400
BRIEF C O M M U N I C A T I O N S
Effects of Lateral Reticular Nucleus Lesions on the
Exercise Pressor Reflex in Cats
Gary A. Iwamoto, Marc P. Kaufman, Barry R. Botterman, and Jere H. Mitchell
From the Deportments of Cell Biology and Physiology, and the Harry S. Moss Heart Center,
University of Texas Health Science Center, Dallas, Texas
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SUMMARY. Electrical stimulation of ventral roots gives rise to a reflex cardiovascular reponse
similar to that observed during static exercise. Although the afferent limb of the reflex is known to
be comprised of small diameter afferent fibers from the contracting muscle, little is known of the
central nervous system pathway(s) involved. The lateral reticular nucleus of the brainstem is known
to be an important site of integration for numerous types of visceral and somatic afferent information,
many of which give rise to cardiovascular responses. However, the linkage between the small
diameter muscle afferents responsible for the exercise pressor reflex and the lateral reticular nucleus
has not been established. In anesthetized cats (n = 7), stimulation of L7 and Si ventral roots increased
mean arterial pressure (18.6 ± 2.4 mm Hg) and heart rate (7.4 ± 1.7 beats/min). Following bilateral
lesions of the lateral reticular nucleus, the increases in mean arterial pressure and in heart rate were
essentially abolished (P < 0.005) (mean arterial pressure increased 1.9 ± 0.8 mm Hg and heart rate
increased 0.7 ± 0.5 beats/min). Unilateral lateral reticular nucleus lesions and control lesions in
pressor sites outside the lateral reticular nucleus (n = 5) did not affect the exercise pressor reflex.
The lateral reticular nucleus lesions also produced decreases (P < 0.01) both in resting mean arterial
pressure (—27 ± 5.5 mm Hg) and heart rate (—31.0 ± 8 beats/min). These data suggest that the
lateral reticular nucleus is important in the central pathway of the exercise pressor reflex and
mediates a tonic pressor influence at rest. (Circ Res 51: 4OO-403, 1982)
IT IS well known that static exercise causes an increase in arterial blood pressure and heart rate. Obviously, while much of the control of these responses
is mediated through the central nervous system
(CNS), little is known of the precise nature of the
neuronal circuitry involved (Shepherd et al., 1981).
Two basic hypotheses exist concerning the patways
responsible for this pressor response, neither of which
are mutually exclusive. One hypothesis suggests that
"central command" originating in the rostral brain
activates the cardiovascular system (Krogh and
Lindhard, 1913). The other hypothesis suggests that
stimuli originating in the exercising muscles trigger a
reflex pressor response (Alam and Smirk, 1937). The
latter hypothesis may be conveniently studied in an
acute animal preparation in which muscular activity
evoked by stimulation of the ventral roots induces an
accompanying pressor response. Investigations using
this model have indicated that the exercise pressor
response is a neurally mediated reflex (Coote et al.,
1971; McCloskey and Mitchell, 1972; Mitchell et al.,
1977) that is initiated by stimulation of muscle receptors which are supplied by small diameter fibers
(McCloskey and Mitchell, 1972). Large diameter muscle afferent fibers apparently play no role in this
response (McCloskey et al., 1972).
Since a part of the ongoing research of this laboratory has dealt with the analysis of this experimental
model of exercise, it was of interest that Ciriello and
Calaresu (1977b) demonstrated that lesions in the
lateral reticular nucleus (LRN) abolished pressor responses evoked by stimulation of the central cut end
of the sciatic nerve. Recent studies by Kniffki et al.
(1981) have shown that, of the higher threshold muscle afferents, only 30% of group IV (unmyelinated)
and 40% of group III (fine myelinated) afferents respond to muscle contraction. Hence, stimulation of a
mixed nerve such as the sciatic is very nonspecific
because all muscle afferents, as well as cutaneous and
joint afferents, are activated. Therefore, the present
study was undertaken to determine whether lesions
of the LRN also abolished the pressor reflex caused
by muscle contraction, a stimulus which activates
only a selected group of the muscle afferents.
Methods
Adult cats 2.7-3.2 kg were anesthetized with sodium
pentobarbital (35 mg/kg). Blood pressure was monitored
by a cannula placed in one common carotid artery. Another
cannula was placed in an external jugular vein for the
infusion of supplemental drugs and fluids.
Using standard Iaminectomy procedures, we exposed
and severed the L7 and Si ventral roots and set up the
peripheral cut end for electrical stimulation on bipolar hook
electrodes. The triceps surae muscle was arranged for the
monitoring of isometric muscle tension. Following appro-
Jwamofo et a/./Brainstem and Exercise
401
Sea
Muscle
Tension
(Kg)
200
150
Blood
Pressure 100
(mmHg) gQ
5SP
Sec.
0 5 10 15 20 25 30
B
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Muscle
Tension
(Kg)
LRN Le»ion •
200
Blood i 5 °
Pressure 100
(mmHg) gg
FIGURE 1. Effects of brainstem lesioning in the region of the lateral reticular nucleus on the exercise pressor response of the cat. A: Top tr a ce
shows muscle tension generated by the triceps surae muscle (gastrocnemius and soleus). Bottom trace shows arterial blood pressure. Effects
of 50 Hz stimulation (0.1 msec duration, 3X motor threshold) of ventral roots LT and S, for 30 seconds, as indicated by the time lines above
the blood pressure traces. Note effects of stimulation on blood pressure. B: Same as A, but following lesions of the brainstem depicted in C.
Note that the exercise-induced changes in blood pressure are abolished after the lesions. Note that, in this case, the hypotensive effect of the
lesions is minimal. A/though the location of the electrode was primarily in the lateral aspect of the LRN, all other effective lesions included
both lateral and medial portions. The figure represents typical lesion size. 55P = spinal nucleus of the trigeminal nerve, PT = pyramidal
tract, IO = inferior olive, LRN = lateral reticular-nucleus.
priate craniectomy procedures, a small portion of the caudal
cerebellar vermis was removed and stainless steel monopolar semimicroelectrodes (Rhodes SNE-300 tip diameter
0.1 mm) were placed either in the lateral reticular nucleus
or other target brain sites using a combination of stereotaxic
coordinates (Berman, 1968) and surface landmarks. The
lateral reticular nucleus electrode placements were made at
the level of the obex. In addition, electrical stimulation (200
fiA, 0.5 msec in duration, 50 Hz) of all the target brainstem
locations identified them as pressor sites. Control levels of
the exercise pressor response were obtained using stimulation of the ventral roots (3X motor threshold, 0.1 msec in
duration, 50 Hz). Lesions of the LRN or other pressor sites
were made by passing DC current (2.5-5 mA; electrode
positive) for 10 seconds. After making the lesions, blood
pressure was allowed to stabilize for 30 minutes to 1 hour
before the ventral roots were again stimulated using the
previous parameters. The effects of those lesions on the
exercise pressor response were observed. The lesions were
later histologically located after the brainstems were cut in
50-/im sections aided by the use of Prussian blue reagents
in fixation procedures. The extent of the lesions was verified
by microscopic examination of the sections following Nissl
staining with cresyl violet. We have included a histological
section in Figure 1 to relate the extent of the electrolytic
lesion. Although the currents used may seem high, the
damaged areas are actually quite discrete, possibly due to
the tip configuration (0.1 mm diameter) of the electrodes.
Results
Figure 1 shows a typical result from one animal in
which bilateral lesions of the lateral reticular nucleus
were made. The muscle contraction caused by ventral
TABLE 1
Effects of Bilateral Lateral Reticular Nucleus Lesions on the
Cardiovascular Responses Evoked by Stimulation of the Ventral
Roots
Before LRN lesion
Arterial pressure
Mean
SE
Heart rate
Mean
SE
After LRN lesion
+18.6 mm Hg
+1.9 mm Hg
±0.8
±2.4
P < 0.005*
+0.7 beats/min
+7.4 beats/min
±1.7
±0.5
P < 0.005*
* Paired mean difference Student's t-test (n = 7).
Circulation Research/Voi. 51, No. 3, September 1982
402
TABLE 2
Effects of Bilateral Lateral Reticular Nucleus Lesions on Resting
Mean Arterial Pressure and Heart Rate
Before LRN lesion
Mean blood pressure
Mean
SE
Heart rate
Mean
SE
After LRN lesion
91.2 mm Hg
73.4 mm Hg
±8.0
±6.3
P < 0.01 *
133 beats/min
103.3 beats/min
±8.5
±8.9
P < 0.01*
* Paired mean difference Student's f-test (n = 7).
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root stimulation causes an increase in both blood
pressure and heart rate (A). However, in B following
bilateral lesions in the LRN (shown in C), the pressor
response to ventral root stimulation is abolished. Results from seven animals are summarized in Table 1.
Before lesioning LRN, ventral root stimulation caused
increases in mean blood pressure and heart rate. After
bilateral lesions of the LRN, the increases in blood
pressure and heart rate were severly reduced (P <
0.005, Table 1). After LRN lesions, the cats also
showed significant decreases in resting mean arterial
pressure and heart rate (P < 0.01, Table 2).
The fall in blood pressure was sufficient to make
it possible to compromise the animal's ability to
generate pressor responses. Therefore, in two animals
in which the exercise pressor response was abolished
by LRN lesions (causing a decrease in resting blood
pressure and heart rate), pressor responses (+52 and
+64 mm Hg; +27 and +12 beats/min) were elicited
by stimulation (50 Hz, 0.5 msec in duration, 200 juA)
in the region of the lateral division of the facial nerve
nucleus, which is rostral to LRN.
Experiments with five additional cats employing
lesions in other pressor sites were also carried out.
These sites were cytoarchitecturally within the lateral
tegmental field as described by Berman (1968). In
each case, the parameters used for making these
lesions were similar to those utilized for the LRN
lesions, resulting in lesions which were the same size
as those used for the LRN. In two of these additional
animals, ipsilateral lesions (referenced to the exercising limb) were placed in the LRN while contralateral
lesions were placed in nearby lateral tegmental field
pressor sites (as demonstrated by electrical stimulation), dorsomedial to LRN in one cat and directly
dorsal to LRN in the other cat. This combination of
lesions did not abolish the ventral root exercise pressor response, but did result in some attenuation of the
response. In two other cats, bilateral control lesions
were placed in the pressor regions of the lateral caudal
brainstem which were described by Alexander (1946)
as dorsal to the LRN and which also correspond to
Berman's (1968) lateral tegmental field. These lesions
also did not abolish the pressor response. Finally, in
one animal, the ventrolateral margin of the brainstem
just adjacent to the LRN was bilaterally Iesioned.
These lesions, while destroying a small portion of the
lateral reticular nucleus external division (Berman,
1968), also did not abolish the pressor responses. It is
of interest to note that, while the lesions described in
the five animals above did not abolish the ventral root
stimulus pressor response, mean blood pressure again
was observed to decrease significantly (109 ± 8.6 mm
Hg to 98.2 + 11.7 mm Hg, F < 0.025) although heart
rate was not as profoundly affected (146.4 ± 13.8 to
134 ± 13.3 beats/min P < 0.125).
Discussion
The present experiments have demonstrated that
the bilateral integrity of the lateral reticular nucleus
is important for the expression of the exercise pressor
reflex. This result is slightly at variance with that
obtained by Ciriello and Calaresu (1977b), since they
were able to abolish the pressor response to sciatic
nerve stimulation with ipsilateral lesions. The major
difference between our study and that of Ciriello and
Calaresu appears to be in the method by which peripheral afferent fibers were activated.
The fall in blood pressure and heart rate due to
LRN lesions was previously observed in cats by Guertzenstein and Silver (1974). However, a lowered blood
pressure has the potential of rendering the animals
unable to generate pressor responses. Therefore, in
two animals, pressor responses were evoked by stimulation of the brainstem from stimulus sites rostral to
the LRN lesions. These responses proved that the
condition of the animals had not deteriorated to the
point at which a pressor response was impossible due
to lowered blood pressure.
The present experiments do not precisely indicate
the nature of the LRN's involvement in the exercise
pressor response, since lesions do not discriminate
between cells and fibers "en passage." Despite this
limitation, there is much supporting evidence to suggest LRN's role as a major relay for this response. It
is well known that the late component of group III
and IV somatosympathetic reflexes relays through the
caudal brainstem (Sato and Schmidt, 1973). In addition, the cells within the LRN itself have been characterized as receiving input from the flexor reflex
afferents (which includes higher threshold muscle
afferents) in a variety of convergent patterns from the
limbs (Rosen and Scheid, 1973). Thus, appropriate
types of information reach this nucleus, which has
also been identified as a pressor site (Thomas et al.,
1977). Furthermore, the projection of the LRN to the
cerebellum may also be an important link in this
possible reflex circuitry, since a reduction in pressor
responses has been observed in exercising conscious
dogs with lesions in the fastigial nucleus (Foreman et
al., 1980). The fastigial nucleus has been identified as
a pressor site (Miura and Reis, 1969) and LRN has
been demonstrated to project both to the fastigial
nucleus and to the cerebellar cortex (Matsushita and
Ikeda, 1976). The fastigial nucleus, in turn, sends
projections to numerous brainstem pressor regions
(Moolenaar and Rucker, 1976), including the para-
403
Iwamoto et a/./Brainstem and Exercise
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median nucleus which appears to be the major brainstem relay for the pressor response to fastigial nucleus
stimulation (Miura and Reis, 1969). This putative
arrangement may be indicative of a type of long loop
cerebellar reflex similar to that which Eccles (1967)
has envisioned for lower threshold muscle afferents
and their interactions in the somatomotor system.
Although we cannot discount the possibility that
the effects of LRN lesions may result from simply
interrupting fibers passing through the nucleus, a few
relationships should be pointed out which indicate
that at least some of the related fiber systems having
cardiovascular function in the area probably are not
involved in producing our observed effects. A descending pressor pathway from the hypothalamus
passes around and through (Ciriello and Calaresu,
1977a) and just ventrolateral (Saper et alv 1976) to the
LRN. In addition, stimulation of the posteromedial
hypothalamus activates cells in LRN (Ciriello and
Calaresu, 1977b). However, interruption of this pathway is not likely to have any effect on the exercise
pressor response, since the reflex is obtained (and
even enhanced) in a decerebrate animal (Coote et al.,
1971; McCloskey and Mitchell, 1972). In addition,
although there are pressor sites just rostral to the
LRN, Dampney and Moon (1980) have suggested, on
the basis of their observations in the rabbit, that the
efferent projection of these areas does not descend
caudalward through the LRN.
Finally, it is important to reemphasize the existence
of the descending pressor pathway arising from hypothalamus and passing through the LRN region. This
pathway probably indicates that the pressor circuitry
utilized during ventral root stimulus-induced exercise
is only a part of that which is activated during electrical stimulation of the LRN. An attenuated pressor
response may still be obtained to stimulation of LRN
in a cerebellectomized animal as compared to the
intact animal (Thomas et al., 1977). This response
may be accounted for by activation of the hypothalamic pathway, since it might be activated separately
from any of the putative exercise pressor reflex pathways possibily involving the cerebellum.
Thus, the present experiments represent a necessary first step in the elucidation of the central reflex
pathway for the exercise pressor response. Further
investigations with single cell recordings probably
will indicate whether or not the LRN and related
nuclear areas respond in a manner appropriate to
participate in these responses.
Supported by the Lawson and Rogers Lacy Research Fund in
Cardiovascular Disease and by National Institutes of Health Grant
HL06296.
Address for reprints: Gary A. Iwamoto, Ph.D., Department of
Cell Biology, University of Texas Health Science Center, 5323
Harry Hines Boulevard, Dallas, Texas 75235.
Received March 25, 1982; accepted for publication June 4, 1982.
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INDEX TERMS: Brainstem • Autonomic nervous system • Group
IV afferents • Cerebellum • Bilateral ventral flexor reflex tract
Effects of lateral reticular nucleus lesions on the exercise pressor reflex in cats.
G A Iwamoto, M P Kaufmann, B R Botterman and J H Mitchell
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Circ Res. 1982;51:400-403
doi: 10.1161/01.RES.51.3.400
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