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Prenatal Nicotine Exposure Alters the Types of Nicotinic Receptors That Facilitate Excitatory Inputs to Cardiac Vagal Neurons

Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037

Submitted 12 May 2004; accepted in final form 19 June 2004

	ABSTRACT

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Nicotinic receptors play an important role in modulating the activity of parasympathetic cardiac vagal neurons in the medulla. Previous work has shown nicotine acts via at least three mechanisms to excite brain stem premotor cardiac vagal neurons. Nicotine evokes a direct increase in holding current and facilitates both the frequency and amplitude of glutamatergic neurotransmission to cardiac vagal neurons. This study tests whether these nicotinic receptor–mediated responses are endogenously active, whether 42 and 7 nicotinic receptors are involved, and whether prenatal exposure to nicotine alters the magnitude of these responses and the types of nicotinic receptors involved. Application of neostigmine (10 µM) significantly increased the holding current, amplitude, and frequency of miniature excitatory postsynaptic current (mEPSC) glutamatergic events in cardiac vagal neurons. In unexposed animals, the nicotine-evoked facilitation of mEPSC frequency, but not mEPSC amplitude or holding current, was blocked by -bungarotoxin (100 nM). Prenatal nicotine exposure significantly exaggerated and altered the types of nicotinic receptors involved in these responses. In prenatal nicotine-exposed animals, -bungarotoxin only partially reduced the increase in mEPSC frequency. In addition, in prenatal nicotine-exposed animals, the increase in holding current was partially dependent on -7 subunit–containing nicotinic receptors, in contrast to unexposed animals in which -bungarotoxin had no effect. These results indicate prenatal nicotine exposure, one of the highest risk factors for sudden infant death syndrome (SIDS), exaggerates the responses and changes the types of nicotinic receptors involved in exciting premotor cardiac vagal neurons. These alterations could be responsible for the pronounced bradycardia that occurs during apnea in SIDS victims.

	INTRODUCTION

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Nicotinic receptors have been shown to be important modulators of parasympathetic cardiac neuron activity originating from the brain stem (Mendelowitz 1998, 1999; Neff et al. 1998, 2003; Wang et al. 2001a, b, 2003b). Nicotine, but not agonists of muscarinic receptors, activates postsynaptic receptors and evokes depolarizing inward currents in premotor cardiac vagal neurons (Neff et al. 1998; Wang et al. 2001a). In addition, nicotine acts at different presynaptic and postsynaptic sites to facilitate glutamatergic neurotransmission to these neurons in the brain stem (Neff et al. 1998; Wang et al. 2001a). Presynaptic nicotinic receptors increase the frequency of glutamatergic transmitter release and are blocked by -bungarotoxin (-BgTX), an antagonist selective for -7 subunit–containing nicotinic receptors (Neff et al. 1998; Wang et al. 2001a). Nicotine has also been shown to elicit an augmentation of postsynaptic non–N-methyl-D-aspartate (NMDA) currents in cardiac vagal neurons (Neff et al. 1998; Wang et al. 2001a).

Activation of nicotinic receptors also facilitates inhibitory GABAergic and glycinergic neurotransmission to cardiac vagal neurons, and this cholinergic facilitation is endogenously active (Wang et al. 2003b). The physiological importance of nicotinic modulation of inhibitory neurotransmission to cardiac vagal neurons is apparent in the interactions between the cardiovascular and respiratory systems. During inspiration, cardiac vagal neurons are strongly inhibited by both GABAergic and glycinergic synaptic events (Neff et al. 2003). This inspiratory-related inhibition of cardioinhibitory cardiac vagal neurons likely mediates respiratory sinus arrhythmia, in which heart rate increases during each inspiration. Focal application of the nicotinic antagonist dihydro--erithroidine (DHE) in an 42 selective concentration (3 µM) abolishes the respiratory-evoked increase in GABAergic frequency but not the increase in glycinergic frequency during inspiration. Presynaptic 42 nicotinic receptors on GABAergic, but not glycinergic, neurons likely mediate the cardiorespiratory interactions in the brain stem responsible for respiratory sinus arrhythmia (Neff et al. 2003).

The involvement of nicotinic receptors in mediating respiratory sinus arrhythmia is particularly interesting because prenatal nicotine exposure is among the highest risk factors for sudden infant death syndrome (SIDS) (Meny et al. 1994; Taylor and Sanderson 1995). Infants that succumb to SIDS often experience a sustained bradycardia, presumably due to increased activity of cardiac vagal neurons, which is preceded or accompanied by a life-threatening apnea (Cote et al. 1998; Meny et al. 1994). These life-threatening events in SIDS victims are thought to be caused by exaggerated central cardiorespiratory responses in response to a challenge, such as hypoxia or apnea (Meny et al. 1994; Slotkin et al. 1997). Nicotinic modulation of GABAergic neurotransmission has been shown to be exaggerated with prenatal exposure to nicotine, and this increased inhibition of cardiac vagal neurons may be responsible for the increased heart rate observed in SIDS victims (Neff et al. 2003).

This study has three goals: 1) test whether the nicotinic activation of cardiac vagal neurons and facilitation of glutamatergic neurotransmission to cardiac vagal neurons is endogenously active; 2) determine if 42 nicotinic receptors are involved; and 3) examine whether prenatal exposure to nicotine alters the types of nicotinic receptors responsible for facilitating glutamatergic neurotransmission to cardiac vagal neurons.

	METHODS

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In an initial surgery, 2- to 6-day-old rats were anesthetized with ketamine/xylazine and exposed to hypothermia during the surgery (10–20 min) to slow the heart and aid in recovery. A right thoracotomy was used to expose the heart, and rhodamine (XRITC, Molecular Probes, 2% solution, 20–40 µl) was injected into the pericardial sac. Control injections of rhodamine either into the chest cavity but outside the pericardial sac or intravenous injections failed to label any neurons in the medulla, except for rare labeling of area postrema neurons observed with intravenous injections.

One group of animals were studied after prenatal nicotine exposure. Adult female rats were anesthetized with ketamine/xylazine on the third day of gestation and implanted with Alzet osmotic minipumps (Durect, Cupertino, CA) containing (–)nicotine (56.1 mg/ml bacteriostatic water; Sigma, St. Louis, MO). Pumps delivered 2.1 mg nicotine/day (a dosage that produces blood nicotine levels approximately equivalent to those that occur in moderate to heavy smokers) to the pregnant dams throughout the pregnancy and prenatal period (Slotkin et al. 1997). These pups were not only exposed to nicotine prenatally but continued to be exposed to nicotine via maternal nursing until death.

On the day of the experiment (1–3 days after injection of the fluorescent tracer), the animals were anesthetized deeply with halothane and killed by cervical dislocation. The brain was submerged in cold (4°C) buffer of the following composition (in mM): 140 NaCl, 5 KCl, 2 CaCl₂, 5 glucose, and 10 HEPES (continually gassed with 100% O₂). Under a dissection microscope, the cerebellum was removed, and the hindbrain was isolated. The brain stem was secured in the slicing chamber of a vibratome filled with the same buffer; its rostral end was set upward, and the dorsal surface was glued to a wax block facing the razor. Slices of 300- to 400-micron thickness were taken. All animal procedures were performed in compliance with the institutional guidelines at George Washington University and are in accordance with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association and the National Institutes of Health publication Guide for the Care and Use of Laboratory Animals. Slices were mounted in a perfusion chamber and submerged in the perfusate of the following composition (in mM): 125 NaCl, 3 KCl, 2 CaCl₂, 26 NaHCO₃, 5 dextrose, and 5 HEPES (constantly bubbled with gas (95% O₂-5% CO₂) and maintained at pH 7.4). To examine spontaneous TTX-independent miniature excitatory synaptic currents (mEPSCs), TTX (1 µM) was included in the bath, and strychnine (1 µM), gabazine (25 µM), D-2-amino-5-phosphonovalerate (AP5, 50 µM), and prazosin (1 µM) were included in the perfusate to block activation of glycine, GABA, NMDA, and -adrenergic receptors, respectively.

Individual cardiac vagal neurons in nucleus ambiguus were identified by the presence of the fluorescent tracer. These identified cardiac vagal neurons were imaged with differential interference contrast (DIC) optics, infrared illumination, and infrared-sensitive video detection cameras to gain better spatial resolution. Cardiac vagal neurons were studied using the whole cell patch-clamp technique and were voltage clamped at a holding potential of –80 mV. The patch pipettes were filled with a solution consisting of (in mM) 135 gluconic acid, 10 HEPES, 10 EGTA, 1 CaCl₂, and 1 MgCl₂.

In experiments that tested whether there is endogenous cholinergic modulation of cardiac vagal neurons, neostigmine (10 µM), an acetylcholinerase inhibitor, was applied via inclusion in the perfusate. Nicotine (100 µM) was applied focally using a picospritzer and ejected from a patch pipette positioned within 30 µm from the patched cardiac vagal neuron. The maximum range of drug application has been previously determined to 100–120 µm downstream from the drug pipette and considerably less behind the drug pipette (Wang et al. 2002).

-BgTX (100 nM) was used to selectively block -7 subunit containing nicotinic receptors, DHE was applied at a concentration of 3 µM to selectively block 42 nicotinic receptors, and DHE was utilized at a concentration of 100 µM to block all nicotinic receptors (Alkondon and Albuquerque 1993). These antagonists were applied cumulatively during the course of each experiment by inclusion in the perfusate. All drugs were purchased from Sigma Aldrich (St. Louis, MO). Analysis of TTX-insensitive mEPSCs were performed using MiniAnalysis (Synaptosoft, version 4.3.1) with minimal acceptable amplitude of 8 pA. Results are presented as means ± SE. Statistical comparisons were performed using ANOVA with repeated measures to examine the responses throughout the time course of the experiment, paired Student's t-tests when comparing the data from control periods to during nicotine application, and unpaired Student's t-tests when comparing the results from control animals to animals exposed to nicotine prenatally. Significant difference was set at P < 0.05.

	RESULTS

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Brief (60 s) applications of nicotine (100 µM) increased both the frequency and amplitude of glutamatergic mEPSCs in premotor cardiac vagal neurons (Fig. 1). Nicotine also evoked a transient inward current (Fig. 1). To determine if repetitive applications of nicotine (100 µM) could evoke consistent repeatable responses, the results from four sequential applications of nicotine, with 10 min between applications, were compared. Each of the three subsequent applications of nicotine (100 µM) evoked significant increases in mEPSC frequency and amplitude and an inward current, which were indistinguishable and not statistically different from the initial responses (P > 0.05; Fig. 1).

View larger version (29K): [in this window] [in a new window]   FIG. 1. Repetitive applications of nicotine (100 µM, 60 s) evoked significant inward currents (top) and elicited increases in miniature excitatory postsynaptic current (mEPSC) frequency (middle) and mEPSC amplitude (bottom) in cardiac vagal neurons. Responses to 4 sequential applications of nicotine, with 10 min between applications, were indistinguishable. Left: responses from a single neuron. Right: summary data from 9 cells. Unfilled bars are control values, and filled bars are responses to nicotine. In this and all subsequent figures, *P < 0.05 and **P < 0.01.

View larger version (31K): [in this window] [in a new window]   FIG. 2. Applications of nicotine (100 µM) evoked significant inward currents (top) and elicited increases in mEPSC frequency (middle) and mEPSC amplitude (bottom). In the presence of -bungarotoxin (100 nM), reapplication of nicotine (100 µM) continued to evoke inward currents and increases in mEPSC amplitudes that were not significantly different from initial responses, but the increase in mEPSC frequency was blocked. In the presence of dihydro--erithroidine (DHE), at a concentration of 3 µM, nicotine continued to evoke an inward current and increases in mEPSC amplitude that were not significantly different from initial responses, but DHE, at a concentration of 100 µM, blocked nicotine responses. Left: responses from a single neuron. Right: summary data from 8 cells (unfilled bars are control values, and filled bars are responses to nicotine).

View larger version (33K): [in this window] [in a new window]   FIG. 3. Applications of nicotine (100 µM) evoked inward currents (top) and increases in mEPSC frequency (middle) and mEPSC amplitude (bottom) in animals prenatally exposed to nicotine. -Bungarotoxin (100 nM) significantly inhibited the inward current and diminished, but did not abolish, the increase in mEPSC frequency. DHE, at a concentration of 3 µM, did not alter nicotine-evoked responses, but DHE, at a concentration of 100 µM, blocked the nicotine responses. Left: responses from a single neuron. Right: summary data from 11 cells (unfilled bars are control values, and filled bars are the responses to nicotine).

View larger version (14K): [in this window] [in a new window]   FIG. 4. Animals prenatally exposed to nicotine (n = 11) had exaggerated inward current responses (top) and increases in mEPSC frequency (middle) and mEPSC amplitude (bottom) that were significantly greater than unexposed animals (n = 8). -Bungarotoxin (100 nM) significantly inhibited the inward current in animals prenatally exposed to nicotine but not in unexposed animals. -Bungarotoxin (100 nM) abolished the increase in mEPSC frequency in unexposed animals, but only diminished the responses in animals prenatally exposed to nicotine. DHE, at a concentration of 3 µM, did not alter the nicotine-evoked responses in both unexposed and animals prenatally exposed to nicotine, but DHE, at a concentration of 100 µM, blocked the nicotine responses.

View larger version (30K): [in this window] [in a new window]   FIG. 5. Neostigmine (10 µM), an acetylcholinerase inhibitor, significantly facilitated the glutamatergic neurotransmission to cardiac vagal neurons in unexposed animals (n = 7; left) and in animals prenatally exposed to nicotine (n = 6; right; unfilled bars are control values, and filled bars are the responses to nicotine). Neostigmine increased the holding current, mEPSC frequency, and mEPSC amplitude in unexposed animals (unfilled bars), and these responses were significantly exaggerated in animals prenatally exposed to nicotine (bottom; filled bars).

	DISCUSSION

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Prenatal nicotine exposure significantly increases the endogenous activation of nicotinic receptors responsible for an inward current and augmentation of mEPSC frequency and amplitude in cardiac vagal neurons. In addition, prenatal nicotine exposure evoked both an exaggeration and change in nicotinic receptors responsible for the nicotine-evoked responses that consist of an inward current and increases in mEPSC frequency and amplitude. In prenatal nicotine-exposed animals, the increase in holding current was partially dependent on -7 subunit–containing nicotinic receptors, whereas in unexposed animals, -BgTX had no effect on the holding current responses. Furthermore, whereas in control animals -BgTX abolished the increase in mEPSC frequency, in prenatal nicotine-exposed animals, -BgTX only partially reduced the increase in mEPSC frequency. These results indicate prenatal nicotine exposure elicits an increase in the responses and types of nicotinic receptors involved in the control of premotor cardiac vagal neurons. More specifically, these results show that prenatal nicotine exposure elicits the postsynaptic expression of -7 subunit–containing nicotinic receptors in cardiac vagal neurons and that nicotinic receptors other than -7 subunit–containing nicotinic receptors are expressed at presynaptic glutamatergic terminals and can facilitate glutamatergic neurotransmission to cardiac vagal neurons. Although not examined in this study, cooperativity could occur between different nicotinic receptors, including between homomeric -7 and heteromeric nicotinic receptors. Recent work has shown cooperativity between nicotinic receptors in which the open state of a nicotinic receptor increases the probability of opening neighboring nicotinic channels (Keleshian et al. 2000).

There is considerable evidence that -7 subunit–containing nicotinic receptors are expressed at presynaptic glutamatergic terminals in other neuronal pathways (Berg and Conroy 2002; Dani 2001; McGehee et al. 1995). However, evidence that -7 subunit–containing nicotinic receptors are involved in postsynaptic synaptic neurotransmission in the CNS is less common. However, some recent studies have shown synaptic currents generated by -7 subunit–containing nicotinic receptors, such as in the nigral dopaminergic neurons, interneurons of the hippocampus, and lamina X of the spinal cord (Alkondon et al. 1998; Bradaia and Trouslard 2002; Frazier et al. 1998; Matsubayashi et al. 2004; Zhang et al. 1996).

It is well accepted that tobacco smoking in humans and chronic nicotine exposure in animals increases the number of nicotinic receptors in the brain, but the mechanisms responsible for this up-regulation are controversial (Breese et al. 1997; Marks et al. 1992; Perry et al. 1999). It has been proposed that the up-regulation is an adaptive response to desensitization of nicotinic receptors. However, more recent reports suggest up-regulation of nicotinic receptors is not caused by long-lasting inactivation and may be due to decreased rate of receptor turnover and/or a conversion of a population of low-affinity nicotinic receptors into high-affinity nicotinic receptors (Buisson and Bertrand 2001; Kawai and Berg 2001; Peng et al. 1994). Chronic nicotine exposure has also been shown to differentially up-regulate specific types of nicotinic receptors, particularly 42 nicotinic receptors (Buisson and Bertrand 2002; Flores et al. 1992, 1997; Mugnaini et al. 2002; Peng et al. 1994). In addition, 42 receptors chronically exposed to nicotine exhibit enhanced responses to acetylcholine and are less sensitive to desensitization (Buisson and Bertrand 2001). The results from this study show that prenatal nicotine exposure initiates both a facilitation of postsynaptic responses involving -7 subunit–containing nicotinic receptors in cardiac vagal neurons that are not present in unexposed animals as well as an augmentation of presynaptic glutamatergic neurotransmission by non–-7 nicotinic receptors that are not involved in unexposed animals.

The nicotinic facilitation of glutamatergic neurotransmission to cardiac vagal neurons may be beneficial. Increased cardiac parasympathetic activity has been shown to terminate ventricular tachycardia and fibrillation (Vanoli et al. 1991; Waxman and Wald 1977). Recovery of parasympathetic activity after myocardial infarction has been associated with decreased mortality (Lampert et al. 2003). In contrast, patients with low parasympathetic activity have a higher risk for sudden death independent of other risk factors (Algra et al. 1993). A delay in the inhibitory actions of this autonomic motor system is a powerful predictor of overall mortality following exercise (Cole et al. 1999).

Nicotinic receptor–mediated facilitation of glutamatergic neurotransmission and excitation of cardiac vagal neurons is likely involved in cardiorespiratory interactions. Nicotinic receptors are responsible for the increased frequency of GABAergic inhibitory inputs to cardiac vagal neurons during inspiration, and these responses are exaggerated in prenatal nicotine-exposed animals (Neff et al. 2003). Cardiac vagal neurons do not receive excitatory glutamatergic inputs during the normal respiratory cycle, but do receive increased glutamatergic inputs during respiratory bursts that only occur with an hypoxic challenge (Wang et al. 2003a). The glutamatergic excitation of premotor cardiac vagal neurons associated with hypoxia may contribute to cardiovascular dysfunction in SIDS. SIDS is the leading cause of death in infants between 1 mo and 1 yr of age, yet the mechanisms of SIDS have not been elucidated. Bradycardia is the most prevalent and predictive event in infants monitored for apparent life-threatening events (Cote et al. 1998). Although the cause(s) for SIDS remains unknown, it has been speculated that an abnormality of cardio-respiratory control, and in particular an exaggerated excitation of parasympathetic control of cardiac function to challenges such as hypoxia, may be involved (Divon et al. 1986; Harper and Bandler 1998; Meny et al. 1994; Schechtman et al. 1992; Spyer and Gilbey 1988). This work shows that one of the highest risk factors for SIDS, prenatal nicotine exposure, exaggerates the glutamatergic excitation of cardiac vagal neurons, and these alterations could be responsible for the pronounced bradycardia that occurs in SIDS victims. While an exaggeration of parasympathetic responses to hypoxia may be involved in SIDS, increased parasympathetic activity with nicotinic receptor activation may be cardioprotective in adults.

	GRANTS

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This study was supported by National Heart, Lung and Blood Institute Grants HL-59895 and HL-72006 to D. Mendelowitz.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: D. Mendelowitz, Dept. of Pharmacology and Physiology, George Washington Univ., 2300 Eye St N.W., Washington, DC 20037 (E-mail: dmendel{at}gwu.edu).

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Algra A, Tijssen JG, Roelandt JR, Pool J, and Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year risk for sudden death. Circulation 88: 180–185, 1993.

Alkondon M and Albuquerque EX. Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes. J Pharmacol Exp Ther 265: 1455–1473, 1993.

Alkondon M, Pereira EF, and Albuquerque EX. -Bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res 810: 257–263, 1998.

Berg DK and Conroy WG. Nicotinic alpha 7 receptors: synaptic options and downstream signaling in neurons. J Neurobiol 53: 512–523, 2002.

Bradaia A and Trouslard J. Fast synaptic transmission mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in lamina X neurones of neonatal rat spinal cord. J Physiol 544: 727–739, 2002.

Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, and Leonard S. Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282: 7–13, 1997.

Buisson B and Bertrand D. Chronic exposure to nicotine upregulates the human (alpha)4((beta)2 nicotinic acetylcholine receptor function. J Neurosci 21: 1819–1829, 2001.

Buisson B and Bertrand D. Nicotine addiction: the possible role of functional upregulation. Trends Pharmacol Sci 23: 130–136, 2002.

Cole CR, Blackstone EH, Pashkow FJ, Snader CE, and Lauer MS. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 341: 1351–1357, 1999.

Cote A, Hum C, Brouillette RT, and Themens M. Frequency and timing of recurrent events in infants using home cardiorespiratory monitors. J Pediatr 132: 783–789, 1998.

Dani JA. Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry 49: 166–174, 2001.

Divon MY, Winkler H, Yeh SY, Platt LD, Langer O, and Merkatz IR. Diminished respiratory sinus arrhythmia in asphyxiated term infants. Am J Obstet Gynecol 155: 1263–1266, 1986.

Flores CM, Davila-Garcia MI, Ulrich YM, and Kellar KJ. Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochem 69: 2216–2219, 1997.

Flores CM, Rogers SW, Pabreza LA, Wolfe BB, and Kellar KJ. A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41: 31–37, 1992.

Frazier CJ, Buhler AV, Weiner JL, and Dunwiddie TV. Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18: 8228–8235, 1998.

Harper RM and Bandler R. Finding the failure mechanism in sudden infant death syndrome. Nat Med 4: 157–158, 1998.

Kawai H and Berg DK. Nicotinic acetylcholine receptors containing alpha 7 subunits on rat cortical neurons do not undergo long-lasting inactivation even when up-regulated by chronic nicotine exposure. J Neurochem 78: 1367–1378, 2001.

Keleshian AM, Edeson RO, Liu GJ, and Madsen BW. Evidence for cooperativity between nicotinic acetylcholine receptors in patch clamp records. Biophys J 78: 1–12, 2000.

Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, and Lee FA. Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the Beta-Blocker Heart Attack Trial. Am J Cardiol 91: 137–142, 2003.

Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, and Collins AC. Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12: 2765–2784, 1992.

Matsubayashi H, Amano T, Seki T, Sasa M, and Sakai N. Postsynaptic alpha4beta2 and alpha7 type nicotinic acetylcholine receptors contribute to the local and endogenous acetylcholine-mediated synaptic transmissions in nigral dopaminergic neurons. Brain Res 1005: 1–8, 2004.

McGehee DS, Heath MJ, Gelber S, Devay P, and Role LW. Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269: 1692–1696, 1995.

Mendelowitz D. Advances in parasympathetic control of heart rate and cardiac function. News Physiol Sci 14: 155–161, 1999.

Mendelowitz D. Nicotine excites cardiac vagal neurons via three sites of action. Clin Exp Pharmacol Physiol 25: 453–456, 1998.

Meny RG, Carroll JL, Carbone MT, and Kelly DH. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 93: 44–49, 1994.

Mugnaini M, Tessari M, Tarter G, Merlo Pich E, Chiamulera C, and Bunnemann B. Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of alpha7 or alpha6 subunit mRNA: an autoradiography and in situ hybridization study in rat brain. Eur J Neurosci 16: 1633–1646, 2002.

Neff RA, Humphrey J, Mihalevich M, and Mendelowitz D. Nicotine enhances presynaptic and postsynaptic glutamatergic neurotransmission to activate cardiac parasympathetic neurons. Circ Res 83: 1241–1247, 1998.

Neff RA, Wang J, Baxi S, Evans C, and Mendelowitz D. Respiratory sinus arrhythmia: endogenous activation of nicotinic receptors mediates respiratory modulation of brainstem cardioinhibitory parasympathetic neurons. Circ Res 93: 565–572, 2003.

Peng X, Gerzanich V, Anand R, Whiting PJ, and Lindstrom J. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol 46: 523–530, 1994.

Perry DC, Davila-Garcia MI, Stockmeier CA, and Kellar KJ. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther 289: 1545–1552, 1999.

Schechtman VL, Raetz SL, Harper RK, Garfinkel A, Wilson AJ, Southall DP, and Harper RM. Dynamic analysis of cardiac R-R intervals in normal infants and in infants who subsequently succumbed to the sudden infant death syndrome. Pediatr Res 31: 606–612, 1992.

Slotkin TA, Saleh JL, McCook EC, and Seidler FJ. Impaired cardiac function during postnatal hypoxia in rats exposed to nicotine prenatally: implications for perinatal morbidity and mortality, and for sudden infant death syndrome. Teratology 55: 177–184, 1997.

Spyer KM and Gilbey MP. Cardiorespiratory interactions in heart-rate control. Ann NY Acad Sci 533: 350–357, 1988.

Taylor JA and Sanderson M. A reexamination of the risk factors for the sudden infant death syndrome. J Pediatr 126: 887–891, 1995.

Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, and Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 68: 1471–1481, 1991.

Wang J, Irnaten M, and Mendelowitz D. Agatoxin-IVA-sensitive calcium channels mediate the presynaptic and postsynaptic nicotinic activation of cardiac vagal neurons. J Neurophysiol 85: 164–168, 2001a.

Wang J, Irnaten M, Neff RA, Venkatesan P, Evans C, Loewy AD, Mettenleiter TC, and Mendelowitz D. Synaptic and neurotransmitter activation of cardiac vagal neurons in the nucleus ambiguus. Ann NY Acad Sci 940: 237–246, 2001b.

Wang J, Irnaten M, Venkatesan P, Evans C, Baxi S, and Mendelowitz D. Synaptic activation of hypoglossal respiratory motorneurons during inspiration in rats. Neurosci Lett 332: 195–199, 2002.

Wang J, Neff RA, Baxi S, Evans C, and Mendelowitz D. Hypoxia evokes excitatory glutamatergic currents in premotor cardiac vagal neurons in the nucleus ambiguus during gasp-like inspiratory activity. Exp Biol D149, 307.7, 2003a.

Wang J, Wang X, Irnaten M, Venkatesan P, Evans C, Baxi S, and Mendelowitz D. Endogenous acetylcholine and nicotine activation enhances GABAergic and glycinergic inputs to cardiac vagal neurons. J Neurophysiol 89: 2473–2481, 2003b.

Waxman MB and Wald RW. Termination of ventricular tachycardia by an increase in cardiac vagal drive. Circulation 56: 385–391, 1977.

Zhang ZW, Coggan JS, and Berg DK. Synaptic currents generated by neuronal acetylcholine receptors sensitive to alpha-bungarotoxin. Neuron 17: 1231–1240, 1996.

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