Vol. 276, Issue 1, H176-H184, January 1999
Inhibition of baroreflex vagal bradycardia by nasal
stimulation in rats
Masayoshi
Kobayashi1,2,
Zhi Bin
Cheng2, and
Shoichiro
Nosaka2
Departments of
1 Otorhinolaryngology and
2 Physiology, Mie University
School of Medicine, Tsu, Mie 514-8507, Japan
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ABSTRACT |
Nasal stimulation
provokes hypertension and bradycardia. We report here that such
stimulation inhibits baroreflex vagal bradycardia (BVB). In chloralose-
and urethan-anesthetized, 
-adrenergic receptor-blocked rats, the
aortic depressor nerves were cut and electrically stimulated to induce
BVB. Nasal application of smoke, warm distilled water, or cold or hot
Ringer solution suppressed BVB, but application of warm Ringer solution
did not. Smoke-induced inhibition was abolished by trigeminal but not
olfactory denervation. Neither suprapontine decerebration nor
C3 spinal cord transection
affected the inhibition. Bradycardia induced by electrical stimulation of the peripheral cut end of the cervical vagus nerve (VIB) was suppressed by long-lasting smoke application. Intravenous prazosin, a
proposed blocker of prejunctional inhibition of acetylcholine release
from the vagus terminals, abolished VIB inhibition but attenuated BVB
inhibition only slightly. Thus nasal stimulation inhibits BVB, and this
inhibition is mediated exclusively by the trigeminal nerve and occurs
principally at the pontomedullary level, although the potential exists
for contribution of the prejunctional mechanism. The inhibition of BVB
might contribute to cardiovascular regulation associated with
protection from atmospheric hazards.
aortic depressor nerve; nociception; smoke; trigeminal
nerve
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INTRODUCTION |
NASOPHARYNGEAL STIMULATION with cigarette
smoke or irritant gases such as ammonia provokes reflex responses that
include apnea, hypertension, and bradycardia (22, 36). Reflex apnea
serves to prevent inhalation of noxious gases, and the cardiovascular reflexes, which are caused by sympathetic vasoconstriction and cardiovagal excitation, are indispensable for the effective utilization of limited stores of oxygen via the preferential redistribution of
blood flow to vital organs, such as the brain and heart, during reflex
apnea (9, 35). Responses with a similar pattern occur when water is
applied into the nasal cavities, for example, during submergence in
water (19, 31). Previous studies showed that afferent fibers that
convey such nociceptive information from the nasal cavities to the
central nervous system travel exclusively in the trigeminal nerve and
not the olfactory nerve (22, 31).
So-called nasopharyngeal reflexes are considered to occur in
life-threatening, emergency situations, all of which would lead to
respiratory distress unless properly coped with. In general, behavioral
and autonomic functions in animals exposed to stressful conditions are
accompanied by and supported by inhibition of arterial baroreflexes
(25). For example, stimulation of the defense area, either in the
hypothalamus (30) or in the dorsal part of the midbrain periaqueductal
gray (dPAG) (29), inhibits arterial baroreflexes. Noxious sensations,
either somatic (28) or visceral (17, 27), also inhibit baroreflexes. In
addition to these extraordinary conditions, exercise and mental stress
also suppress baroreflexes (25).
The nasal mucosa serves as a gateway between the organism and the
atmosphere, and nasal sensation is important for detection of
atmospheric changes that may be hazardous. However, it is unclear whether and how nasal afferent inputs interact with arterial
baroreflex. Previous studies showed that head immersion in water
depresses baroreflex sensitivity in ducks (23), whereas diving
increases baroreflex responsiveness in seals (2) and face immersion in cold water augments baroreflex bradycardia in humans (10). Cigarette smoking is reported to reduce baroreflex sensitivity in humans (21). In
part because the stimuli applied in the cited studies were not
identical and did not involve the nasal mucosa alone, the significance
of the results remains controversial. In addition, no studies have yet
addressed a neural mechanism by which activation of nasal sensory
nerves influences the baroreflex. The present study was designed to
investigate whether and in what way arterial baroreflex is affected by
activation of intranasal sensory receptors. Control arterial
baroreflexes were induced by electrical stimulation of the aortic
depressor nerve (ADN). The major advantage of ADN stimulation for
production of baroreflexes in rats is that the ADN in this species
contains baroreceptor afferents exclusively (33, 34).
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MATERIALS AND METHODS |
General procedures.
The experiments were performed with male Wistar rats (350-400 g)
anesthetized by intraperitoneal injection of 
-chloralose (60 mg/kg)
and urethan (600 mg/kg). One-sixth of the initial dose of anesthetics
was injected intravenously at 3-h intervals to maintain anesthesia
during the experiments. Polyethylene tubing was introduced into the
left femoral artery and vein for recording of blood pressure and
administration of drugs, respectively. After tracheal intubation, the
animals were immobilized by intravenous injection of succinylcholine
(10 mg/kg; an additional dose of 5 mg/kg was given if necessary) and
ventilated artificially throughout the experiment. The adequacy of
depth of anesthesia under muscle paralysis was assessed by stability of
arterial blood pressure and heart rate. In all animals in all
experiments, -adrenergic receptors were blocked throughout by
intravenous injection of propranolol (initial dose, 0.5 mg/kg; an
additional dose of 0.25 mg/kg was given as needed). Under such
conditions, changes in heart rate were attributable entirely to vagal
activity to the heart.
After an incision in the ventral part of the neck skin, the ADN of both
sides were dissected for electrical stimulation as described previously
(27). Each animal was placed on a stereotaxic apparatus in the prone
position. The dorsal neck skin was incised, and the muscles of the
dorsolateral part of the neck were removed. The ADN was pulled dorsally
into the hollow space generated by removal of the muscles, where it was
placed on bipolar stainless steel hook electrodes for electrical
stimulation. Parameters of ADN stimulation were 8 V, 0.5 ms, and 25 Hz
for 4 s.
Nasal application of smoke and fluids.
To prevent intranasal irritants from leaking into and stimulating the
pharyngolarynx, each animal's choana was occluded by packing with a
cotton pledget. Furthermore, the glossopharyngeal nerves of both sides
were cut lateral to junctions with the carotid sinus nerves (CSN), and
the superior laryngeal nerves were also cut medial to the junctions
with the ADN, to interrupt sensory afferent transmission from the
pharyngolarynx. The former transection inevitably decentralized the CSN
and served to exclude any possible interactions between inputs from the
ADN and the CSN.
The smoke used in this study was obtained by burning "tissue
paper," which was made from 100% wood pulp, in room air. The paper
was cut in fragments (ca. 2 × 2 mm2) and packed into a column
that was 0.8 cm in diameter and 5 cm in height and the wall of which
was also made from wood pulp paper stiffer than tissue paper. The final
density of each packed column was 0.2 g/cm3. After ignition of one end
of the column, smoke was collected by application of constant negative
pressure in a plastic syringe via a pulp filter attached to the other
end of the column. Table 1 shows the
concentrations of ingredients in the smoke, some of which was sampled
and analyzed with a Kitagawa Precision Gas Detector (APS; Komyo, Tokyo,
Japan). Noteworthy was that variation was relatively small, indicating
that smoke collection could be achieved invariably. Unlike the smoke
used in previous studies (35, 36), the smoke used in this study was not
obtained from burning cigarettes to rule out any direct effects of
nicotine and related compounds on the cardiovascular and central
nervous systems (4, 13). One milliliter of smoke was gently introduced into an animal's bilateral nasal cavities, through polyethylene tubes
connected to the plastic syringe, over a period of 2 s, at a constant
flow rate of 0.5 ml/s.
In some cases, 0.2 ml of one of the following fluids was infused into
the bilateral nasal cavities: warm distilled water (37°C) and cold
(4°C), warm (37°C), and hot (50°C) Ringer solution. In advance of the experiments, we applied identical amounts of innocuous dye solution [Fast Green dissolved (0.01%) in saline] to
the nose and confirmed that there was no substantial leakage of
solution through the cotton-occluded choana to the pharynx.
Transection of afferent nerves.
To identify the afferent pathway that mediates the smoke-induced
modification of baroreflex vagal bradycardia (BVB), we examined the
effects of olfactory and trigeminal denervation. After frontal craniotomy, olfactory denervation was performed by crushing the bilateral olfactory bulbs rostral to the frontal lobe. Trigeminal denervation was performed as follows. After occipital craniotomy, the
cerebellum was removed with a hydraulic aspirator. Lateral to the pons,
the trigeminal nerves of both sides were carefully cut medial to the
semilunar ganglia. The frontal and occipital craniotomy and cerebellar
removal were finished before the start of these series of experiments.
Decerebration.
In some rats, we attempted to determine the contribution of the
forebrain to smoke-induced modification of BVB by suprapontine decerebration that, in effect, transected the midbrain extending from
the inferior colliculus to the interpeduncular nucleus. We compared the
effects on BVB of smoke application before and at least 1 h after the decerebration.
Examination of peripheral modulation of BVB.
In several rats, we attempted to determine whether smoke-induced
modification of baroreflex, if it occurred, involved the central
nervous system or a peripheral, prejunctional site of vagus nerve
endings. The latter type of modification was reported to occur because
of sympathetically mediated inhibition of acetylcholine release from
the cardiac branch of the vagus (26). We compared the effects of the
application of smoke on BVB before and after spinal cord transection at
the C3 level. The decrease in
blood pressure induced by the transection was reversed by infusion of Ringer solution containing dextran (3%, wt/vol). We also examined the
effect of application of smoke to nasal cavities on vagus-induced bradycardia (VIB), which was provoked by electrical stimulation of the
peripheral cut ends of the bilateral cervical vagus nerves (8 V, 0.5 ms, and 10 Hz for 4 s).
A previous study (26) demonstrated that significant prejunctional
inhibition of VIB is produced by stimulation of the dorsal part of the
dPAG for >40 s. Thus we examined the effects of the long-lasting
application of smoke (40 s; total volume, 20 ml) on VIB as well as on
BVB. Subsequently, prazosin hydrochloride, a selective antagonist of
1-adrenergic receptors, was
administered intravenously to confirm the contribution of
1-adrenergic receptors to the
prejunctional inhibitory effect, as reported in the case of inhibition
of VIB by the dPAG (26). According to the method described in a
previous report (26), we administered prazosin hydrochloride
continuously at a rate of 60 µg · kg
1 · min1
with a microinjection pump (IM-1; Narishige, Tokyo, Japan) to maintain
the sustained blocking effect while we examined modification of VIB by
smoke application.
Termination of experiments.
At the end of the experiments, the animals were euthanized with an
overdose of intravenous anesthetics (-chloralose and urethan). Completeness of decerebration and transections of the olfactory bulbs
and the trigeminal nerves were ascertained under a dissecting microscope.
Analysis of data.
The magnitude of BVB or VIB was assessed by calculating the number of
heartbeats by which the heart rate was reduced during stimulation of
the ADN and vagus nerve, respectively. The calculation was
made by measurement of the response area (time integral of decreased
heart rate) in a heart rate tachogram recording after normalization
(25, 26). Inhibition caused by a conditioning nasal stimulation was
expressed as a percentage and was calculated from the ratio of the
reduction in an actual test response caused by conditioning stimulation
to the control test response, as follows
All numerical data obtained in the present experiments are expressed as
means ± SE. The statistical significance of differences was
evaluated by Wilcoxon's signed-rank test for comparison of paired
values or Friedman's analysis of variance for repeated measurements
followed by the Wilcoxon's test. Significance of each percentage value
itself was assessed by comparison between the actual and control
responses to ADN or cervical vagus stimulation. Differences were
regarded as significant when P < 0.05.
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RESULTS |
Effect of sinoaortic denervation on blood pressure and heart rate.
When both the ADN and the CSN were sectioned baseline blood pressure
increased significantly (from 102 ± 4 to 120 ± 5 mmHg; P < 0.0005;
n = 18), whereas heart rate was little
changed (from 350 ± 9 to 344 ± 9 beats/min;
n = 18). After 7 ± 2 min blood
pressure returned to the baseline level (102 ± 4 mmHg), whereas
heart rate remained unchanged (344 ± 9 beats/min).
Effect of nasal stimulation on blood pressure and heart rate.
When smoke was introduced into the nasal cavities, blood pressure
increased immediately and markedly, with a decrease in heart rate
(Table 2, Fig.
1). The elevated blood pressure was
maintained for 10-20 s after the application, but the bradycardia
was transient and was sometimes followed by slight tachycardia. As
shown in Table 2, nasal application of warm distilled water (37°C)
and either cold or hot Ringer solution (4 or 50°C) also produced
hypertension and tachycardia (Table 2; see Fig. 3). However, the
application of warm Ringer solution (37°C) produced a slight but
statistically insignificant increase in blood pressure while at the
same time eliciting significant bradycardia.
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Fig. 1.
Effects of smoke application to nasal mucosa on baroreflex vagal
bradycardia (BVB). 1,
3, Control BVB induced by electrical
stimulation of aortic depressor nerve (ADN).
2, effects of smoke on BVB. Horizontal
bars show duration of stimulation of ADN. ABP, arterial blood pressure;
MBP, mean blood pressure; HR, heart rate; bpm, beats per minute.
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Effect of nasal application of smoke on BVB.
The test ADN stimulation was applied when heart rate had stabilized
after the intranasal application of smoke. Smoke suppressed ADN-induced
BVB considerably, and the percent inhibition was 53 ± 4%
(n = 30; Table 2, Fig. 1).
To examine the possibility that inhibition of BVB was influenced by the
considerable smoke-induced decrease in the baseline heart rate, we
studied responses to stimulation of the ADN with varying intervals
between the conditioning application of smoke and the test stimulation
of the ADN. As illustrated in Fig. 2, inhibition of BVB was evident at all tested periods after the start of
exposure to smoke, not only during the tachycardic but also during the
initial transient bradycardic phases. This result confirmed that BVB
was inhibited regardless of the transient change in the baseline heart
rate. Thus, in all subsequent experiments, we stimulated the ADN at a
time when smoke-induced hypertension was maintained and the heart rate
had returned to and was stabilized at the baseline level, to estimate
the magnitude of inhibition of BVB precisely.
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Fig. 2.
Inhibition of BVB by smoke application to nasal mucosa: effect of
varying intervals between conditioning smoke application and test ADN
stimulation. 1, Control BVB;
2, effects of smoke application.
Intervals between onset of nasal stimulation and ADN stimulation were 1 (A), 2 (B), and 4 (C) s. ADN was stimulated during
smoke-induced bradycardic phases in A,
2 and
B, 2,
whereas it was stimulated during subsequent recovering phase in
C,
2.
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Similarly, BVB was inhibited by nasal application of warm (37°C)
distilled water or cold (4°C) or hot (50°C) Ringer solution (Table 2, Fig. 3). However, the
application of warm Ringer solution (37°C) had
little effect on BVB.
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Fig. 3.
Effects of nasal application of distilled water and Ringer solution of
various temperatures on BVB. A: effect
of distilled water (37°C).
B-D: effects of 37, 4, and
50°C Ringer solution, respectively.
1, Control BVB;
2, effects of nasal application of
respective fluids.
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The nasal application of smoke or water was repeated more than twice at
20-min intervals. The effects on BVB were reproducible, and the
magnitude of inhibition was almost identical for every trial of the
same stimulation in every animal.
As shown in Table 2, smoke was the most powerful modulator of BVB among
the nasal stimuli that we tested. Thus smoke was chosen as the nasal
stimulant in subsequent experiments.
Effect of olfactory and trigeminal denervation on smoke-induced
inhibition of BVB.
To identify the afferent pathway that mediated inhibition of BVB, we
cut the bilateral olfactory and trigeminal nerves successively and
studied the effects of such interventions on inhibition of BVB by smoke
application. As reported previously by others (22, 31), neither the
baseline blood pressure nor the heart rate was changed by transection
of olfactory nerves (79 ± 6 mmHg and 368 ± 16 beats/min before;
77 ± 4 mmHg and 368 ± 16 beats/min after neurectomy;
n = 6), and hypertension and
bradycardia caused by the nasal stimulation were unaffected by the
transection (Table 3, Fig.
4). Inhibition of BVB was unaffected by
prior olfactory neurectomy. After subsequent transection of the
trigeminal nerve, smoke no longer had an appreciable effect on blood
pressure or heart rate. The inhibitory effect on BVB also disappeared.
When the trigeminal nerve was sectioned but the olfactory nerve was left intact, inhibition of BVB was similarly eliminated (Table 3).
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Table 3.
Effects of brief application of smoke on MBP, HR, and BVB before and
after afferent denervation, decerebration, and spinal cord transection
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Fig. 4.
Effects of bilateral olfactory and trigeminal nerve transection on
smoke-induced inhibition of BVB: responses to stimulation of ADN before
(A) and after
(B) olfactory nerve transection and
after subsequent trigeminal nerve transection
(C).
1, Control BVB;
2, responses after smoke
application.
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Effects of decerebration on smoke-induced inhibition of BVB.
To determine whether inhibition of BVB by the application of smoke to
the nasal mucosa was mediated by suprapontine structures, we compared
the inhibition before and after decerebration at the suprapontine
level. Immediately after decerebration, both blood pressure and heart
rate increased [from 58 ± 2 to 88 ± 7 mmHg (P < 0.05) and from 354 ± 14 to
383 ± 19 beats/min (P < 0.05), respectively; n = 7]. After
stabilization for 1 h the increase in blood pressure was slightly
reduced (from 88 ± 7 to 75 ± 8 mmHg), whereas the increase in
heart rate was unchanged (383 ± 19 before; 386 ± 16 beats/min after decerebration). Subsequent application of smoke to the
nasal mucosa induced hypertension and a transient decrease in heart
rate (Table 3, Fig. 5). Inhibition of BVB
by smoke was not significantly altered by decerebration. This result
indicates that trigeminal inputs produce inhibition via projection to
neural elements in the ADN-related baroreflex arc, predominantly in the
pontomedullary region of the brain stem.
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Fig. 5.
Effects of suprapontine decerebration on smoke-induced inhibition of
BVB. A: responses to stimulation of
ADN before (1) and after
(2) nasal stimulation by smoke
before decerebration. B: ADN responses
before (1) and after
(2) nasal stimulation by smoke 1 h
after decerebration.
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Effects of spinal cord transection on smoke-induced inhibition of
BVB.
To investigate whether inhibition of BVB by smoke occurs at a
peripheral level, as was the case for inhibition of VIB by stimulation of dPAG (26), we compared inhibition of BVB by smoke before and after
spinal cord transection at the C3
level. Spinal cord transection reduced blood pressure (from 83 ± 6 to 65 ± 4 mmHg, P < 0.05;
n = 6) but had no appreciable effect
on the basal heart rate (335 ± 26 beats/min before and 315 ± 23 beats/min after transection; n = 6;
Table 3). The absence of an appreciable change in heart rate was likely
caused by the preceding blockade of -adrenergic receptors. When
smoke was applied to the nasal cavities transient bradycardia was
observed, with a slight decrease in blood pressure (Table 3, Fig.
6). The magnitude of inhibition of BVB by
smoke did not change significantly after spinal cord transection. This result suggests that, on exposure to smoke, inhibition of BVB occurs
mainly at the level of the central nervous system without significant
contribution of a peripheral inhibitory mechanism.
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Fig. 6.
Effects of spinal cord transection at
C3 level on smoke-induced
inhibition of BVB. A: responses to
stimulation of ADN before (1) and
after (2) nasal stimulation by smoke
before C3 transection.
B: ADN responses before
(1) and after
(2) nasal stimulation by smoke 1 h
after C3 transection.
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Effects of nasal stimulation on VIB.
To determine whether application of smoke to the nasal mucosa can
influence cardiovagal outflow by sympathetic inhibitory action on vagus
nerve terminals, we cut the cervical vagus nerves bilaterally and
stimulated the distal cut ends electrically. We examined the effect of
intranasal smoke on the resultant VIB. After the vagus nerves had been
sectioned bilaterally, both blood pressure and heart rate increased
[from 68 ± 4 to 86 ± 6 mmHg (P < 0.05) and from 322 ± 14 to
391 ± 11 beats/min (P < 0.01), respectively; n = 9]. In these
vagotomized animals nasal application of smoke had no effect on heart
rate, but it did increase blood pressure [from 391 ± 11 to
394 ± 11 beats/min and from 86 ± 6 to 123 ± 10 mmHg
(P < 0.01), respectively;
n = 9; Fig.
7]. When the test vagal stimulation
was applied after brief application of smoke, VIB was not affected
(percent inhibition 
1.0 ± 1.3%; n = 9; Fig. 7).
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Fig. 7.
Effects of brief application of smoke on vagus-induced bradycardia
(VIB). VIB was produced by electrical stimulation of peripheral cut
ends of cervical vagus nerves. 1,
3, Control VIB;
2, effects of nasal application of
smoke on VIB.
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When smoke application was sustained for 40 s, however, VIB was
obviously suppressed (Table 4, Fig.
8A).
When prazosin, an antagonist of
1-adrenergic receptors, was
administered continuously, blood pressure fell (from 94 ± 12 to 56 ± 7 mmHg; P < 0.05;
n = 6) with little change in heart
rate (from 365 ± 14 to 361 ± 13 beats/min; not significant;
n = 6). Hypotension was reversed by
infusion of dextran-containing Ringer solution (to 75 ± 4 mmHg). When smoke was then applied to the nasal cavities, neither blood pressure nor heart rate changed at all (Table 4, Fig.
8B). The inhibition of VIB was
abolished by prazosin.
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Table 4.
Effects of intravenous prazosin and spinal cord transection at
C3 level on inhibition of vagus-induced bradycardia and
BVB after long-lasting application of smoke
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Fig. 8.
Effects of long-lasting application of smoke on VIB.
A: responses to vagus stimulation
before (1) and after
(2) exposure to smoke. B:
responses before (1) and after
(2) exposure to smoke during
intravenous administration of prazosin.
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These results indicate that long-lasting stimulation of nasal cavities
with smoke inhibits VIB via
1-adrenergic receptors at vagus
nerve terminals and suggest that smoke has the potential to inhibit BVB
by a prejunctional mechanism.
Effects of long-lasting application of smoke on BVB.
When smoke was applied for 40 s, powerful hypertension was induced that
was sustained during the entire application (from 72 ± 8 to 164 ± 7 mmHg; P < 0.05;
n = 8; Fig. 9).
Bradycardia occurred initially (from 348 ± 11 to 325 ± 18 beats/min; P < 0.05; n = 8), but it
was transient and tachycardia was observed subsequently (385 ± 8 beats/min; P < 0.05 vs.
preapplication; n = 8). The magnitude of inhibition of BVB caused by long-lasting stimulation was slightly greater than that caused by brief stimulation (54 ± 5% after brief stimulation; 61 ± 5% after 40-s stimulation;
P < 0.05;
n = 8).
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Fig. 9.
Effects of long-lasting application of smoke on BVB before and after
spinal cord transection at C3
level. A: responses to stimulation of
ADN before (1) and after
(2) long-lasting application of
smoke. B: responses to stimulation of
ADN before (1) and after
(2) long-lasting application of
smoke 1 h after C3 transection.
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During intravenous injection of prazosin, the magnitude of the
inhibition caused by long-lasting stimulation by smoke was slightly
reduced (Table 4). C3 transection
reduced the magnitude of the inhibition similarly (Table 4, Fig. 9).
These findings indicate that inhibition of BVB caused by nasal
stimulation is produced predominantly by a central mechanism of
immediate onset and that a peripheral inhibitory mechanism is activated
after the long-lasting application of smoke but, in reality, plays only a subsidiary role in inhibition of BVB because of the long delay in the activation.
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DISCUSSION |
It is generally accepted that cardiovascular responses to
nasopharyngeal stimulation include hypertension and bradycardia. In the
present study, however, the latter response was only transient and not
marked. In intact animals, the bradycardic response to nasal
stimulation consists of components of multiple origins: a primary
reflex response to trigeminal input, baroreflex bradycardia secondary
to the reflex increase in blood pressure, and chemoreflex bradycardia
secondary to reflex apnea (16, 22, 36). In the present study, however,
animals were paralyzed and artificially ventilated, and their arterial
baroreceptors were all denervated. Thus the smoke-induced bradycardia
was caused by the primary response alone, and as a consequence, its
magnitude was small and the duration was transient. In addition, the
bradycardia is exclusively caused by vagal activation because
-adrenergic receptors were blocked with propranolol. This notion is
supported by the fact that the bradycardia did not appear after vagotomy.
The present study reveals for the first time that BVB is inhibited by
selective stimulation of the nasal mucosa alone. The results of the
nerve-transection study indicate that the afferent nerve that conveys
the information responsible for the inhibition is predominantly the
trigeminal nerve. This finding is in agreement with the results of
previous studies, which demonstrated that cardiovascular changes after
nasal stimulation are initiated exclusively by trigeminal input (22,
31).
In our study, no attempt was made to identify the ingredients in smoke
or the type of trigeminal sensory receptors that were responsible for
inducing inhibition of BVB. However, previous studies showed that
trigeminal sensory terminals in the nasal mucosa form free endings (5),
many of which are nociceptors (31) and contain substance P or
calcitonin gene-related peptide (12). Lin and Kou (20) demonstrated
recently that free radicals are present in smoke generated by
incomplete combustion of wood and that these free radicals stimulate
laryngeal sensory receptors to provoke a reflex apneic response, in
addition to particulate matter, high levels of CO and
CO2, and hypoxia. Thus the
numerous chemical irritants and particles in smoke seem to directly
stimulate the sensory receptors in the nasal mucosa. Our own analysis
indicated that the smoke from burning tissue paper contains several
aldehydes at very high concentrations. This finding suggests that
aldehydes are candidates for the agents that induce cardiovascular
responses to smoke. Such aldehydes should be tested respectively in
future studies to determine which of them can selectively stimulate
nociceptors in the nasal mucosa.
When distilled water is applied to the nasal mucosa, it diffuses into
the mucosa depending on the osmotic gradient, stimulating free nerve
endings to cause nociception. In our study, BVB was inhibited by nasal
stimulation with not only distilled water but also either hot or cold
Ringer solution. By contrast, application to the nasal mucosa of warm
Ringer solution (37°C), which was osmotically and thermally
neutral, did not affect BVB even though it induced a slight increase in
blood pressure and bradycardia. These results suggest that inhibition
of BVB can be produced only by intense thermal and/or
nociceptive input but not by innocuous tactile stimulation.
The results obtained after decerebration indicated that suprapontine
structures are not important for inhibition of BVB by trigeminal
afferents. In previous studies, cardiovascular reflexes induced by the
trigeminal system were unaffected by decerebration at the mesencephalic
or supracollicular level (1, 18), whereas White et al. (36) suggested
that reflex bradycardia might be dependent, in part, on cerebral
hemispheres. In our study, the reflex bradycardia by nasal stimulation
with smoke was similarly reduced moderately by suprapontine
decerebration. However, BVB was unaffected by smoke after
decerebration, suggesting that BVB is mainly inhibited by trigeminal
input at the pontine or infrapontine level.
There have been a number of studies of the centripetal projections and
pathways from trigeminal afferents. Trigeminal afferents project
primarily from the nasal mucosa to the spinal trigeminal nucleus. In
particular, the nociceptive afferents project to the subnucleus
caudalis and its adjacent regions (3, 9). For the most part, these
trigeminal subnuclei project, in turn, to the parabrachial (PB) and
caudal aspects of Kölliker-Fuse nuclei (KF) (7, 11). The PB-KF
are sites worth mentioning with regard to cardiovascular regulation.
Electrical stimulation of the PB evokes hypertension and tachycardia in
cats (24) and hypertension and bradycardia in rabbits (14). In rats,
electrical stimulation of the external lateral PB-KF causes
hypertension and tachycardia whereas that of the dorsal lateral PB
elicits hypotension and bradycardia (8). Baroreceptor inputs project
onto the PB via the nucleus tractus solitarii (NTS) (6, 14), whereas
the PB in turn projects to the NTS (11, 14). Furthermore, the PB-KF
project not only to the NTS but also to the nucleus ambiguus region, a
site of vagal cardiac preganglionic cells (32). In this regard, we
reported previously that the baroreflex inhibition that originates from
the hypothalamus or the dPAG is mediated predominantly by the PB in
rats (29) and that the target sites of inhibition of BVB by stimulation
of the hypothalamus and/or dPAG are mainly the vagal cardiac
preganglionic cells in the region of the nucleus ambiguus and not the
NTS interneurons (15, 29, 30). Therefore, it is suggested that
trigeminal nociceptive projections also inhibit the BVB at the level of
the preganglionic cells.
In a previous study we showed that baroreflex inhibition caused by
brief conditioning stimulation of the dPAG was predominantly of central
origin (29). However, we recently found that long-lasting stimulation
of the dPAG, which elicited powerful sympathoexcitation, as indicated
by a remarkable increase in blood pressure, could suppress the VIB at a
peripheral, prejunctional site of the cardiac vagus (26). In the
present study, inhibition of BVB caused by brief nasal stimulation was
unaffected by spinal transection. These results suggest that such
inhibition was attributable entirely to a central nervous system. By
contrast, long-lasting nasal stimulation provoked a remarkable increase
in blood pressure, as did stimulation of the dPAG, and it suppressed
the VIB. This inhibition was abolished by blockade of
1-adrenergic receptors. These
findings imply that excess norepinephrine reflexly released from the
cardiac sympathetic nerve suppresses acetylcholine release from the
terminals of the cardiac vagus by acting on the prejunctional
1-adrenergic receptors (prejunctional inhibition). This view further suggests a contribution of a peripheral, prejunctional mechanism via
1-adrenergic receptors to
trigeminally mediated inhibition of BVB. Actually, however, 1-adrenergic blockade only
slightly attenuated inhibition of BVB caused by prolonged application
of smoke. The discrepancy between these results can be explained as
follows. Because a major fraction of BVB was suppressed at a central
site with a short delay, only a small fraction of the BVB remained to
be inhibited by the peripheral, prejunctional mechanism with longer
latency of onset. Thus the contribution of the latter mechanism to
inhibition of BVB could not be large as a whole, as noted in the case
of inhibition of BVB by the dPAG (26).
The physiological significance of inhibition of BVB in response to
nasal stimulation can be speculated as follows. In animals which
breathe spontaneously, and in which baro- and chemoreflexes occur
normally, full-sized bradycardic responses develop to nasal stimulation
and can reduce the rate of oxygen consumption to prevent the rapid
progression of hypoxia and/or asphyxia (9, 35). However, after
vasoconstriction of slower onset is completed as a result of
sympathoexcitation, the role of bradycardia in conserving stored oxygen
becomes less important and excessive bradycardia might, rather,
endanger life. In general, a stressful condition provokes hypertension
as a component of the defense reaction, but expected reflex bradycardia
does not occur because a powerful inhibitory mechanism starts operating
simultaneously (25). This inhibition of BVB is an important feature of
the defense reaction because BVB, if uninhibited, would hinder full
expression of the defense reaction. Thus reflex bradycardia in the
nasopharyngeal reflex is considered to have two opposite effects, one
that is beneficial for saving stored oxygen and the other that is
disadvantageous for impeding the defense reaction. Inhibition of BVB on
nasopharyngeal stimulation might give priority to full expression of
the defense reaction at the expense of conservation of stored oxygen.
In awake animals, inhibition of BVB occurs not only reflexly on
nociceptive activation of the nasal mucosa but also by a centrally
initiated mechanism. For example, in the event of a fire or drowning,
smoke or cold water stimulation of nasal mucosa and the fear-associated activation of the defense area will, in conjunction, produce full-scale inhibition of BVB that contributes, in turn, to maximal expression of
the defense reaction.
| |
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. §1734 solely to indicate this fact.
Address for reprint requests: M. Kobayashi, Dept. of Physiology,
Mie Univ. School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
Received 25 February 1998; accepted in final form 24 September
1998.
| |
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