol Regul Integr Comp Physiol 2001;280:R1134–R1140.[Abstract/Free Full Text]
  48. Hayde M, Bernaschek G, Stevenson DK, Knight GJ, Haddow JE, Widness JA. Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers. Acta Paediatr 1999;88:327–331.[CrossRef][Medline]
  49. Oncken CA, Hardardottir H, Hatsukami DK, Lupo VR, Rodis JF, Smeltzer JS. Effects of transdermal nicotine or smoking on nicotine concentrations and maternal-fetal hemodynamics. Obstet Gynecol 1997;90:569–574.[Abstract]
  50. Navarro HA, Seidler FJ, Schwartz RD, Baker FE, Dobbins SS, Slotkin TA. Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth. Brain Res Bull 1989;23:187–192.[CrossRef][Medline]
  51. Rebuck AS, Woodley WE. Ventilatory effects of hypoxia and their dependence on PCO2. J Appl Physiol 1975;38:16–19.[Abstract/Free Full Text]
  52. Smith TF, Hudgel DW. Decreased ventilation response to hypoxia in children with asthma. J Pediatr 1980;97:736–741.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
J. D. Pendlebury, R. J. A. Wilson, S. Bano, K. J. Lumb, J. M. Schneider, and S. U. Hasan
Respiratory Control in Neonatal Rats Exposed to Prenatal Cigarette Smoke
Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1255 - 1261.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
Z. G. Huang, K. J. S. Griffioen, X. Wang, O. Dergacheva, H. Kamendi, C. Gorini, and D. Mendelowitz
Nicotinic Receptor Activation Occludes Purinergic Control of Central Cardiorespiratory Network Responses to Hypoxia/Hypercapnia
J Neurophysiol, October 1, 2007; 98(4): 2429 - 2438.
[Abstract] [Full Text] [PDF]

Home page
 CMAJHome page
C. E. Hunt and F. R. Hauck
Sudden infant death syndrome.
Can. Med. Assoc. J., June 20, 2006; 174(13): 1861 - 1869.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. Simakajornboon, V. Vlasic, H. Li, and H. Sawnani
Effect of prenatal nicotine exposure on biphasic hypoxic ventilatory response and protein kinase C expression in caudal brain stem of developing rats
J Appl Physiol, June 1, 2004; 96(6): 2213 - 2219.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H. Sawnani, T. Jackson, T. Murphy, R. Beckerman, and N. Simakajornboon
The Effect of Maternal Smoking on Respiratory and Arousal Patterns in Preterm Infants during Sleep
Am. J. Respir. Crit. Care Med., March 15, 2004; 169(6): 733 - 738.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
E. R. Spindel
Neuronal nicotinic acetylcholine receptors: not just in brain
Am J Physiol Lung Cell Mol Physiol, December 1, 2003; 285(6): L1201 - L1202.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
I. Kato, P. Franco, J. Groswasser, S. Scaillet, I. Kelmanson, H. Togari, and A. Kahn
Incomplete Arousal Processes in Infants Who Were Victims of Sudden Death
Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1298 - 1303.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, and Pulmonary Function Testing in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 306 - 318.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002
Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 333 - 344.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
E. Nattie and H. Kinney
Nicotine, Serotonin, and Sudden Infant Death Syndrome
Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): 1530 - 1531.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hafström, O.
Right arrow Articles by Sundell, H. W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2002 American Thoracic Society