Download Central Nervous System Mechanisms Involving GABA

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Central Nervous System Mechanisms
Involving GABA Influence Arterial Pressure
and Heart Rate in the Cat
DANIEL J. WILLIFORD, BETTY L. HAMILTON, JANETTE DIAS SOUZA,
THOMAS P. WILLIAMS, JOSEPH A. DIMICCO, AND RICHARD A. GILLIS
SUMMARY Administration of the y-aminobutyric acid (GABA) receptor agonist, muscimol, into the
third ventricle of anesthetized cats causes decreases in blood pressure and heart rate. To determine the
brain areas involved, we administered muscimol into the (1) entire ventricular system, (2) lateral and
3rd ventricles, and (3) 4th ventricle. Muscimol 0.05-16.65 /ig administered into the entire ventricular
system resulted in dose-dependent decreases in blood pressure, and at the two highest doses of 6.65
and 16.65 fig, significant reductions in heart rate. These changes in blood pressure and heart rate were
mimicked when muscimol was localized to the 4th ventricle. Pressure and rate changes were not
observed when muscimol was restricted to the lateral and 3rd ventricles. To determine the autonomic
nerves involved in mediating the responses produced by muscimol administered into the 4th ventricle,
bilateral vagotomy and bilateral stellate ganglionectomy were performed. Vagotomy had no effect on
the responses evoked by muscimol, whereas stellate ganglionectomy prevented the decrease in heart
rate without altering the effect of muscimol on blood pressure. To determine the efficacy of muscimol,
the hypotensive and bradycardic effects of this agent were compared to those obtained with clonidine.
The depressor response obtained with muscimol was greater than that seen with clonidine. In addition,
muscimol produced an additional fall in pressure after a plateau effect had been obtained with
clonidine; the converse was not observed. Pretreatment with the GABA receptor antagonist, bicuculline
(25-100 pg) administered into the fourth ventricle in doses which had no effects on blood pressure or
heart rate prevented the effect of muscimol. Treatment with bicuculline after a peak response had been
obtained with muscimol restored pressure and rate to normal. These results indicate that activation of
GABA receptors in the region of the hindbrain causes hypotension and bradycardia, and that both
of these responses are mediated by a reduction in sympathetic outflow to the vasculature and heart.
Circ Res 47: 80-88, 1980
Y-AMINOBUTYRIC ACID (GABA) may be an
important neurotransmitter in central nervous
system (CNS) pathways influencing activity in
both divisions of the autonomic nervous system
and thereby causing changes in cardiovascular function. Evidence for this is derived from studies using
drugs that either interfere with or enhance CNS
GABAergic mechanisms. Drugs known to interfere
with the function of GABA, such as picrotoxin
which inhibits the effect of GABA on chloride conductance (Ticku et al., 1978) and bicuculline which
blocks the GABA receptor (Johnston, 1976), increase central sympathetic outflow and arterial
pressure (DiMicco, 1978; Antonaccio et al., 1978a).
These agents also increase parasympathetic outflow
and decrease heart rate (DiMicco et al., 1977;
DiMicco and Gillis, 1979; DiMicco et al., 1979).
Similarly, a drug that inhibits the synthesis of
From the Departments of Pharmacology and Anatomy, Georgetown
University, Schools of Medicine and Dentistry, Washington, D.C.
Supported by Grant NS-12566 from the U.S. Public Health Service
and by a Grant-in-Aid from the American Heart Association with funds
contributed in part by the American Heart Association, Nation's Capital
Affiliate, Inc.
Address for reprints: Daniel J. Williford, Department of Pharmacology, Schools of Medicine and Dentistry, Washington, D.C. 20007.
Original manuscript received June 11, 1979; accepted for publication
February 26, 1980.
GABA in the CNS [thiosemicarbazide (Killam,
1957)] and an agent that has been found to block
the release of GABA [tetanus toxin (Curtis et al.,
1973)] increase sympathetic outflow (Taylor et al.,
1977; Kerr et al., 1968).
Conversely, substances that presumably act by
directly stimulating GABA receptors (e.g., GABA
and muscimol) decrease sympathetic outflow and
arterial pressure and heart rate (DiMicco, 1978;
Antonaccio and Taylor, 1977; Antonaccio et al.,
1978b). In addition, representatives of a class of
drugs thought to act in the CNS by increasing the
affinity of the GABA receptor for GABA, the benzodiazepines (Costa, 1977), have been shown to
decrease both sympathetic outflow and arterial
pressure (Chai and Wang, 1966; Sigg et al., 1971;
Antonaccio and Halley, 1975; Bolme and Fuxe,
1977).
The purpose of the present study was to obtain
more information on the influence of CNS
GABAergic mechanisms in exerting control over
arterial pressure and heart rate. Specifically, we
used the selective GABA receptor agonist, muscimol, and determined: (1) where in the CNS muscimol was producing an effect that results in decreases in pressure and rate, (2) what division of the
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CNS GABA CONTROL OF CARDIOVASCULAR FUNCTION/ Williford et al.
autonomic nervous system is involved in the decrease in pressure and rate induced by muscimol,
(3) the efficacy of muscimol to lower pressure and
rate as compared to the prototype CNS-active hypotensive agent, clonidine, and (4) whether or not
the CNS actions of muscimol are a consequence of
this agent interacting with GABA receptors.
Methods
Adult cats of both sexes and weighing from 1.9 to
3.3 kg were anesthetized with a-chloralose, 70-80
mg/kg, iv. A femoral artery and vein were cannulated for measurement of arterial pressure and systemic administration of drugs, respectively. The
trachea was cannulated and all cats were artificially
ventilated with room air. Animals then were immobilized with decamethonium bromide, 0.25 mg/
kg, iv, given every 45 minutes or as needed. Rectal
temperature was monitored and maintained between 37° and 38°C by an infrared lamp. Blood
pressure and lead II of the ECG were monitored
continuously on a Grass polygraph. In some animals, the cervical vagus nerves were isolated and
sectioned bilaterally. In addition, some cats were
subjected to bilateral stellate ganglionectomy. This
was accomplished by opening the chest through a
lateral approach and removing both stellate ganglia.
For intracerebroventricular administration of
drugs, the cat's head was mounted in a David-Kopf
stereotaxic apparatus. Three types of injections
were performed in order to limit drug distribution.
These were as follows:
1. for perfusion of the entire ventricular system,
drugs were administered through a 26-gauge stainless steel spinal needle positioned in the left lateral
ventricle at coordinates AP +11.5, HD +8.5, and
RL +4.0, as indicated by the atlas of Snider and
Neimer (1961). A short length of PE-160 tubing was
inserted into the cisterna magna to provide an exit
for displaced CSF.
2. for perfusion of the forebrain ventricles only
(lateral and 3rd ventricles), injections were made
through a needle placed in the left lateral ventricle
as described above, with collection of perfusate
through a cannula lodged in the Aqueduct of Sylvius, thereby preventing drug from reaching the 4th
ventricle.
3. for perfusion of the 4th ventricle only, injections were made through a needle placed in the 4th
ventricle at coordinates AP -8.5 HD —4.5 and RL
0 (Snider and Niemer, 1961).
In all experiments, needle placement and drug
distribution were confirmed by infusion of methylene blue dye and postmortem examination of the
brain. All drugs infused intracerebroventricularly
were dissolved in artificial cerebrospinal fluid (CSF)
(Merlis, 1940, as modified by Feldberg et al., 1970)
in a volume of 0.05 ml followed by a CSF flush of
the same volume. Drugs administered systemically
were dissolved in saline.
The following drugs were used: a-chloralose (Es-
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tablissements Kuhlmann), decamethonium bromide (Sigma Chemical Co.), muscimol (Biosearch),
bicuculline methiodide (Pierce), clonidine HC1
(Boehringer Ingelheim), and y-aminobutyric acid
(Sigma Chemical Co.).
Statistical analysis was performed by using the
grouped and paired £-tests, analysis of variance and
Duncan's new multiple range test, and linear regression analysis by least squares. Criterion for statistical significance was p < 0.05. All values are reported as mean ± SEM.
Results
Effects of Muscimol Administered into the Left
Lateral Ventricle on Arterial Pressure and
Heart Rate
According to Antonaccio and Taylor (1977), muscimol administered into the 3rd ventricle of anesthetized cats in doses ranging from 0.03 to 3.0 jug/kg
produces dose-dependent reductions in arterial
blood pressure and heart rate. In our study, a similar
dose range of muscimol administered into the left
lateral ventricle and allowed to perfuse the entire
ventricular system of anesthetized cats produced a
dose-dependent reduction in arterial pressure. Experiments were performed in seven animals and the
data are illustrated graphically in the left side of
Figure 1. Responses were observed with a dose as
low as 0.05 ng and appeared maximal with a cumulative dose of 16.65 jug. Doses were treated in a
cumulative fashion as the r'^ponse seen with each
dose was maintained, and no evidence of recovery
was observed over the duration of the observation
period (30 minutes for the smaller doses and up to
2 hours for the larger doses). In terms of timeaction, arterial pressure began to fall within a minute or two after injection and the nadir was reached
nearly always by 10 minutes after injection. Intervals between doses of muscimol therefore were approximately 10 minutes. The baseline mean blood
pressures of these cats averaged 130 ± 6 mm Hg
and the fall in pressure was to an average absolute
value of 71 ± 8 mm Hg with the cumulative dose of
16.65 jug.
Heart rate also was decreased by muscimol, but
this was not reflected in the linear regression analysis of the data shown in the right side of Figure 1.
However, using analysis of variance and Duncan's
new multiple range test to analyze the data, a
significant reduction in heart rate was observed
with the two largest cumulative doses (6.65 and
16.65 jug). The baseline heart rates of these animals
averaged 197 ± 10 beats/min and the fall in heart
rate was to an average absolute value of 163 ± 5
beats/min with the cumulative dose of 16.65 /ig.
The largest dose of muscimol accumulated in the
intraventricular studies (16.65 jug) also was given as
a single intravenous bolus injection to seven animals. By this route, muscimol produced no significant changes in arterial pressure or heart rate.
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CIRCULATION RESEARCH
VOL. 47, No. 1, JULY 1980
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1 Changes in mean blood pressure (left panel) and heart rate (right panel) produced by muscimol administered in cumulative doses (indicated by the horizontal axis) into the entire ventricular system. Values represent the
mean ± SEM of data obtained from seven cats.
FIGURE
Baseline values for arterial pressure and heart rate
in these animals were 142 ± 7 mm Hg and 191 ± 7
beats/min, and at 10 minutes after injection of
muscimol (the time at which the peak effect of
muscimol was observed following intraventricular
administration) the corresponding values were 138
± 6 mm Hg and 189 ± 7 beats/min.
Studies Designed to Localize the CNS Site of
Action of Muscimol
Two types of studies were performed and consisted of observing arterial pressure and heart rate
changes following either (1) administration of muscimol into the left lateral ventricle and restricting
the drug to the lateral and 3rd ventricles by cannulating the Aqueduct of Sylvius, or (2) administration of muscimol into the 4th ventricle. Data obtained from both types of studies are presented in
Figure 2 and indicate significant dose-related decreases in pressure and rate when muscimol was
administered into and restricted to the 4th ventricle, but no significant dose-related changes in pressure and rate when muscimol was administered into
and restricted to the lateral and 3rd ventricles. The
decrease in pressure and rate with the highest cumulative dose of muscimol administered into the
4th ventricle was similar to that seen when this
dose was administered into the entire ventricular
system. The absolute values attained were 84 ± 12
mm Hg (from 141 ± 10 mm Hg) and 154 ± 9 beats/
min (from 198 ± 16 beats/min).
Peripheral Autonomic Nerves Involved in
Mediating Pressure and Rate Changes
Induced by Administration of Muscimol into
the 4th Cerebroventricle
The effect of bilateral vagotomy alone and vagotomy combined with bilateral stellate ganglionectomy on the heart rate and arterial pressure effects
of muscimol were evaluated and the data are presented in Figure 3. As can be seen, bilateral vagotomy per se had no significant effect on responses
produced by muscimol. Bilateral stellate ganglionectomy, however, prevented the dose-dependent
decreases in heart rate normally observed when
muscimol was administered into the 4th ventricle.
This procedure, however, did not prevent the normally observed dose-dependent decreases in arterial pressure, although a slight attenuation of these
responses was observed (see Fig. 3). Statistical analysis of the data revealed no significant differences
between the hypotensive responses in cats with
intact autonomic nerves, those with sectioned vagus
nerves, or those with vagus nerves sectioned and
stellate ganglia extirpated.
Comparison of the Hypotensive and
Bradycardic Effects of Muscimol with Those
of Clonidine
To obtain information on the potency and efficacy of muscimol administered into the 4th ventricle, we compared the depressor and bradycardic
responses obtained with this agent to those ob-
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CNS GAB A CONTROL OF CARDIOVASCULAR FUNCTION/ WMiford et al.
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2 Changes in mean blood pressure (left panel) and heart rate (right panel) produced by muscimol administered in cumulative doses (horizontal axis) into either the 4th ventricle (O) or into the lateral and 3rd ventricles (%).
Values represent the mean ± SEM of data obtained from seven and six cats, respectively.
FIGURE
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3 Effect of bilateral vagotomy (O) and vagotomy plus bilateral stellate ganglionectomy (9) on the changes
in mean blood pressure (left panel) and heart rate (right panel) produced by cumulative doses (horizontal axis) of
muscimol administered into the 4th ventricle. Values represent the mean ± SEM of data obtained from seven and four
cats, respectively.
FIGURE
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84
CIRCULATION RESEARCH
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FIGURE 4 Changes in mean blood pressure (left panel) and heart rate (right panel) produced by clonidine administered in cumulative doses (horizontal axis) into the 4th ventricle of vagotomized cats. Values represent the mean ±
SEM of data obtained from eight cats.
tained with clonidine, the prototype drug that acts
primarily in the hindbrain to lower blood pressure
and heart rate, (Schmidt, 1977). Clonidine was administered in three doses into the 4th ventricle of
eight vagotomized cats, and the data are summarized in Figure 4. As can be seen, dose-dependent
decreases in pressure and rate can be obtained with
doses of 1, 6, and 31 fig of clonidine. The maximal
effect of clonidine occurred with a cumulative dose
of 31 jug (see Fig. 4).
In five cats we observed that, once a maximal
hypotensive effect had been obtained with clonidine, the additional administration of muscimol
caused a further reduction in pressure of 18.4 ± 4.6
mm Hg (P < 0.05). When the converse experiment
was performed, i.e., clonidine was administered into
the 4th cerebroventricle of three animals in a dose
of 25 jttg after a maximal hypotensive effect of muscimol had been attained, no additional decrease in
arterial pressure occurred. Indeed, in all three experiments performed, only a pressor response occurred after the administration of clonidine.
A comparison of the maximal effect produced by
clonidine and muscimol on arterial pressure and
heart rate when administered into the 4th ventricle
is shown in Figure 5. The interesting finding was
that muscimol produced a greater hypotensive effect than did clonidine. However, the heart rate
effects of each agent were nearly equal.
Role of GABAergic Mechanisms in Pressure
and Rate Changes Induced by
Administration of Muscimol into the 4th
Ventricle
Two types of experiments were performed to
determine whether the hypotension and bradycardia produced by muscimol were caused by this
Muscimol
Clondre
Muscimol
Oomdne
5 Comparative effects of muscimol (seven cats)
and clonidine (eight cats) on mean blood pressure (left
panel) and heart rate (right panel). Control levels of
pressure and rate are indicated by the unfilled histograms, and the responses of mean blood pressure and
heart rate to cumulative dose regimens of muscimol
(16.65 fig) and clonidine (31 fig) producing maximal
responses are indicated by the cross-hatched histograms.
FIGURE
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85
CNS GAB A CONTROL OF CARDIOVASCULAR FUNCTION/ Williford et al.
Dose of GABA imgi
6 Peak changes in mean blood pressure (left
panel) and heart rate (right panel) produced by GABA
administered in increasing noncumulative doses into
the 4th ventricle of seven vagotomized cats. Values represent the mean ± SEM.
FIGURE
agent activating GABA receptors in the hindbrain
(i.e., in tissue in the vicinity of the 4th ventricle).
The first type involved observing whether the neurotransmitter, GABA, could produce the hypotension and bradycardia seen with muscimol. GABA
was administered into the 4th ventricle of seven
cats subjected to bilateral vagotomy. Each animal
received single doses of GABA consisting of 0.5, 2.5,
and 10 mg. At these doses, GABA produced dosedependent reductions in pressure and rate (Fig. 6).
These effects were transient (lasting from 10 to 30
minutes), and complete recovery to baseline values
was attained before administering each subsequent
dose.
The second type of experiment involved testing
the effect of the GABA receptor antagonist, bicuculline, on the hypotensive and bradycardic effects
of muscimol. In some experiments, bicuculline was
administered prior to muscimol to determine
whether the responses could be prevented. In other
experiments, bicuculline was administered after attaining the peak responses to muscimol to determine whether the responses could be counteracted.
These experiments all were performed in animals
subjected to bilateral vagotomy, and the drugs were
restricted to the 4th ventricle. The data from the
bicuculline pretreatment experiments appear in
Figure 7. The magnitude of the decreases in pressure and rate with a single injection of 16.65 jug of
muscimol given without bicuculline pretreatment is
indicated from the vertical scales of the unfilled
histograms in the figure. The cross-hatched histograms indicate the responses after administering
16.65 fig of muscimol to cats pretreated 10 minutes
earlier with bicuculline in doses ranging from 25 to
100 /tg injected into the 4th ventricle. Bicuculline at
these doses produced no significant changes in pressure or rate per se, but prevented the usual responses seen with 16.65 ng of muscimol.
In the experiments in which bicuculline was
tested for its capacity to reverse established responses obtained with muscimol, bicuculline in a
dose of 25 fig was first administered into the 4th
ventricle. Only slight and transient increases in
pressure and rate were observed (see representative
experiment depicted as Figure 8 and the unfilled
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FIGURE 7 Effect of bicuculline pretreatment on the hypotensive (left panel) and bradycardic responses (right
panel) produced by muscimol in four animals. Standard
errors of the mean are indicated on each histogram (see
text for details); a = significantly different compared to
muscimol alone.
HO
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FIGURE 8 Representative experiment depicting the interaction between muscimol and bicuculline (BMI) on
heart rate (top panel) and mean blood pressure (bottom
panel). (See text for details.)
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CIRCULATION RESEARCH
86
histogram of data summarized in Figure 9). After
an interval of 30 minutes, muscimol in doses required to produce pronounced depressor and bradycardic responses (this varied from cat to cat and
ranged from 2.5 to 16.65 fig) was administered (Fig.
8). Once responses reached the nadir and stabilized,
25 fig of bicuculline was readministered; this was
observed to counteract both the hypotensive and
bradycardic effects of muscimol (see Fig. 8). Readministration of muscimol abolished the antagonistic
effect of bicuculline. The decreases in pressure and
rate observed with muscimol were 73 ± 15 mm Hg
and 44 ± 9 beats/min, respectively. Readministration of bicuculline produced increases of 64 ± 12
mm Hg and 38 ± 10 beats/min, as indicated by the
cross-hatched histograms in Figure 9. Thus bicuculline administration completely reversed the hypotensive and bradycardic effects of muscimol. In
addition, and as indicated by the histograms in
Figure 9, bicuculline injected initially into the 4th
ventricle produced only slight increases in pressure
and rate, but when this agent was injected at a time
when muscimol-induced changes in pressure and
rate had occurred, pronounced rises in pressure and
rate were observed.
To test the selectivity of bicuculline to reverse
muscimol-induced decreases in pressure and rate,
bicuculline was administered to five vagotomized
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FIGURE 9 Effect of bicuculline treatment on the hypotensive and bradycardic responses produced by muscimol and clonidine. This figure illustrates the mean blood
pressure (left panel) and heart rate effects (right panel)
produced by bicuculline when administered alone (unfilled histograms—10 animals), after peak responses
were obtained with muscimol (cross-hatched histograms—seven cats), and after peak responses were obtained with clonidine (filled histograms—five cats).
Standard errors of the mean are also presented on each
of the histograms. (See text for details.) a = Significantly
different compared to changes produced by bicuculline
alone; b = significantly different compared to changes
produced by bicuculline in muscimol-pretreated group.
VOL. 47, No. 1, JULY 1980
cats that had been given clonidine by injection into
the 4th ventricle to lower pressure and rate. The
depressor and bradycardic effects of clonidine (dose
used was 31 fig) were 49 ± 7 mm Hg and 39 ± 13
beats/min, respectively. In contrast to what was
observed with muscimol, bicuculline administration
(25 jug) did not result in a reversal of these responses. Pressure increased by only 14 ± 4 mm Hg,
whereas rate increased by 0.8 ± 0.6 beats/min.
These values are depicted by the filled histograms
in Figure 9.
Discussion
Muscimol administered into the entire ventricular system of chloralose-anesthetized cats decreased
arterial pressure and heart rate. Effective doses
ranged from 0.05 to 16.65 ng. This is not a new
finding, as a similar dose range administered into
the 3rd ventricle of chloralose-anesthetized cats had
been reported by Antonaccio and Taylor (1977) to
produce hypotension and bradycardia as well as
dose-related reductions in renal sympathetic nerve
discharge. Both studies indicated that these effects
were due to a CNS rather than a peripheral site of
action, because muscimol in doses that caused
marked effects when administered by intracerebroventricular injection had no effect when given by
the intravenous route. The new observation that
has been made in the present study is that the site
of action where muscimol causes reductions in pressure and rate is in the hindbrain (areas surrounding
the 4th ventricle). We have excluded forebrain areas
as a site of action by demonstrating that muscimol
exerts no effect on arterial pressure and heart rate
when restricted to the lateral and 3rd ventricles. It
is not clear from our studies where muscimol acts
in the hindbrain to produce these changes in pressure and rate.
Our experiments also provide data indicating
that muscimol produces hypotensive and bradycardic effects by activating GABA receptors in the
hindbrain. This was demonstrated in the studies
using bicuculline, an agent previously shown to act
competitively to block the actions of muscimol and
GABA at the receptor level (Johnston, 1976). Bicuculline given into the 4th ventricle in doses which
had no significant pressure or rate effects prevented
the hypotensive and bradycardic effects of muscimol. In addition, bicuculline administered into the
4th ventricle counteracted the fall in pressure and
rate elicited by muscimol. The selectivity of action
of bicuculline was shown by its inability to counteract hypotension and bradycardia produced by administration of a non-GABAmimetic drug, clonidine, into the 4th ventricle. Antonaccio and Taylor
(1977) and Antonaccio et al. (1978b) also have used
bicuculline to counteract the central cardiovascular
actions of muscimol. However, the dose and method
of administering bicuculline (0.5 mg/kg, iv, and 50
/xg/kg into the 3rd ventricle) results in significant
pressure and rate effects per se (DiMicco and Gillis,
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CNS GAB A CONTROL OF CARDIOVASCULAR FUNCTION/ Williford et al.
1979). Hence the antagonism observed between bicuculline and muscimol in their study also could be
interpreted as being due to a physiological interaction. That is, the fall in pressure and rate produced
by one agent was being counteracted by the rise in
pressure and rate induced by a second agent.
The similarity between the CNS cardiovascular
effects of muscimol and GABA also argue for a
GABAergic mechanism being involved in decreases
in pressure and rate evoked by muscimol. Both
agents produced decreases in pressure and rate
when administered into the 4th ventricle, and the
arterial pressure effect was the most sensitive response produced by both substances. On the other
hand, when clonidine was administered into the 4th
ventricle, decreases in pressure and rate occurred
in parallel.
As pointed out by Antonaccio and Taylor (1977),
muscimol is more potent than clonidine in producing centrally mediated decreases in pressure and
rate. More importantly, it appears from our data
that muscimol has greater efficacy in lowering pressure than does clonidine. This was shown by the
larger reductions in pressure observed after muscimol as compared to clonidine, as well as by the
depressor response observed with a single dose of
muscimol after a plateau effect of clonidine had
been attained. It should be pointed out that muscimol did not produce an additional slowing in heart
rate after the peak effect of clonidine had been
attained. This suggests that clonidine and muscimol
cause a similar withdrawal of sympathetic tone to
the heart but not to the vasculature. Both agents
appear to have a relatively long duration of action,
as the responses are maintained for at least 30
minutes and the doses have to be treated in a
cumulative fashion.
The division of the autonomic nervous system
responsible for the bradycardic and hypotensive
effect of CNS GABA receptor stimulation is the
sympathetic nervous system. This was shown in the
present study by noting the absence of any modifying effect on muscimol-induced bradycardia by bilateral vagotomy and abolition of the response by
bilateral stellate ganglionectomy. Thus, cardiac
slowing appears to be due entirely to withdrawal of
sympathetic tone to the heart. Acute denervation
of the heart however, had no significant effect on
the hypotension produced by muscimol, suggesting
that this response was due to withdrawal of sympathetic tone to the vasculature. Consistent with
this suggestion are the earlier findings of Antonaccio and colleagues (Antonaccio and Taylor, 1977;
Antonaccio et al., 1978b) that muscimol administered into the 3rd ventricle produced dose-dependent decreases in spontaneous discharge of renal
sympathetic nerves.
Finally, the data of the present study indicate
that, whereas GABA receptor activation in the
hindbrain produces pronounced decreases in pressure and rate presumably secondary to a reduction
87
in central sympathetic outflow, these receptors are
not normally under the influence of GABA. This is
indicated by the fact that administration of bicuculline into the 4th ventricle, in doses which blocked
GABA receptors, had little or no effect on either
pressure or rate. Thus, while a GABAergic mechanism is present in the hindbrain and may be considered as another approach to developing antihypertensive agents, this mechanism may not be operating under normal circumstances.
References
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Instantaneous Femoral Artery PressureFlow Relations in Supine Anesthetized Dogs
and the Effect of Unilateral Elevation of
Femoral Venous Pressure
WALTER EHRLICH, ROBERT W. BAER, RONALD F. BELLAMY, AND RANDALL RANDAZZO
SUMMARY Instantaneous femoral artery pressure-flow (P/Q) relations were evaluated in consecutive 50-msec intervals of the pulseless flow changes during cardiac arrest in six anesthetized dogs and
in two anesthetized dogs with a-adrenergic blockade. In all 245 P/Q graphs obtained under conditions
of normal or elevated venous pressure, either with or without a blockade, the pressure-flow relations
are linear, and the zero-flow intercept on the pressure axis—reached in less than 3 seconds after the
onset of cardiac arrest—is markedly higher than the simultaneous venous pressure. We believe that
the zero-flow intercept is the effective downstream pressure to arterial flow and that the reciprocal of
the slope of the pressure-flow line indicates the arterial resistance. The elevation of femoral venous
pressure raises the effective downstream pressure and the resistance to arterial flow in the same leg.
The effective downstream pressure in the contralateral leg is raised also. a-Adrenergic blockade
abolishes the reflex change in the contralateral leg, but a change in P/Q relations in the manipulated
leg remains. We believe that the.central reflex change could be triggered by stretch receptors in the
wall of the small veins transmitted to the arterioles through a-adrenergic receptors. The encroachment
on the smallest arterioles by distended small veins and by the rise in interstitial fluid pressure might
be the local mechanism by which venous pressure elevation directly changes arterial P/Q relations in
the manipulated leg. CircRes 47: 88-98, 1980
IN 1933, Whittaker and Winton found in the isolated hindlimb of dogs linear pressure-flow relations
with a positive zero-flow intercept on the pressure
axis. In the intact hindlimb of dogs, Gomez and Veil
(1936) observed that the femoral artery pressure
fell during aortic occlusion to about 45 mm Hg. By
increasing the sympathetic nervous tone, Pappenheimer and Maes (1942) shifted the projection of
their straight femoral artery pressure-flow lines to
higher pressures at zero-flow. Conversely, lowering
sympathetic nervous tone shifted the projection of
their lines to lower pressures at zero-flow values.
From The Johns Hopkins University, Department of Psychiatry and
Behavioral Sciences and Department of Environmental Health Sciences,
Division of Physiology, Baltimore, Maryland and Walter Reed Army
Institute of Research, Washington, D.C.
Supported by Public Health Service Grant HL-10342.
Address for reprints: Walter Ehrlich, M.D., The Johns Hopkins University, School of Hygiene and Public Health, Division of Environmental
Physiology, 615 North Wolfe Street, Baltimore, Maryland 21205.
Original manuscript received September 15, 1978; accepted for publication February 21, 1980.
The femoral artery pressure-flow lines obtained
by Green et al. (1944) also led to markedly positive
zero-flow intercepts on the pressure axis, but the
pressure-flow lines were convex to the pressure axis.
Levy and Share (1953), Doyle (1953), and Levy et
al. (1954) also obtained convex pressure-flow lines.
These lines, however, point to a zero-flow intercept
of about zero pressure.
It is, of course, easy to dismiss the earlier reported
linear pressure-flow relations and the positive zeroflow pressures with the argument that they were
obtained with less advanced experimental technology than the convex pressure-flow relations with
zero-flow intercepts at zero pressure obtained more
recently. We believe, however, that the difference
between the results of these two groups can be
explained by the difference in experimental approach.
Whittaker and Winton (1933) and Gomez and
Veil (1936) followed the instantaneous fall of the
femoral arterial pressure from continuous direct
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Central nervous system mechanisms involving GABA influence arterial pressure and heart
rate in the cat.
D J Williford, B L Hamilton, J D Souza, T P Williams, J A DiMicco and R A Gillis
Circ Res. 1980;47:80-88
doi: 10.1161/01.RES.47.1.80
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