Vol. 84, Issue 4, 1388-1394, April 1998
Effect on airway caliber of stimulation of the hypothalamic
locomotor region
Christian A.
Beyaert,
Janeen M.
Hill,
Brock K.
Lewis, and
Marc P.
Kaufman
Division of Cardiovascular Medicine, Departments of Internal
Medicine and Human Physiology, University of California, Davis,
California 95616
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ABSTRACT |
Airway dilation
is one of the many autonomic responses to exercise. Two neural
mechanisms are believed to evoke these responses: central command and
the muscle reflex. Previously, we found that activation of central
command, evoked by electrical and chemical stimulation of the
mesencephalic locomotor region, constricted the airways rather than
dilated them. In the present study we examined in decerebrate paralyzed
cats the role played by the hypothalamic locomotor region, the
activation of which also evokes central command, in causing the airway
dilator response to exercise. We found that activation of the
hypothalamic locomotor region by electrical and chemical stimuli evoked
fictive locomotion and, for the most part, airway constriction. Fictive
locomotion also occurred spontaneously, and this too, for the most
part, was accompanied by airway constriction. We conclude that central
command plays a minor role in the airway dilator response to exercise.
dynamic exercise; autonomic nervous system; cholinergic pathways; cats; 
-adrenergic pathways
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INTRODUCTION |
DYNAMIC EXERCISE EVOKES a large number of
cardiovascular and respiratory responses (19), one of which is airway
dilation (8, 15, 27). The neural mechanism responsible for the
exercise-induced airway dilation is not known, but central command is
an important candidate and is defined as the parallel activation of
locomotor, ventilatory, and autonomic circuits at the onset of exercise
(12). Central command is not dependent on feedback from the periphery (5).
In animals, central command can be simulated by activation of two
sites: the cuneiform nucleus of the midbrain (5, 6, 21) and in or near
the H2 field of Forel of the
posterior hypothalamus (5, 23). The former site has been termed the
mesencephalic locomotor region and the latter the hypothalamic
locomotor region (HLR) (25). In a recent study our laboratory showed
that electrical and chemical stimulation of the mesencephalic locomotor
region increased total lung resistance, an effect that was caused by the activation of cholinergic receptors on airway smooth muscle (16).
This finding was surprising because it provided no support for the
hypothesis that central command contributed to the airway dilation
evoked by dynamic exercise. In the present study we have sought support
for this hypothesis by stimulating the other central command site,
i.e., the HLR. In addition, we have examined the effect of fictive
locomotion, occurring spontaneously, on airway caliber.
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METHODS |
General.
For anesthesia, cats were placed in a plastic box into which flowed a
halothane (5%)-nitrous oxide and oxygen gas mixture. After they were
anesthetized, the cats were removed from the box and inhaled the gas
mixture through a nose cone. The cervical trachea was cannulated, and
the lungs were ventilated mechanically with a halothane (3%)-nitrous
oxide and oxygen gas mixture. One common carotid artery and jugular
vein were cannulated. The chest was opened by placing bilateral
incisions between the ribs. The expiratory outlet of the ventilator was
placed under 1-2 cmH2O to
prevent collapse of the lungs. The cats were placed in a Kopf stereotaxic instrument and were then decerebrated by a blunt spatula passed at a 70° angle through the brain stem. The incision started 7 mm anterior to the sulcus between the superior and inferior colliculi. All neural tissue rostral to the section was removed, bleeding was controlled, and the cranial vault was filled with agar.
After the decerebration the halothane and nitrous oxide were removed
from the gas mixture ventilating the lungs and were replaced with room
air, which was supplemented with oxygen.
The biceps femoris nerve was exposed and sectioned. The central cut end
of this nerve, which supplies the hamstring muscles of the hindlimb,
was covered with petroleum jelly and mineral oil and was placed on a
bipolar hook recording electrode. Similarly, the
C5 rootlet of the phrenic nerve
was exposed and cut, and its central end was placed on a bipolar hook
recording electrode. Both electrodes were connected to high-impedance
probes (model HIP511, Grass), which in turn were connected to
preamplifiers (model P511, Grass). The signals from both nerves were
viewed on an oscilloscope and integrated (see below).
Airflow was measured by a heated pneumotach (no. 00, Fleisch) that was
placed between the ventilator and the tracheal cannula. The pneumotach
was connected to a differential pressure transducer (model DP45-24,
Validyne). Transpulmonary pressure was measured with a differential
pressure transducer (model DP45-14, Validyne), one end of which was
connected to a side port in the tracheal cannula; the other end was
left open to the atmosphere. Total lung resistance and dynamic
compliance were calculated breath by breath with a Po-ne-mah digital
acquisition, analysis, and archive system (version 1.0). The method of
Amdur and Mead (2) formed the basis for these calculations. Arterial
blood pressure was measured by connecting the cannula in the carotid
artery to a transducer (model P23XL, Statham). Heart rate was
calculated beat to beat from the arterial pressure pulse by the
Po-ne-mah system.
Protocols.
Before attempting to collect any data, we paralyzed the cats with
pipecuronium bromide (0.2 mg/kg iv). We then stimulated the HLR
(10-20 Hz, 0.75 ms, 50-150 µA) and selected the minimum current intensities that produced fictive locomotion. Our index of
airway caliber was total lung resistance. The HLR was stimulated with a
monopolar stainless steel electrode (model SNE-100, Rhodes); the
indifferent electrode was an alligator clip attached to the scalp. A
Grass S88 stimulator attached to a PSIU-6 constant-current unit was
used to pass current through the stimulating electrode. At the end of
the study, anodal current (4 mA, 10 s) was passed through the electrode
tip to mark stimulation sites. The Prussian blue reaction was used to
visualize sites.
In three cats the HLR was stimulated chemically as well as
electrically. Specifically, picrotoxin (8 mM) was microinjected through
one barrel of a double-barreled glass pipette, which in turn was
connected to a picospritzer (General Valve). In two cats the volume
microinjected into the HLR was 200 nl, and in the remaining one it was
100 nl. The interval between microinjection of picrotoxin and
subsequent electrical stimulation was ~20 min. The other barrel of
the pipette contained Chicago sky blue (2%), which was microinjected (100 nl) at the end of the study to mark the site. The HLR was identified using functional criteria, i.e., the elicitation of rhythmic
bursts of activity from the biceps femoris nerve (i.e., fictive
locomotion) and increases in arterial pressure, heart rate, and phrenic
nerve discharge when the posterior hypothalamus was stimulated
chemically or electrically (5, 25). In some instances the tibial nerve
was stimulated electrically (10-20 Hz, 0.75 ms, 8 mA) and total
lung resistance was assessed.
Data analysis.
Control values for total lung resistance and dynamic compliance were
determined by averaging values "breath by breath" for the 20 ventilatory cycles preceding the onset of stimulation. The peak
response to stimulation was determined by averaging five consecutive
"breaths" that displayed the largest change from control values
during fictive locomotion. Control values for arterial pressure and
heart rate were taken as the steady-state values; peak responses were
taken as the highest values observed during fictive locomotion. Phrenic
nerve discharge was integrated and quantified using the method
described by Eldridge (4). Briefly, activity was integrated (Gould) by
a sample-and-hold function that reset every 100 ms. Biceps femoris
nerve discharge was integrated in the same way as was phrenic
nerve discharge, except activity was summed over 5-s periods.
Values are means ± SE. A one-way ANOVA was used to determine
statistical significance. The criterion for significance was P < 0.05.
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RESULTS |
Electrical stimulation of the HLR.
Electrical stimulation of the posterior hypothalamus evoked fictive
locomotion in 23 paralyzed, decerebrate cats. On average, total lung
resistance increased during fictive locomotion from a baseline value of
29.0 ± 1.4 to a peak value of 31.6 ± 1.8 cmH2O · l
1 · s
(P < 0.01, n = 23). Dynamic compliance decreased
during fictive locomotion in these 23 cats from a baseline value of
4.08 ± 0.18 to a peak value of 3.87 ± 0.19 ml/cmH2O
(P < 0.01). As expected, mean
arterial pressure increased (from 143 ± 5 to 194 ± 5 mmHg, P < 0.01) as did heart
rate (from 210 ± 9 to 244 ± 8 beats/min, P < 0.01) and phrenic nerve
discharge (187 ± 15% of baseline, P < 0.01).
In 16 of the 23 cats studied, total lung resistance increased
during fictive locomotion, whereas in the remaining 7 cats, total lung
resistance decreased (Figs. 1,
2, A and
B, and 3,
A and
B). The delay between the onset of
fictive locomotion and the onset of the increase in total lung
resistance (n = 16) was 2.1 ± 0.9 s. Similarly, the delay between the onset of fictive locomotion and the
onset of the pressor response in cats displaying an increase in total
lung resistance was only 0.1 ± 0.3 s.
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Fig. 1.
Airway, phrenic nerve, and cardiovascular responses to electrical
stimulation of hypothalamic locomotor region.
A: data from 16 cats in which
stimulation of hypothalamic locomotor region caused airways to
constrict. B: data from 7 cats in
which stimulation of this region caused airways to dilate.
RL, total lung resistance; Cdyn,
dynamic compliance; MAP, mean arterial pressure; HR, heart rate; Loc,
locomotion; bpm, beats/min. * Significantly different (P < 0.05) from baseline.
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Fig. 2.
Airway responses to electrical and chemical stimulation of hypothalamic
locomotor region. A and
B: responses to electrical stimulation
of hypothalamic locomotor region on 2 different time scales. Electrical
stimulation occurred between 1st and 2nd vertical lines on time base.
C-F: responses of hypothalamic
locomotor region to chemical stimulation (i.e., microinjection with 200 nl of 8 mM picrotoxin). C: slow time
base; D: time period in
C labeled D. In
C, sensitivity of amplifier receiving
input from biceps femoris nerve was first adjusted downward and then
upward. Downward shift can be seen in
D as well.
E and
F: responses to chemical injection of
picrotoxin into hypothalamic locomotor region during time periods in
C labeled
E and
F. In
E and
F, every burst of "locomotor"
activity from biceps femoris nerve evokes increases in total lung
resistance. BP, blood pressure in mmHg.
RL is expressed in
cmH2O · l1 · s
and Cdyn in ml/cmH2O. All traces
are from the same cat.
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Fig. 3.
Airway responses to electrically induced and spontaneously occurring
fictive locomotion. A and
B: responses to electrical stimulation
of hypothalamic locomotor region, a maneuver that in turn caused
fictive locomotion. Airways constricted during both trials, one of
which was longer than the other. Horizontal bars above traces, period
of stimulation. C: airway response to spontaneously occurring fictive locomotion. Airways constricted and
phrenic nerve activity and blood pressure increased during period of
spontaneous locomotion, which is depicted by activity from biceps
femoris nerve. D: electrical
stimulation of tibial nerve evoked airway dilation (i.e., decreased
total lung resistance). Bracket above trace, period of stimulation. BP
is expresssed in mmHg, RL in
cmH2O · l1 · s,
and Cdyn in ml/cmH2O. All traces
are from the same cat.
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The delay between the onset of fictive locomotion and the onset
of the decrease in total lung resistance
(n = 7) was 
1.9 ± 1.1 s. In
other words, the decrease in total lung resistance began 1.9 ± 1.1 s before the onset of fictive locomotion in the cats showing a decrease
in total lung resistance. Moreover, the increase in arterial pressure
began 3.3 ± 1.7 s before the onset of fictive locomotion.
We examined the effects of nadolol (1 mg/kg iv), a -adrenergic
antagonist, followed by atropine methyl nitrate (1 mg/kg iv), a
muscarinic antagonist, on the airway, phrenic, and cardiovascular responses to fictive locomotion. These antagonists were given sequentially to 8 of the 16 cats showing an increase in total lung
resistance in response to fictive locomotion (Fig.
4) as well as to 4 of the 7 cats showing a
decrease in total lung resistance (Fig. 5).
We found that nadolol increased the airway constriction evoked by
fictive locomotion in the former group of cats and converted the airway
dilation evoked by fictive locomotion to a constriction in the latter
group. Atropine abolished all airway effects evoked by fictive
locomotion.
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Fig. 4.
Airway and cardiovascular responses to electrical stimulation of
hypothalamic locomotor region before and after autonomic blockade in 8 cats in which airways constricted in response to this maneuver.
* Significantly different (P < 0.05) from baseline.
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Fig. 5.
Airway and cardiovascular responses to electrical stimulation of
hypothalamic locomotor region before and after autonomic blockade in 5 cats in which airways dilated in response to this maneuver.
* Significantly different (P < 0.05) from baseline.
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Chemical stimulation of the HLR.
In three cats, we compared the airway, phrenic, and cardiovascular
responses to microinjection of picrotoxin (8 mM) into the HLR with the
responses to electrical stimulation of the HLR. In each of the three
cats tested, picrotoxin microinjection and electrical stimulation
increased total lung resistance, increased mean arterial pressure,
increased heart rate, increased phrenic nerve discharge, and decreased
dynamic compliance (Fig. 2,
C-F). The picrotoxin-induced fictive locomotion was long lasting and averaged 23.7 ± 3.7 min. Fictive locomotion started 7 ± 1.7 min after the last
microinjection of picrotoxin.
Spontaneous fictive locomotion.
In seven paralyzed cats, fictive locomotion occurred spontaneously,
i.e., without electrical or chemical stimulation of the HLR. In five of
these cats, total lung resistance increased significantly (P < 0.05; Table
1, Fig.
3C), whereas in two it decreased
slightly (data not shown). Fictive locomotion evoked by electrical
stimulation of the HLR changed total lung resistance in the same
direction as did spontaneous fictive locomotion in six of the cats
(Fig. 3B). In the one remaining cat
we were unable to evoke fictive locomotion by electrical stimulation of
the HLR, even though it occurred spontaneously. In each of the seven
cats studied, spontaneous and electrically induced fictive locomotion
increased mean arterial pressure, heart rate, and phrenic nerve
discharge. The magnitude of these increases appeared to be the same as
in cats displaying an increase in total lung resistance and in cats
displaying a decrease in total lung resistance.
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Table 1.
Effects of spontaneous fictive locomotion and fictive locomotion
induced by electrical stimulation of HLR on airway,
ventilatory, and cardiovascular function
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Histology.
Histological analysis revealed that all sites, stimulated electrically
or chemically, were in the HLR as defined previously (5, 25) (Fig.
6).
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Fig. 6.
Histological analysis of stimulation sites that evoked fictive
locomotion.  , Sites in posterior hypothalamus that caused airways to
constrict when electrically stimulated;  , sites in posterior
hypothalamus that caused airways to dilate when electrically stimulated;  , 3 sites that were chemically stimulated with
picrotoxin. These sites also caused airway constriction. MT, medial
mamillary nucleus; F, fornix; VMH, ventromedial hypothalamus; INF,
infundibular nucleus; OT, optic tract; V, ventricle; SUB, subthalamic
nucleus; HLA, lateral hypothalamic area; MM, medial mamillary nucleus; PP, pes pedunculi. [Diagrams are from Waldrop et al.
(25).]
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Tibial nerve stimulation.
In 16 paralyzed cats the tibial nerve was stimulated electrically with
current intensities that recruited C fibers. In 12 of the 16 cats,
total lung resistance decreased (from 29.4 ± 2.9 to 25.3 ± 1.9 cmH2O · l1 · s,
P < 0.05), and in the remaining 4 cats it increased (from 29.9 ± 2.8 to 32.5 ± 3.0 cmH2O · l1 · s,
P < 0.05). For the group as a whole,
(i.e., n = 16), tibial nerve
stimulation significantly decreased total lung resistance (from 29.6 ± 2.2 to 27.1 ± 1.7 cmH2O · l1 · s,
P < 0.05). In every instance, tibial
nerve stimulation increased mean arterial pressure and phrenic nerve
discharge.
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DISCUSSION |
We have examined the role of the HLR in the control of airway caliber.
Specifically, we tested the hypothesis that activation of this region
is responsible for the airway dilation seen during dynamic exercise (8,
15, 27). Our requirements for the successful activation of the HLR, and
therefore central command, were based on functional criteria. These
included increases in mean arterial pressure, increases in heart rate,
increases in phrenic nerve discharge, and fictive locomotion, each of
which must have occurred for the data to be included in our analysis.
Overall, our data were not supportive of the hypothesis that the HLR
plays an important role in causing the airway dilation evoked by
dynamic exercise. For example, in ~70% of the 23 cats tested,
electrical stimulation of the HLR constricted the airways. When
dilation of the airways did occur (i.e., in ~30% of cats), its
magnitude was modest. In addition, the airway constriction evoked by
electrical stimulation did not appear to be an artifact caused by the
activation of fibers of passage, because the same effect was caused by
microinjection of picrotoxin, a GABA antagonist, which functions by
blocking chloride iontophores on cell bodies and dendrites (22).
When stimulation of the HLR did evoke airway dilation, the response was
converted by -adrenergic blockade to airway constriction and
subsequently was abolished by atropine. We can offer two explanations for the mechanism causing the airway dilator response to HLR
stimulation. First, stimulation of the HLR activated -adrenergic
receptors located on airway smooth muscle. This activation could occur
by the release of transmitter from sympathetic postganglionic nerves or
by the release of epinephrine from the adrenal gland (24). Second, the
pressor response to HLR stimulation evoked the baroreflex, one
component of which is airway dilation (20). We do not know which
explanation is correct, but when airway dilation was evoked by HLR
stimulation, the pressor response was, on average, 18 mmHg greater than
that when airway constriction was evoked by HLR stimulation (Fig. 2).
We speculate that in the seven cats showing a dilator response to HLR
stimulation the large pressor effect may have been sufficient to
overwhelm the airway constriction usually observed when this maneuver
is initiated.
Nevertheless, electrical stimulation of the HLR for the most part
evoked airway constriction, as evidenced by an increase in total lung
resistance. This increase was not effected by
-adrenergic blockade but was abolished by muscarinic blockade. This
finding is consistent with previous reports that the constrictor
response to stimulation of the brain stem is caused by the activation
of cholinergic pathways to airway smooth muscle (7, 17).
If central command is not the major neural mechanism causing the
exercise-induced airway dilation, then what is? Two candidates come to
mind: the Hering-Breuer reflex and the muscle reflex. Both evoke
bronchodilation by withdrawal of cholinergic tone to airway smooth
muscle (3, 10, 11, 13, 28). Slowly adapting stretch receptors comprise
the afferent arm of the Hering-Breuer reflex arc. The activity of these
slowly adapting receptors will be increased by exercise-induced
increases in tidal volume and the rate of breathing. Similarly, group
III and IV afferents comprise the afferent arm of the muscle reflex arc
(14). The activity of these thin fiber afferents is known to be
increased by dynamic exercise (1, 18).
Our conclusion that activation of the HLR is not the major mechanism
causing exercise-induced airway dilation applies to the tracheobronchial tree but not to the upper airways. In our experiments the cats were paralyzed, which prevented neurotransmission from the HLR
to the skeletal muscles. In addition, the trachea was cannulated below
the larynx, which removed the upper airways from our calculations of
total lung resistance and dynamic compliance. Consequently, the role of
central command in the control of the upper airways during exercise
remains to be determined.
The fact that the cats used in our experiments were paralyzed and
ventilated had another consequence; i.e., feedback from pulmonary
stretch receptors to brain stem neurons controlling airway caliber and
breathing was abnormal. In turn, afferent input from these receptors
reached the brain stem out of phase with central respiratory drive.
Therefore, we cannot exclude the possibility that this factor was
responsible for our inability to evoke major dilation of the airways
during stimulation of the HLR. We were, however, able to evoke airway
dilation in our preparation when the tibial nerve was stimulated
electrically (present results) or when the triceps surae muscles were
contracted statically (16).
There is no doubt that central command plays an important role in the
control of cardiovascular and ventilatory function during exercise.
Indeed, central command is thought to be the dominant mechanism causing
the ventilatory response to exercise (9, 26). Nevertheless, central
command appears to play a minor role in the airway smooth muscle
dilation known to occur during dynamic exercise. This conclusion is
based on the assumption that the hypothalamic and mesencephalic
locomotor regions of the decerebrate unanesthetized cat comprise the
neuroanatomic substrate for central command. Other sites in the brain
stem may also be involved in the generation of central command, and
their effects on airway caliber will need to be investigated as these
sites are identified.
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ACKNOWLEDGEMENTS |
This work was supported by National Heart, Lung, and Blood
Institute Grant HL-40910.
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FOOTNOTES |
Present addresses: C. A. Beyaert, Laboratoire de Physiologie,
Faculté de Médecine, 9 Ave. de la Forêt de Haye-BP
184, 54505 Vandoeuvre-les-Nancy, Cedex, France; J. M. Hill, Dept. of
Movement and Exercise Science, Chapman University, Orange, CA 92666.
Address for reprint requests: M. P. Kaufman, Div. of Cardiovascular
Medicine, TB 172, Bioletti Way, University of California, Davis, CA
95616.
Received 9 September 1997; accepted in final form 5 December 1997.
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Abstract
Introduction
