Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: Implications for sudden infant death syndrome

Slotkin, Theodore A.; Lappi, Simon E.; McCook, E.C.; Lorber, Brian A.; Seidler, Frederic J.

doi:10.1016/0361-9230(95)00073-n

Cited by 176 publications

(123 citation statements)

References 33 publications

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“…8). Similar to previous findings (Slotkin et al, 1995), group 2 pups experienced a significantly higher mortality in which 38.6 Ϯ 4.1% of them died after a similar hypoxic exposure (n ϭ 40) (Fig. 8).…”

Section: Hif-2␣ Activation Is Involved In the Nicotine-mediated Loss supporting

confidence: 90%

“…These findings raised the possibility that activation of nicotinic acetylcholine receptors (nAChRs) on chromaffin cells may be involved in the postnatal loss of direct chemosensing properties in these cells. Indeed, prenatal nicotine exposure is known to cause a loss of hypoxia tolerance, decreased arousal responses in the neonate, and impaired hypoxia-induced CAT secretion (Slotkin et al, 1995;Slotkin, 1998;Cohen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Buttigieg¹,

Brown²,

Holloway³

et al. 2009

J. Neurosci.

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Fetal nicotine exposure blunts hypoxia-induced catecholamine secretion from neonatal adrenomedullary chromaffin cells (AMCs), providing a link between maternal smoking, abnormal arousal responses, and risk of sudden infant death syndrome. Here, we show that the mechanism is attributable to upregulation of K ATP channels via stimulation of ␣7 nicotinic ACh receptors (AChRs). These K ATP channels open during hypoxia, thereby suppressing membrane excitability. After in utero exposure to chronic nicotine, neonatal AMCs show a blunted hypoxic sensitivity as determined by inhibition of outward K ϩ current, membrane depolarization, rise in cytosolic Ca 2ϩ , and catecholamine secretion. However, hypoxic sensitivity could be unmasked in nicotine-exposed AMCs when glibenclamide, a blocker of K ATP channels, was present. Both K ATP current density and K ATP channel subunit (Kir 6.2) expression were significantly enhanced in nicotine-exposed cells relative to controls. The entire sequence could be reproduced in culture by exposing neonatal rat AMCs or immortalized fetal chromaffin (MAH) cells to nicotine for ϳ1 week, and was prevented by coincubation with selective blockers of ␣7 nicotinic AChRs. Additionally, coincubation with inhibitors of protein kinase C and CaM kinase, but not protein kinase A, prevented the effects of chronic nicotine in vitro. Interestingly, chronic nicotine failed to blunt hypoxia-evoked responses in MAH cells bearing short hairpin knockdown (Ͼ90%) of the transcription factor, hypoxia-inducible factor-2␣ (HIF-2␣), suggesting involvement of the HIF pathway. The therapeutic potential of K ATP channel blockers was validated in experiments in which hypoxia-induced neonatal mortality in nicotine-exposed pups was significantly reduced after pretreatment with glibenclamide.

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Section: Hif-2␣ Activation Is Involved In the Nicotine-mediated Loss supporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Buttigieg¹,

Brown²,

Holloway³

et al. 2009

J. Neurosci.

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“…24,25 Neonatal rats exposed prenatally to nicotine had increased mortality during hypoxic challenge. 26 Nonetheless, subsequent experimental studies in the neonatal rat subjected to hypoxia, 27 anoxia, 28 or hypercapnia, 29 showed unaffected respiratory response after maternal nicotine exposure during gestation. In contrast, lambs subjected to acute infusion of nicotine had decreased ventilation during hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…NIC ϩ IL-1␤ had significantly more spontaneous apneas the last 5 minutes before induction of apnea (2 [.3-3] vs 0 [0 -0]; P Ͻ .03; Fig 2). Apneas were prolonged (46 seconds [39 -51] vs 26 seconds [22][23][24][25][26][27][28][29][30][31]; P Ͻ .01; Fig 2) with greater fall in Sao 2 (Fig 3), and followed by far more spontaneous apneas the following 5 minutes (6.6 [4.0 -7.9 Fig 3). These prolonged adverse effects on ventilation were reflected in lowered Pao 2 , elevated Paco 2 and lowered pH 2, and even 5, minutes after induction of apnea (all P Ͻ .04; Table 2).…”

Section: Of 5 Adverse Effects Of Nicotine and Interleukin-1␤ On Apneamentioning

confidence: 99%

Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

et al. 2000

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ABSTRACT. Objectives. Maternal cigarette smoking is established as a major dose-dependent risk factor for sudden infant death syndrome (SIDS). Both prenatal and postnatal exposures to constituents of tobacco smoke are associated with SIDS, but no mechanism of death attributable to nicotine has been found. Breastfeeding gives a substantial increase in absorbed nicotine compared with only environmental tobacco smoke when the mother smokes, because the milk:plasma concentration ratio of nicotine is 2.9 in smoking mothers. Furthermore, many SIDS victims have a slight infection and a triggered immune system before their death, thus experiencing a release of cytokines like interleukin-1␤ (IL-1␤) that may depress respiration. Because apneas in infancy are associated with SIDS, we have tested the hypothesis that postnatal exposure to tobacco constituents and infections might adversely affect an infant's ability to cope with an apneic episode. This is performed by investigating the acute effects of nicotine and IL-1␤ on apnea by laryngeal reflex stimulation and on the subsequent autoresuscitation.Design. Thirty 1-week-old piglets (؎1 day) were sedated with azaperone. A tracheal and an arterial catheter were inserted during a short halothane anesthesia. The piglets were allowed a 30-minute stabilization period before baseline values were recorded and they were randomized to 4 pretreatment groups (avoiding siblings in the same group): 1) immediate infusion of 10 pmol IL-1␤ intravenously/kg (IL-1␤ group; n ‫؍‬ 8); 2) slow infusion of 5 g nicotine intravenously/kg 5 minutes later (NIC group; n ‫؍‬ 8); 3) both IL-1␤ and NIC combined (NIC ؉ IL-1␤ group; n ‫؍‬ 6); or 4) placebo by infusion of 1 ml .9% NaCl (CTR group; n ‫؍‬ 8). Fifteen minutes later, apnea was induced by insufflation of .1 ml of acidified saline (pH ‫؍‬ 2) in the subglottic space 5 times with 5-minute intervals, and variables of respiration, heart rate, blood pressure, and blood gasses were recorded.Results. Stimulation of the laryngeal chemoreflex by insufflation of acidified saline in the subglottic space produced apneas, primarily of central origin. This was followed by a decrease in heart rate, a fall in blood pressure, swallowing, occasional coughs, and finally autoresuscitation with gasping followed by rapid increase in heart rate, rise in blood pressure, and (in the CTR group) an increase of respiratory rate. Piglets pretreated with nicotine had more spontaneous apneas, and repeated spontaneous apneas caused an inability to perform a compensatory increase of the respiratory rate after induced apnea. This resulted in a lower SaO 2 than did CTR at 2 minutes after apnea (data shown as median ABBREVIATIONS. SIDS, sudden infant death syndrome; IL-1␤, interleukin-1␤; CRP, C-reactive protein; IL-6, interleukin-6; IL-1␤ group, 10 pmol IL-1␤ intravenously/kg; NIC group, 5 g nicotine intravenously/kg; NIC ϩ IL-1␤ group, both IL-1␤ and NIC combined; CTR group, placebo. M aternal cigarette smoking is established as a major dose-dependent risk factor for sudden infan...

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“…Nicotine is an active ingredient of cigarette smoke, and maternal smoking has been identified as a key risk factor in the development of sudden infant death syndrome (see Holgert et al, 1995;Slotkin et al, 1995). Since nicotine can be readily transferred to the infant via the placenta prenatally and in breast milk postnatally (for refs.…”

Section: Discussionmentioning

confidence: 99%

Role of Acetylcholine Receptors and Dopamine Transporter in Regulation of Extracellular Dopamine in Rat Carotid Body Cultures Grown in Chronic Hypoxia or Nicotine

Jackson

Nurse

1998

Journal of Neurochemistry

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Using dissociated rat carotid body (CB) cultures, we compared levels of extracellular dopamine (DA) around oxygen-sensitive glomus cells grown for -~12 days in normoxia (Nox; 20% 02), chronic hypoxia (CHox; 6% 02), or chronic nicotine (CNic; 10~tMnicotine, 20% 02), with or without acetylcholine (ACh) receptor (AChR) agonists/antagonists and blockers of DA uptake. In Nox cultures, extracellular DA, determined by HPLC and normalized to the number of tyrosine hydroxylase-positive glomus cells present, was augmented by acute (-.15-mm) exposure to hypoxia (5% 02;~-~6x basal), high extracellular K~(30 mM; --lOx basal), nomifensine (1 1.sM; a selective DA uptake inhibitor; --.3x basal), and nicotine (100~sM; --5x basal), but not methylcholine (300 1zM; a specific muscarinic agonist). In contrast, in CHox cultures where basal DA release is markedly elevated (--9x control), the stimulatory effect of high K~(3-4x basal) and acute hypoxia (--2x basal) on DA release persisted, but nicotine and nomifensine were no longer effective and methylcholine had a partial inhibitory effect. In CNic cultures, basal DA levels were also elevated (-~9xcontrol), similar to that in CHox cultures; however, although acute hypoxia had a stimulatory effect on DA release (.-2x basal), nicotine, nomifensine, and high K~were ineffective. The elevated basal DA in both CHox and CNic cultures was attenuated by acute or chronic treatment with mecamylamine (100~sfl~, a nicotinic AChR (nAChR) antagonist. In addition, long-term (16-h), but not acute (15-mm), treatment with the muscarinic antagonist atropine (1~M)produced an additional enhancement of basal DA levels in CHox cultures. Thus, after chronic hypoxia or nicotine in vitro, extracellular DA levels around CB chemoreceptor cell clusters appear to be set by a variety of factors including released ACh, positive and negative feedback regulation via nAChRs and muscarinic AChRs, respectively, and modulation of DA transporters. These results provide insight into roles of endogenous transmitters in the adaptation of CB chemoreceptors to chronic hypoxia and suggest pathways by which neuroactive drugs, e.g., nicotine, can interfere with the protective chemoreflex response against hypoxia. Key Words: Dopamine uptake-Glomus cell culture-Nicotinic and muscarinic acetylcholine receptors-a2 chemoreceptors-HPLC.

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Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: Implications for sudden infant death syndrome

Cited by 176 publications

References 33 publications

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

Role of Acetylcholine Receptors and Dopamine Transporter in Regulation of Extracellular Dopamine in Rat Carotid Body Cultures Grown in Chronic Hypoxia or Nicotine

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Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: Implications for sudden infant death syndrome

Cited by 176 publications

References 33 publications

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of KATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of KATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Adverse Effects of Nicotine and Interleukin-1β on Autoresuscitation After Apnea in Piglets: Implications for Sudden Infant Death Syndrome

Role of Acetylcholine Receptors and Dopamine Transporter in Regulation of Extracellular Dopamine in Rat Carotid Body Cultures Grown in Chronic Hypoxia or Nicotine

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Resources

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Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α

Chronic Nicotine Blunts Hypoxic Sensitivity in Perinatal Rat Adrenal Chromaffin Cells via Upregulation of K_ATPChannels: Role of α7 Nicotinic Acetylcholine Receptor and Hypoxia-Inducible Factor-2α