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J Neurophysiol (May 1, 2003). 10.1152/jn.00934.2002
Submitted on Submitted 25 October 2002; accepted in final form 14 January 2003
Department of Pharmacology, George Washington University, Washington, DC 20037
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Wang, Jijiang,
Xin Wang,
Mustapha Irnaten,
Priya Venkatesan,
Cory Evans,
Sunit Baxi, and
David Mendelowitz.
Endogenous Acetylcholine and Nicotine Activation Enhances
GABAergic and Glycinergic Inputs to Cardiac Vagal Neurons.
J. Neurophysiol. 89: 2473-2481, 2003.
The heart slows during expiration and heart rate increases during
inspiration. This cardiorespiratory interaction is thought to occur by
increased inhibitory synaptic events to cardiac vagal neurons during
inspiration. Since cholinergic receptors have been suggested to be
involved in this cardiorespiratory interaction, we tested whether
endogenous cholinergic activity modulates GABAergic and glycinergic
neurotransmission to cardiac vagal neurons in the nucleus ambiguus,
whether nicotine can mimic this facilitation, and we examined the
nicotinic receptors involved. Cardiac vagal neurons in the rat were
labeled with a retrograde fluorescent tracer and studied in an in vitro
slice using patch-clamp techniques. Application of neostigmine (10 µM), an acetylcholinerase inhibitor, significantly increased the
frequency of both GABAergic and glycinergic inhibitory postsynaptic
currents (IPSCs) in cardiac vagal neurons. Exogenous application of
nicotine increased the frequency and amplitude of both GABAergic and
glycinergic IPSCs. The nicotinic facilitation of both GABAergic and
glycinergic IPSCs were insensitive to 100 nM 
-bungarotoxin but were
abolished by dihydro-
-erythrodine (DHE) at a concentration (3 µM) specific for 42 nicotinic receptors. In the presence of
TTX, nicotine increased the frequency of GABAergic and glycinergic
miniature synaptic events, which were also abolished by DHE (3 µM). This work demonstrates that there is endogenous cholinergic
facilitation of GABAergic and glycinergic synaptic inputs to cardiac
vagal neurons, and activation of 42 nicotinic receptors at
presynaptic terminals facilitates GABAergic and glycinergic neurotransmission to cardiac vagal neurons. Nicotinic facilitation of
inhibitory neurotransmission to premotor cardiac parasympathetic neurons may be involved in generating respiratory sinus arrhythmia.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The neural control of
heart rate and cardiac function are dominated by the parasympathetic
activity to the heart, while cardiac sympathetic activity plays a minor
role under resting conditions (Loewy and Spyer 1990
;
Mendelowitz 1999, 1996). Premotor cardiac vagal neurons
are located in the nucleus ambiguus and the dorsal motor nucleus of the
vagus (DiMicco et al. 1979; Mendelowitz 1999, 1996; Standish et al. 1995; Stuesse
1982). Since premotor cardiac vagal neurons are intrinsically
silent, their activity is determined by excitatory and inhibitory
synaptic inputs (Mendelowitz 1999, 1996;
Mendelowitz and Kunze 1991).
Excitatory inputs to premotor cardiac vagal neurons include
glutamatergic inputs from the nucleus tractus solitarius (NTS) and
cholinergic nicotinic receptors that can directly excite premotor cardiac vagal neurons (Neff et al. 1998a,b; Wang
et al. 2001a). In addition nicotine can enhance glutamatergic
neurotransmission to premotor cardiac vagal neurons at both presynaptic
and postsynaptic sites (Neff et al. 1998a; Wang
et al. 2001a). The presynaptic facilitation can be blocked by
antagonists specific for 7-subunit-containing nicotinic receptors
and this presynaptic TTX-insensitive facilitation is dependent on the
activation of voltage-gated calcium channels (Neff et al.
1998a; Wang et al. 2001a).
However considerably less is known about the function and modulation of
inhibitory synaptic inputs to premotor cardiac vagal neurons.
Stimulation of the NTS has been shown to evoke a monosynaptic inhibitory GABAergic pathway to premotor cardiac vagal neurons (Wang et al. 2001b). Although there have been no
previous electrophysiological studies of glycinergic innervation of
premotor cardiac vagal neurons, these neurons also likely receive
glycinergic inputs, since microinjection of glycine into the nucleus
ambiguus elicits tachycardia in spinal rats (Chitravanshi et al.
1991).
The inhibitory neurotransmission to premotor cardiac vagal neurons is
likely involved in cardiorespiratory interactions. In each respiratory
cycle, the heart beats more rapidly in inspiration and slows during
postinspiration and expiration (referred to as respiratory sinus
arrhythmia). In an in vivo study the input resistance decreased and
premotor cardiac vagal neurons were hyperpolarized during inspiration,
and the hyperpolarization was reversed upon injection of
Cl
(Gilbey et al. 1984).
Paradoxically, however, in a review it is stated the
inspiratory-related inhibition of cardioinhibitory neurons was not
antagonized by the iontophretic application of either the
GABAA antagonist bicuculline or the glycine
antagonist strychnine (Loewy and Spyer 1990). More
recent work in vitro has indicated premotor cardiac vagal neurons
receive increased inhibitory GABAergic synaptic currents during
inspiration and that this increased GABAergic activity during
inspiration can be abolished by nicotinic receptor antagonists
(Neff and Mendelowitz 2002).
The goals of the present study were 1) to test whether endogenous cholinergic activity modulates GABAergic and glycinergic neurotransmission to cardiac vagal neurons, 2) to test whether exogenous application of nicotine alters spontaneous GABAergic and glycinergic activity to premotor cardiac vagal neurons, and 3) to determine the nicotinic receptor subtypes involved and to investigate the sites of action of nicotine on the GABAergic and glycinergic neurons that synapse on premotor cardiac vagal neurons.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In an initial surgery, 2- to 6-day-old rats were anesthetized with halothane and exposed to hypothermia during the surgery (10-20 min) to slow the heart and to aid in recovery. A right thoracotomy was used to expose the heart and rhodamine (XRITC, 2% solution, 20-40 µl, Molecular Probes) was injected into the pericardial sac. Control injections of rhodamine either into the chest cavity but outside the pericardial sac or intravenously failed to label any neurons in the medulla, except for rare labeling of area postrema neurons observed with intravenous injections. On the day of the experiment (1-3 days later), the animals were anesthetized deeply with halothane and decapitated at the supracollicular level. The brain was submerged in cold (4°C) buffer of the following composition (mM): 140 NaCl, 5 KCl, 2 CaCl2, 5 glucose, and 10 HEPES, and continually gassed with 100% O2. Under a dissection microscope the cerebellum was removed and the hindbrain was isolated. The brain stem was then 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 700-µm 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 following composition (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. In experiments that examined spontaneous TTX-independent miniature synaptic events (mIPSCs), TTX (1 µM) was included in the bath and the concentration of KCl was increased to 23 mM to increase the frequency of GABAergic and glycinergic mIPSCs.
Individual cardiac vagal neurons in nucleus ambiguus were identified by
the presence of the fluorescent tracer. These identified cardiac vagal
neurons were then imaged with differential interference contrast
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 
70 mV. The patch pipettes were
filled with a solution consisting of (in mM) 150 KCl, 2 MgCl2, 2 EGTA, 10 HEPES, and 2 Mg-ATP, pH 7.35. With this pipette solution the Cl current
induced by activation of GABA or glycine receptors was recorded as an
inward current (calculated reversal potential of Cl: +4 mV).
To examine whether there is endogenous cholinergic modulation of either
GABAergic or glycinergic synaptic activity to cardiac vagal neurons,
neostigmine (10 µM), an acetylcholinerase inhibitor, was applied by
inclusion in the perfusate. D-2-Amino-5-phosphonovalerate (AP5, 50 µM) and
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50 µM) were included in
the perfusate to block glutamatergic receptors. GABAergic inhibitory
postsynaptic currents (IPSCs) and mIPSCs were isolated by the inclusion
of strychnine (1 µM) in the perfusate and glycinergic IPSCs and
mIPSCs were isolated by the inclusion of either picrotoxin (1 µM) or
gabazine (50 µM) in the perfusate. To determine whether activation of
nicotinic receptors could mimic the cholinergic facilitation of
GABAergic and glycinergic neurotransmission, nicotine (0.1-1 mM) was
dissolved in perfusate and was focally applied for 10-20 s through a
puffer pipette positioned within 10 µm of the neuron. To test whether
this method of focal application produced any artifacts, the external
solution was puffed onto cardiac vagal neurons with identical pressure
settings and close proximity. Application of external solution had no
significant effect on the frequency (1.4 ± 0.1, 1.3 ± 0.1 Hz, n = 4, P > 0.05), amplitude
(174 ± 32, 171 ± 35 pA, n = 4, P > 0.05) of GABAergic IPSCs, or the holding current
(53 ± 11, 50 ± 14 pA, n = 4, P > 0.05). A similar lack of effect of puffing the
perfusate occurred when glycinergic events were isolated (frequency,
1.3 ± 0.1, 1.3 ± 0.1 Hz, n = 4, P > 0.05; amplitude, 44 ± 2, 43 ± 1 pA,
n = 4, P > 0.05; holding current,
53 ± 13, 52 ± 14 pA, n = 4, P > 0.05).
In some experiments nicotine was reapplied to a slice after a delay of
20 min to minimize any desensitization of the neurons in the slice. At
the end of each experiment the GABAergic IPSCs and mIPSCs were
abolished with gabazine (50 µM) and the glycinergic IPSCs and mIPSCs
were abolished with strychnine (1 µM). -Bungarotoxin (-BgTX,
100 nM) was used to block 7-subunit-containing nicotinic receptors
and dihydro--erythrodine (DHE) at a concentration of 3 µM was
used to selectively block 42 nicotinic receptors (Alkondon
and Albuquerque 1993). All drugs were purchased from Sigma
Aldrich (St. Louis, MO).
Analysis of action potential-dependent IPSCs and TTX-insensitive mIPSCs were performed using MiniAnalysis (Synaptosoft, version 4.3.1) with a minimal acceptable amplitude of GABAergic or glycinergic IPSCs at 20 pA and that of the mIPSCs at 15 pA. Results are presented as means ± SE and statistically compared with paired and unpaired Student's t-tests when appropriate. Significant difference was set at P < 0.05.
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RESULTS |
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|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Application of neostigmine (10 µM), an acetylcholinerase inhibitor, significantly increased the frequency of both GABAergic and glycinergic IPSCs in cardiac vagal neurons. The data from typical GABA and glycine experiments are shown in Fig. 1, A and B, respectively, while the summary data for the GABAergic and glycinergic experiments are illustrated in Fig. 1, C and D, respectively. Neostigmine (10 µM) significantly increased the GABAergic IPSC frequency in cardiac vagal neurons from 1.7 ± 0.1 to 3.5 ± 0.7 Hz (P < 0.05, n = 6) but did not significantly alter the amplitude of the GABAergic IPSCs or the holding current in cardiac vagal neurons. Neostigmine (10 µM) also significantly increased the glycinergic IPSC frequency in cardiac vagal neurons from 3.0 ± 0.6 to 4.9 ± 0.7 Hz (P < 0.05, n = 6) but did not significantly alter the amplitude of the glycinergic IPSCs or the holding current.
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As shown from a representative experiment in Fig. 2A, exogenous application of nicotine (1.0 mM) increased both the frequency and amplitude of GABAergic IPSCs in premotor cardiac vagal neurons but did not change the holding current. The results from one experiment, as well as the summary data from 13 neurons, are shown in Fig. 2B, which also illustrates that nicotine (1.0 mM) evokes an increase in the frequency of GABAergic IPSCs from 4.1 ± 0.4 to 8.8 ± 0.6 Hz (P < 0.001), and the amplitude of GABAergic IPSCs increased from 43.6 ± 3.4 to 60.4 ± 5.4 pA (P < 0.001) in premotor cardiac vagal neurons.
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To test whether the nicotine-evoked increase in GABAergic frequency and
amplitude was dependent on 7-subunit-containing nicotinic receptors, the neurons were exposed to a second application of nicotine
(1.0 mM) in the presence of the selective 7 nicotinic receptor
antagonist -BgTx. The second application of nicotine in the presence
of -BgTX was indistinguishable from the first application (Fig.
2C). These experiments also demonstrate that repetitive
nicotine-evoked responses (with 20 min between nicotine application)
could be obtained with brief (10-20 s) focal application of nicotine
(1.0 mM). To ensure the lack of effect with -BgTX was not dependent
on the sequence of application, -BgTX was applied during the first
application of nicotine in some experiments. The nicotine-evoked
responses in the presence of -BgTX were not different from control
responses in the absence of -BgTX (P > 0.05).
Nicotine also increased both the frequency and amplitude of glycinergic
IPSCs. As shown from a representative experiment in Fig.
3A, nicotine (1.0 mM)
increased both the frequency and amplitude of glycinergic IPSCs in
premotor cardiac vagal neurons. The time course from one experiment is
shown in Fig. 3A, and the results from 16 neurons are shown
in Fig. 3B. Nicotine increased the glycinergic IPSC
frequency from 3.3 ± 0.5 to 7.3 ± 1.0 Hz (P < 0.001), and the amplitude was increased from 49.7 ± 3.3 to
65.9 ± 3.7 pA (P < 0.001) in premotor cardiac
vagal neurons. Similar to the lack of effect with GABAergic IPSCs, the
selective 7 nicotinic receptor antagonist -BgTX had no effect of
the nicotine-evoked increase in glycinergic frequency or amplitude
(Fig. 3C).
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In contrast the nicotine-evoked facilitation of both GABAergic and
glycinergic IPSCs was abolished by DHE at a concentration of 3 µM.
As shown in a representative experiment in Fig.
4A, nicotine (0.1 mM) evoked
an increase in both the frequency and amplitude of the GABAergic IPSCs,
and these responses were abolished by 3 µM DHE. The summary data
from seven neurons is shown in Fig. 4B.
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The nicotine-evoked facilitation in glycinergic IPSCs was also
sensitive to DHE. As shown in a representative example in Fig.
5A, nicotine (0.1 mM) evoked
an increase in both frequency and amplitude of glycinergic IPSCs, and
this nicotine-evoked facilitation was prevented by 3 µM DHE. The
results from nine neurons are summarized in Fig. 5B.
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To test whether the site of action of nicotine could be on the
GABAergic and glycinergic presynaptic terminals, TTX was applied to
block action potential-dependent events, and TTX-insensitive GABAergic
and glycinergic mIPSCs were examined. Nicotine (0.1 mM) evoked an
increase in GABA minifrequency, but did not alter GABA mini-amplitude,
as shown in a typical example in Fig. 6, A and B. The nicotine-evoked increase in GABA
mini-frequency was abolished by 3 µM DHE, as shown in a
representative example (Fig. 6B) and in the average results
from seven neurons (Fig. 6C). Similar to the GABAergic
mIPSCs, in the presence of TTX nicotine (0.1 mM) evoked an increase in
the frequency, but not amplitude of glycinergic mIPSCs, as shown in
Fig. 7, A and B.
DHE prevented the nicotine-evoked increase in glycinergic
mini-frequency (Fig. 7, B and C).
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DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
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There are four major results from this study. Premotor cardiac
vagal neurons receive glycinergic input. Application of neostigmine (10 µM), an acetylcholinerase inhibitor, significantly increased the
frequency of both GABAergic and glycinergic IPSCs to cardiac vagal
neurons, indicating endogenous cholinergic activity facilitates GABAergic and glycinergic neurotransmission to cardiac vagal neurons in
the nucleus ambiguus. Nicotine increases the frequency and amplitude of
both glycinergic and GABAergic IPSCs, which were not diminished by the
7-subunit nicotinic blocker -BgTX, but were abolished by the
nicotinic antagonist DHE at a concentration (3 µM) specific for
42 nicotinic receptors (Alkondon and Albuquerque 1993). The fourth major result from this study is that, in the presence of TTX, nicotine increased the frequency, but not the amplitude of both glycinergic and GABAergic mIPSCs, and this
nicotine-mediated facilitation was also abolished by DHE (3 µM).
The observation that premotor cardiac vagal neurons receive glycinergic
input is supported by both anatomical and in vivo microinjection
studies. Microinjection of glycine into the nucleus ambiguus has been
shown to elicit tachycardia in spinal rats presumably by
disinhibition:inhibition of these cardioinhibitory neurons (Chitravanshi et al. 1991). In addition premotor cardiac
vagal neurons have been found to be densely innervated by fibers
immunoreactive for glycine (Batten 1995).
There have been only two previous reports on the effect of nicotine on
glycinergic synaptic transmission. In the rat, sympathetic preganglionic neurons nicotinic antagonists inhibit glycinergic IPSCs,
suggesting there may be an endogenous activation of nicotinic receptors
that facilitates glycinergic neurotransmission to these sympathetic
spinal cord neurons (Dun and Mo 1989). Also in the rat
spinal cord nicotine has been shown to increase the frequency, but not
amplitude of glycinergic mIPSCs, and the nicotine-mediated increase in
glycinergic mini-frequency was not altered by -BgTX, but was blocked
by the nicotinic antagonist DHE (Kiyosawa et al.
2001). The block of nicotinic responses by DHE but not by -BgTX is identical to the results in this study.
Nicotine has been shown in many other studies to enhance GABAergic
neurotransmission, but one controversial issue is whether the nicotinic
facilitation of GABAergic activity is "preterminal" and dependent
on action potential generation in the GABAergic neuron or whether
nicotine can act at the presynaptic terminal to enhance GABAergic
neurotransmission independent of an action potential. In the ventral
tegmental area the nicotinic facilitation of GABAergic
neurotransmission is blocked by TTX, suggesting that nicotinic
receptors are not sufficiently present on the presynaptic terminal to
alter transmitter release, but presumably act by altering the action
potential or other TTX-sensitive activity in the GABAergic neuron
(Mansvelder et al. 2002). Similar results have been
obtained in GABAergic neurotransmission to the rat interpeduncular
nucleus, cerebellar Purkinje cells, dorsal motor nucleus, and CA1
neurons of the hippocampus (Alkondon et al. 1997;
Bertolino et al. 1997; Kawa 2002;
Lena et al. 1993; McMahon et al. 1994).
However, in another study of the rat hippocampus, as well as in the
mouse amygdala, the nicotinic enhancement of GABAergic
neurotransmission occurred in the presence of TTX, suggesting that
nicotine can act at the presynaptic terminal to facilitate GABA release
(Barazangi and Role 2001; Fisher et al.
1998; Radcliffe et al. 1999). The results of
this study demonstrate that nicotine can facilitate GABAergic and
glycinergic neurotransmission in the presence of TTX, indicating that
nicotine can enhance inhibitory neurotransmission to cardiac vagal
neurons independent of action potential activity by activating
nicotinic receptors present on the GABAergic and glycinergic
presynaptic terminals.
The nicotine-evoked increase in both GABAergic and glycinergic IPSC
amplitude could be due to changes in the activity of the preceding
neurons, such as changes in the action potential waveform to alter
neurotransmitter release, as well as augmentation of the postsynaptic
inhibitory responses. Nicotine-mediated increases in GABAergic IPSC
amplitude has also been observed in other work (Covernton and
Lester 2002). However, since nicotine evoked an increase in
GABAergic and glycinergic mini-frequency, but did not alter their
amplitude, a more likely explanation for the increase in IPSC amplitude
is that nicotine may be evoking summation of IPSCs by either
recruitment of additional GABAergic and glycinergic neurons or
summation of increased activity of previously active inhibitory neurons.
Interestingly, the nicotinic facilitation of both inhibitory GABAergic
and glycinergic neurotransmission to cardiac vagal neurons is
insensitive to -BgTX and can be abolished by DHE at a
concentration (3 µM) specific for 42 nicotinic receptors (Alkondon and Albuquerque 1993), but the nicotinic
facilitation of glutamatergic neurotransmission to cardiac vagal
neurons is blocked by the 7-subunit nicotinic antagonist -BgTX
(Neff et al. 1998a). The heterogeneous profile of
nicotinic enhancement of inhibitory neurotransmission by 42
nicotinic receptors and excitatory glutamatergic neurotransmission by
7-subunit-containing nicotinic receptors has also been observed in
other neurons (Guo et al. 1998; Mansvelder et al.
2002).
The GABAergic results in this study is potentially complicated by the
evidence that strychnine can inhibit 7 nicotinic receptors as well
as glycine receptors (Matsubayashi et al. 1998). This would cause an underestimate of the importance of 7 nicotinic receptors in the nicotinic facilitation of GABAergic inputs to cardiac
vagal neurons. However the inhibition of 7 nicotinic receptors with
1 µM strychnine is only partial and is <10% (Matsubayashi et
al. 1998). In other work from this laboratory (Neff et
al. 1998a; Wang et al. 2001a) performed in the
presence of 1 µM strychnine, activation of 7 nicotinic receptors
facilitated glutamatergic neurotransmission to cardiac vagal neurons.
It is therefore unlikely the complete absence of an effect with
-BgTX in this study is due to a prior antagonism with strychnine.
Another potential complication of this study is that neostigmine can
directly inhibit nicotinic receptors (Clarke et al.
1994; Nagata et al. 1997; Zheng et al. 1998). This would cause an underestimate of the endogenous
activation of nicotinic receptors in facilitating both glycinergic and
GABAergic neurotransmission to cardiac vagal neurons observed in this
study with neostigmine. However, the underestimate of endogenous
nicotinic activation due to neostigmine (10 µM) directly inhibiting
nicotinic receptors in this study is likely small, since only
neostigmine concentrations of 30 µM or larger significantly inhibited
nicotinic receptors in rat CNS neurons, with an estimated
IC50 of 100 µM (Clarke et al.
1994).
In summary, endogenous cholinergic activity facilitates GABAergic and
glycinergic neurotransmission to cardiac vagal neurons in the nucleus
ambiguus. Activation of nicotinic receptors increases the frequency of
both glycinergic and GABAergic IPSCs as well as GABAergic and
glycinergic mIPSCs to cardiac vagal neurons. These responses were not
diminished by the 7-subunit nicotinic blocker -BgTX, but were
abolished by the nicotinic antagonist DHE at a concentration
specific for 42 nicotinic receptors. This nicotinic facilitation
of inhibitory synaptic inputs to cardioinhibitory vagal neurons may be
one mechanism for the increased heart rate prevalent in smokers. The
nicotinic augmentation of inhibitory neurotransmission to cardiac vagal
neurons may also be involved in the respiratory modulation of heart
rate, since one cholinergic input to cardiac vagal neurons originates
from neurons active in respiration (Irnaten et al.
2001).
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ACKNOWLEDGMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-59895 and HL-49965 to D. Mendelowitz.
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FOOTNOTES |
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Address for reprint requests: D. Mendelowitz, Department of Pharmacology, George Washington University, 2300 Eye St N.W., Washington, DC 20037 (E-mail: dmendel{at}gwu.edu).
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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