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Introduction
Heart rate and cardiac functions are under dual control
of the sympathetic and the parasympathetic nerves, and the
activity of the cardiac parasympathetic nerves dominates in
this balance[1,2]. Anatomical and functional studies indicated
that 5-hydroxytryptamine (5-HT) is involved in the reflex
parasympathetic control of cardiac vagal tone.
Immunochemical studies demonstrated that the nucleus ambiguus
(NA) and the dorsal motor nucleus of the vagus (DMV), the
sites at which cardiac vagal preganglionic neurons (CVPN)
are primarily located[3_6], are densely innervated by 5-HT
immunoreactive terminals[7,8], and terminal buttons containing
5-HT make synaptic contact with
CVPN[9,10]. There are also binding sites for
5-HT1A/7 agonists in both the NA and the
DMV in cats[11], rats[12,13], and
humans[14]. The activation of central
5-HT1A/7 receptors caused a vagally-mediated
bradycardia in cats[9,15_18] and
rats[19,20]. The ionophoretic
application of 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT),
an agonist of 5-HT1A/7 receptors, activated CVPN at larger
electrophoretic currents in cats, which was attenuated by
the co-application of the 5-HT1A/7 receptor antagonist
WAY-100635[21]. The blockade of central
5-HT1A/7 receptors attenuated the reflex activation of
CVPN[21_24].
The synaptic mechanism that the
5-HT1A/7 receptor agonist activates CVPN and
5-HT1A/7 receptor antagonist attenuates the reflex control of cardiac vagal tone is not clear at the
level of CVPN. Since the activation of
5-HT1A/7 receptors is generally known to be inhibitory via opening
hyperpolarizing K+
channels[25] and the inhibition of
Na+ channels[26], Wang and
Ramage[21] assumed that the
5-HT1A/7 agonist might excite CVPN via "disinhibition" of their GABAergic inputs.
CVPN receive both GABAergic and glycinergic inhibitory
inputs[27]. At least some of the GABAergic inputs originate
from the nucleus tractus solitarius (NTS) and can be
activated by stimulation of this
nucleus[28]; the stimulation-evoked GABAergic currents, compared with the
spontaneous GABAergic synaptic currents, are commonly believed
to be more closely related to the reflex control of these
neurons. In a recent study, the
5-HT1A/7 agonist was found to inhibit the spontaneous GABAergic synaptic currents of
CVPN[29], but its effect on the stimulation-evoked GABAergic
currents has not been examined. In addition, whether the
glycinergic inputs are also involved in the 5-HT
receptor-mediated excitation of CVPN is not known. Thus, the
purpose of the present study is to test the hypothesis that the
5-HT1A/7 receptor agonist excites CVPN via the inhibition of
both the GABAergic and the glycinergic inputs.
Materials and methods
Retrograde fluorescent labeling of CVPN Inhalation
agent halothane (0.5 mL) was dripped into a glass box (5×5×5
cm) with a lid and a cotton pad at the bottom of the box.
Sprague_Dawley rats (Shanghai Institute for Family
Planning, Shanghai, China) that were 3_4 d old were put in
the box for 30 s with the lid closed. This procedure
anesthetized the rats, but kept their breathing at a relatively normal
state. When the rats had no response to a needle
puncturing the limbs, the body was buried in ice-filled bags to
decrease the body temperature and slow the heart rate. After
automatic breathing ceased (usually within 2 min), the
animals were placed on an ice-filled bag in a supine posture; a
right thoracotomy was made to expose the heart. A glass
pipette (tip diameter, 30 µm) filled with 1% rhodamine (XRITC,
Molecular Probes, Carlsbad, CA, USA) was gently
punctured into the fat pad at the base of the heart and 5 µL
solution was injected in a 20 s period. The fat pad of the heart
contains the major cardiac parasympathetic ganglions, and
neurons in these ganglions receive innervations from the
terminals of CVPN[30]. The application of fluorescent tracers
at the terminals of CVPN has been a well-established method
to retrogradely label CVPN[29]. Special care was taken to
avoid rhodamine leaking into the cardiac sac, which could
lead to the mislabeling of the brain stem neurons innervating
the tissues near the cardiac sac[31]. The incision was sutured
and the animals were heated with a thermo-pad to help
recovery. During the whole surgery period (approximately 5
min), the body temperature of the animals was approximately
10 oC, and the animals had no automatic breathing and did
not struggle to breathe. After the surgery, the animals
usually started automatic breathing within 3 min and started
moving freely within a further 5 min. The animals were
allowed 1_2 d to recover. The experiments were performed at
when the animals were 4.4±0.2 d old (n=43). Rats at this age
have been shown to have similar respiratory-related and
reflex-related parasympathetic heart rate control as adult
rats[32,33].
Slice preparation The animals were anesthetized deeply
with halothane and decapitated at the supracollicular level.
The hind brain was exposed, isolated, and immerged in cold
(4 oC) artificial cerebral spinal fluid (ACSF) of the following
composition (in mmol/L): NaCl (124), KCl (3),
KH2PO4 (1.2),
CaCl2 (2.4), MgSO4 (1.3),
NaHCO3 (26), D-glucose (10), and
sucrose (10), and constantly bubbled with gas (95%
O2, 5% CO2) at pH 7.4. The cerebellum was removed and the brain
stem was dissected using a dissection microscope. The brain
stem was then secured in the slicing chamber of a vibratome
(Leica VT 1000 S), filled with the same ACSF, and
sequentially sectioned at 400 µm thickness in the transverse plane.
The slice was transferred into the recording chamber and
submerged in the ACSF and maintained at a temperature of
20 oC.
Electrophysiological recording Individual CVPN in the
NA were identified by the presence of the fluorescent tracer
using an Olympus upright microscope through a 40× water
immersion objective. The pipette resistance (2_5
MΩ) and capacitance were not compensated either before or after
gaining intracellular access. To access the glutamatergic
spontaneous excitatory postsynaptic currents (sEPSC) the patch
pipettes were filled with a solution consisting of (in mmol/L):
K+ gluconate (150), HEPES (10), EGTA (10),
CaCl2 (1), and MgCl2 (1) at pH 7.3. The cells were clamped at _80 mV. With
this pipette solution and the holding voltage, the
Cl_-mediated inhibitory synaptic currents were minimized and only
excitatory synaptic events were detectable. To access the
GABAergic and the glycinergic synaptic currents, the patch
pipettes were filled with a solution consisting of (in mmol/L):
KCl (150), MgCl2 (2), EGTA (2), HEPES (10), and Mg-ATP (2)
at pH 7.3. With this pipette solution, the
Cl- current induced by the activation of the GABAergic receptors and the
glycinergic receptors was recorded as an inward current.
The osmolarity of the ACSF and pipette solutions was
adjusted to 320 mosm/L before use. A 200 ms, 5 mV
hyperpolarizing voltage was applied at an interval of 4 s for calculating
the input resistance. In some experiments, a pair of bipolar
tungsten electrodes (tip diameter, 5 µm;
distance between tips, 30 µm) was placed in the dorsomedial subnucleus of the
ipsilateral NTS. Single square wave currents (1_2 ms duration,
10_70 µA) were injected at an interval of 2 s to evoke
GABAergic currents in CVPN. The patch-clamp signal was
amplified with an Axopatch 200B amplifier (sampling
frequency, 10 kHz; filter frequency, 1 kHz), digitized with
1322A Digidata, and collected with Clampex 9.0 software
(Axon instruments, USA). All animal procedures were
performed in compliance with the institutional guidelines at
Fudan University (Shanghai, China), and were in accordance
with the internationally accepted ethical standards for the
experimental use of animals.
Drug application The drugs were either globally used in
the bath or focally applied through a puffer pipette
positioned within 10 µm of the patched neuron. Strychnine (1
µmol/L) and picrotoxin (10 µmol/L) were used to block
glycine receptors and GABA receptors, respectively.
6-Cyano-7-nitroquinoxaline-2, 3-dione (CNQX; 50 µmol/L) and
D-2-amino-5-phosphonovalerate
(AP5; 50 µmol/L) were used to block non-NMDA and NMDA glutamate receptors,
respectively. The GABAergic synaptic currents were isolated by the
inclusion of AP5 (50 µmol/L), CNQX (50 µmol/L), and
strychnine (1µmol/L) in the perfusate. The glycinergic synaptic
currents were isolated by the inclusion of
AP5 (50 µmol/L), CNQX (50 µmol/L), and picrotoxin (10 µmol/L) in the perfusate.
In the experiments that examined miniature inhibitory
postsynaptic currents (mIPSC), tetrodotoxin (1 µmol/L) was
included in the bath, and the concentration of KCl was
increased to 23 mmol/L to increase the frequency of
mIPSC[27]. In some experiments, exogenous GABA (100 µmol/L) or
glycine (100 µmol/L) was focally applied (100 ms duration)
in the presence of TTX to evoke GABAergic or glycinergic
currents, respectively. WAY-100635 (100 nmol/L and 1
µmol/L) was used to block 5-HT1A/7 receptors.
8-OH-DPAT (1 nmol/L_10 µmol/L), of which the affinity for
5-HT1A/7 receptors is over 100 times stronger than that of
5-HT[34], was used to activate the
5-HT1A/7 receptors. The duration of 8-OH-DPAT
application was 2 min, and each slice was applied only once
to avoid desensitization. All of the drugs were purchased
from Sigma_Aldrich (St Louis, MO, USA).
Data analysis Spontaneous or miniature synaptic
currents were analyzed with MiniAnalysis (version 4.3.1,
Synaptosoft), with a minimally acceptable amplitude at 10
pA. The data from a 2 min period before 8-OH-DPAT
application and the data from a 30 s period during the maximal
response were averaged for comparison. The results are
presented as mean±SEM, and statistically compared with
paired Student's t-test or ANOVA followed by post-test
Bonferroni correction when appropriate. Significant
difference was set at P<0.05.
Results
8-OH -DPAT inhibited the GABAergic synaptic currents
At all of the concentrations tested (10 nmol/L, 100 nmol/L, 1
µmol/L, and 10 µmol/L), 8-OH-DPAT significantly decreased
the frequency of the GABAergic spontaneous inhibitory
postsynaptic currents (sIPSC; paired Student's
t-test) as shown in Figure 1A. The frequency decreases (measured in
percentage of controls) caused by 100 nmol/L, 1 µmol/L, and
10 µmol/L 8-OH-DPAT were not significantly different, but
the frequency decrease caused by 10 µmol/L 8-OH-DPAT
was significantly larger compared with that caused by 10
nmol/L 8-OH-DPAT (ANOVA, Bonferroni), as shown in
Figure 1B. The amplitude of the GABAergic sIPSC was not
significantly changed by 8-OH-DPAT at 10 nmol/L, but was
significantly decreased by 8-OH-DPAT at 100 nmol/L, 1
µmol/L, and 10 µmol/L (paired Student's
t-test), as shown in Figure 1C,1D. These results indicated that both the frequency
inhibition and the amplitude inhibition of the GABAergic sIPSC
by 8-OH-DPAT had dose-dependent tendencies. 8-OH-DPAT also caused an amplitude decrease of the GABAergic
currents evoked by stimulation of the NTS. 8-OH-DPAT (1
µmol/L) inhibited the amplitude of the stimulation-evoked
GABAergic synaptic currents by 55% (paired
Student's t-test; P<0.05,
n=6). An experiment is shown in Figure 1E_1H,
which shows that 8-OH-DPAT caused decreases in the
frequency and the amplitude of the GABAergic sIPSC and
caused a simultaneous amplitude decrease of the
stimulation-evoked GABAergic synaptic currents. The responses
of the GABAergic sIPSC to 8-OH-DPAT usually started
within 15 s, reached the nadir within 30 s and 2 min,
lasted for 10_40 min, and were reversible. At any
concentration, 8-OH-DPAT did not alter the baseline current and did not cause a
significant change in the input resistance. The input
resistance measured before and after the application of 1 µmol/L
8-OH-DPAT was 227.61±12.63 and 230.12±15.34
MΩ, respectively (P>0.05, n=7; paired
Student's t-test). At the end of each experiment 10 µmol/L picrotoxin abolished the
spontaneous or the evoked GABAergic synaptic currents.
8-OH-DPAT inhibited glycinergic sIPSC The glycinergic
sIPSC were more sensitive to 8-OH-DPAT. 8-OH-DPAT
significantly decreased the frequency of the glycinergic sIPSC
at a concentration as low as 1 nmol/L (Figure 2A). The
frequency decrease (measured in percentage of controls) caused
by 1 µmol/L 8-OH-DPAT was significantly larger compared
with that caused by 1 nmol/L 8-OH-DPAT (ANOVA,
Bonferroni), as shown in Figure 2B. The amplitude of the
glycinergic sIPSC was not significant changed by 8-OH-DPAT
at 1 nmol/L, but was slightly although significantly decreased
by 8-OH-DPAT at 10 nmol/L, 100 nmol/L, and 1 µmol/L (paired
Student's t-test), and the amplitude decrease (measured in
percentage of controls) caused by 1 µmol/L and 100 nmol/L
8-OH-DPAT was significantly larger compared with that
caused by 10 nmol/L 8-OH-DPAT (ANOVA,
Bonferroni), as shown in Figure 2C,2D. These results indicated that both
the frequency inhibition and the amplitude inhibition of the
glycinergic sIPSC by 8-OH-DPAT had dose-dependent tendencies. The time-course of responses of the glycinergic
sIPSC to 8-OH-DPAT was similar to the responses of the
GABAergic synaptic currents to 8-OH-DPAT. At the end of
each experiment, 1 µmol/L strychnine abolished the
glycinergic sIPSC.
WAY-100635 blocked the inhibition of the GABAergic
and glycinergic sIPSC by 8-OH-DPAT During the slow
recovery process of the GABAergic or the glycinergic sIPSC
from their responses to the 8-OH-DPAT applications, the
addition of WAY-100635 (at the same doses as 8-OH-DPAT)
abolished the responses within several seconds (tested in 3
CVPN of which the GABAergic sIPSC were recorded, and in
4 CVPN of which the glycinergic sIPSC were recorded). An
experiment is shown in Figure 3A. In 15 CVPN pretreated
with WAY-100635 (100 nmol/L in 8 CVPN and 1 µmol/L in 7
CVPN) the baseline frequency and the baseline amplitude of
the GABAergic sIPSC were unaltered, and further
application of 8-OH-DPAT at the same doses did not cause changes
in the frequency and the amplitude. These 15 CVPN were
analyzed as 1 group. The data from a representative
experiment are shown in Figure 3B, 3C, and the data from the 15
experiments are summarized in Figure 3D,3E. In 9 CVPN
pretreated with WAY-100635 (100 nmol/L in 5 CVPN and
1 µmol/L in 4 CVPN) the baseline frequency and the baseline
amplitude of the glycinergic sIPSC were unaltered, and further
application of 8-OH-DPAT at the same doses did not cause
changes in the frequency and the amplitude. These 9 CVPN
were also analyzed as 1 group. The data from a
representative experiment are shown in Figure 3F, 3G, and the data from
the 9 experiments are summarized in Figure 3H, 3I.
8-OH-DPAT had no effect on the GABAergic or the
glycinergic mIPSC, and had no effect on the currents evoked
by exogenous GABA or glycine The decreases in sIPSC
frequency could be caused by the action of 8-OH-DPAT on
the GABAergic or the glycinergic terminals, or preterminally
on the dendrites, somas, or axons. The decreases in sIPSC
amplitude could be caused by weakened summation of
synaptic events or alterations in the activity of the GABAergic
or the glycinergic neurons, such as changes in their action
potential waveform or reduced recruitment of neurons.
Another possibility is that the decreases in sIPSC amplitude are
due to post-synaptic alterations in the responses to the
released GABA or glycine. To distinguish between these
possibilities, we examined the effect of 8-OH-DPAT on the
GABAergic and the glycinergic mIPSC and examined the
effect of 8-OH-DPAT on the currents evoked by exogenous
GABA or glycine. The application of 1 µmol/L 8-OH-DPAT
did not cause significant changes in the GABAergic or the
glycinergic mIPSC in either the frequency or the amplitude
(Figure 4). The GABAergic or the glycinergic currents
evoked by exogenous GABA or glycine did not show any
change upon application of 8-OH-DPAT (1 µmol/L), as shown
in Figure 5.
8-OH-DPAT had no effect on the glutamatergic
sEPSC In the initial attempt to isolate the glutamatergic
sEPSC, we added picrotoxin (10 µmol/L) and strychnine (10
µmol/L) in the perfusate. Unfortunately, this protocol evoked
intermittent excitatory inward currents in CVPN mediated by
NMDA and non-NMDA glutamatergic inputs, as we reported
elsewhere[35]. We then omitted picrotoxin and strychnine in
the recording of glutamatergic sEPSC. The application of 1
µmol/L 8-OH-DPAT did not cause any detectable change in
the baseline currents and did not cause significant changes
in either the frequency (1.15±0.40
vs 1.05±0.37 Hz; P>0.05,
n=7; paired Student's t-test) or the amplitude (11.19±1.23
vs 10.85±1.28 pA; P>0.05;
n=7; paired Student's t-test) of the
glutamatergic sEPSC.
Discussion
There are 3 major findings in the present study. First, in
CVPN the 5-HT1A/7 receptor agonist 8-OH-DPAT caused
significant decreases in both the frequency and the amplitude
of the GABAergic sIPSC, and also caused significant
amplitude decrease of the GABAergic currents evoked by
stimulation of the NTS, but had no effect on the GABAergic mIPSC
and the GABAergic currents evoked by exogenous GABA.
Both the frequency inhibition and the amplitude inhibition
of the GABAergic sIPSC by 8-OH-DPAT had dose-dependent tendencies and could be reversed by the
5-HT1A/7 receptor antagonist WAY-100635. Second, in CVPN
8-OH-DPAT caused significant decreases in both the frequency
and the amplitude of the glycinergic sIPSC, but had no effect
on the glycinergic mIPSC and the glycinergic currents evoked
by exogenous glycine. Both the frequency inhibition and
the amplitude inhibition of the glycinergic sIPSC by
8-OH-DPAT had dose-dependent tendencies and could be reversed
by the 5-HT1A/7 receptor antagonist WAY-100635. Third,
8-OH-DPAT had no effect on the glutamatergic sEPSC of CVPN.
The functional roles of the synaptic inputs identified in
CVPN are poorly understood with regard to the reflex
control of cardiac vagal tone. Both the present study and a
recent study by others[29] demonstrated that 8-OH-DPAT
inhibited the GABAergic sIPSC of CVPN. The present study
demonstrated that 8-OH-DPAT also inhibited the GABAergic
currents of CVPN evoked by stimulation of the NTS. These
results strongly suggested that
5-HT1A/7 receptor-mediated inhibition of the GABAergic inputs are involved in the
excitation of CVPN during cardiopulmonary reflex since the
cardiopulmonary reflex control of CVPN is known to involve
5-HT1A/7 receptor activation in
vivo[21]. In addition, the present
study has proved that 8-OH-DPAT also inhibited the
glycinergic inputs of CVPN, suggesting that the
5-HT1A/7 receptor-mediated inhibition of these inputs is also involved
in the excitation of CVPN during cardiopulmonary reflex.
It is quite surprising that the present study, as well as the
study of Wang and Ramage[21], does not indicate any role of
the glutamatergic inputs to CVPN in the
5-HT1A/7 receptor-mediated reflex control of CVPN. One possibility is that the
glutamatergic inputs of CVPN just account for their tonic
control and on which the 5-HT1A/7 receptor-mediated
inhibition of the GABAergic and the glycinergic inputs are
superimposed and are responsible for their reflex control. The
other possibility is that 5-HT might modulate the glutamatergic inputs of CVPN via other subtypes of 5-HT
receptors. This second possibility is supported by a
previous study that found 5-HT, an endogenous non-selective
agonist of 5-HT receptors, caused either an increase or a
decrease of the sEPSC of DMV preganglionic neurons
controlling the gastrointestinal
tract[36]. It has also been indicated by Wang
et al[29] that other subtype of 5-HT receptors,
such as 5-HT4α receptors, are involved in the control of the
synaptic inputs of CVPN.
WAY-100635 had no effect on the baseline frequency
and the baseline amplitude of the GABAergic or the
glycinergic sIPSC of CVPN. These results suggested that
the 5-hydroxytryptaminergic mechanism in the
cardiopulmonary reflex pathway is not spontaneously active and its
primary function is reflex related. This suggestion is also
supported by the study of Wang and
Ramage[21] that demonstrated that the ionophoretic application of WAY-100635 had
no effect on the baseline firing of CVPN.
8-OH-DPAT caused significant frequency decreases of
both the GABAergic and the glycinergic sIPSC of CVPN,
but did not cause significant frequency changes of either
the GABAergic or the glycinergic mIPSC. These results
suggested that the modulation of the GABAergic and the
glycinergic inputs by 8-OH-DPAT are action
potential-dependent, and that 5-HT1A/7 receptors are located on the
preterminal sites other than on the terminals. These results
are consistent with the report that the 5-HT1A/7
agonist inhibits Na+
channels[26]. It is easy to imagine that in our
experiments TTX, via the blockade of the
Na+ channels on the GABAergic or the glycinergic neurons preceding CVPN,
abolished the effect of 8-OH-DPAT. Of course it is also
possible that the inhibition the GABAergic and the
glycinergic sIPSC of CVPN by 8-OH-DPAT is just the
consequence of polysynaptic actions.
8-OH-DPAT also caused significant amplitude decreases
of both the GABAergic and the glycinergic sIPSC of CVPN.
However, 8-OH-DPAT did not cause significant changes in
the amplitude of the GABAergic or the glycinergic mIPSC, or
in the amplitude of the GABAergic, or the glycinergic
currents evoked by exogenous GABA or glycine. In addition,
8-OH-DPAT did not change the baseline currents and the
input resistance of CVPN. These results suggested that the
amplitude responses of the GABAergic and the glycinergic
sIPSC to 8-OH-DPAT are presynaptic and are in part due to
the decreased summation of sIPSC.
In summary, the present study demonstrated that the
activation of 5-HT1A/7 receptors inhibited the GABAergic and
the glycinergic inputs to CVPN. We conclude that the
5-HT1A/7 receptor-mediated reflex control of CVPN is via the
inhibition of both the GABAergic and the glycinergic inputs
to CVPN. Our findings have at least in part revealed the
synaptic mechanisms involved in the
5-HT1A/7 receptor-mediated reflex control of cardiac vagal nerves in intact animals.
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