Download efferent vagal discharge and heart rate in response to

Br. J. Anaath. (1982), 54,1105
EFFERENT VAGAL DISCHARGE AND HEART RATE IN RESPONSE
TO METHOHEXITONE, ALTHESIN, KETAMINE
AND ETOMIDATE IN CATS
K. INOUE AND J. O. ARNDT
SUMMARY
The effects of methoheatone, Altfaesin, lr^tamjp^ and etomidate on single fibre discbarge of cardiac vagal
efferents and on heart rate were studied in cats. Cardiac vagal efferents were inhibited markedly and regularly
for equihypnotic doses of methohexitone (2.0mgkg~')) Althesin (0.1 ml kg"1) and ketamine (S.Omgkg"1),
but not of etomidate (0.8mgkg"'). These inhibitory effects were independent of arterial pressure and
mirrored the increases of heart rate elicited by the first three agents. Etomidate did not consistently affect
cardiac vagal discharge or heart rate. Thus methohexitone, Althesin and ketamine inhibit efferent cardiac
vagal drive by their central action independently of baroreflex function. This central vagolysis is probably the
cause of their positive chronotropk effects.
I.v. anaesthetics such as barbiturates, steroids and
phencyclidine derivatives cause tachycardia in man
and animals (Arndt and Zindler, 1978).
Since all these agents slow the isolated heart
(Reynolds, Chiz and Pasquet, 1970; Fischer, 1973;
Fischer and Marquort, 1977) and most of them also
markedly inhibit efferent sympathetic nerve activity
(Millar et al., 1970; Skovsted, Price and Price, 1970;
MacKenzie et al., 1976; Skovsted and Sapthavichaikul, 1977) the tachycardia seems to result
from an inhibition of cardiac vagal drive. However,
the mechanism is not generally agreed. The arterial
hypotension usually associated with anaesthesia has
tacitly been considered the prime mover which, via
baroreflex, would inhibit vagal cardiac tone, but
there is no direct proof for this notion and the
hypertensive action of ketamine, for example, is
certainly not compatible with such a view.
This study was undertaken to analyse the effects
of i.v. anaesthetics on cardiac vagal drive and it will
be shown that they attenuate markedly the activity
of cardioinhibitory neurones independently of
baroreflex function.
METHODS
The analysis of the effects of i.v. anaesthetics on
efferent vagal activity was performed on 58 cats with
a body weight between 2.0 and 4.2kg. In these
K. INOUE. M D., J. O. ARNDT, M.D ; Abteilung fur Experiment-
elle Anaesthesiologie des Institutes fur Anaesthesiologie der
Univeraitat DGsseldorf, Gebaude 23.02.01, Universititsstrasse
1, D-4000 Dusseldorf, Federal Republic of Germany.
0007-0912/82/101105-12 $01.00
experiments, vagal transmission to the heart was
blocked by vagal dissection in the course of fibre
dissection and the use of the muscle relaxant, pancuronium. We therefore evaluated the heart rate
response to these agents in additional experiments
on awake cats with intact vagal cardiac innervation
and, for comparison, also during nitrous oxide
anaesthesia.
Anaesthesia. For induction of anaesthesia, the
animals were placed in an airtight box into which
3-4% halothane in nitrous oxide in oxygen (3:1)
was administered. After intubation of the trachea,
the lungs were ventilated with a Starling pump to
provide an end-expiratory carbon dioxide concentration of about 4% measured continuously by massspectrometry (Perkin Elmer MGA 1100). Surgery,
which required 2 h on average to prepare for nerve
activity recording was performed under 0.5-1.5%
halothane in nitrous oxide in oxygen (3:1).
Halothane was discontinued at least 1 h before starting nerve activity recording and the animals were
immobilized with pancuronium, 0.2mgkg"' i.v.
initially and 0.1 mg kg"1 i.v. supplements as needed,
so that the actual experiments were performed
under nitrous oxide in oxygen (3:1). The animals
with an intact vagal innervation, in which the heart
rate responses to the agents were analysed using
nitrous oxide anaesthesia, received suxamethonium
lmgkg" 1 i.v. intermittently instead of pancuronium.
Body temperature was maintained at 37.5+0.5 °C
with a heating lamp.
Recording of nerve activity. The right cervical
© The Macmillan Press Ltd 1982
BRITISH JOURNAL OF ANAESTHESIA
1106
Identification of cardiac and non-cardiac vagal efvagus was dissected free in the neck, covered with
paraffin oil at body temperature to prevent drying ferents. Various vagal efferents (named type A, B
and filamented under a microscope until single ac- and C in the present study) were identified accordtive fibres were obtained from central nerve bundles ing to their response to a brief increase in arterial
separated from the nerve trunk. Spikes were picked pressure induced by occlusion of the descending
up with bipolar platinum -iridium electrodes and aorta with an inflatable balloon (Fogarty biliary
amplified with a capacitance-coupled amplifier of probe No. 5; fig. 1): type A activity increased when
our own design which had an input impedance of arterial pressure was increased. Such fibres, the
discharge of which has been shown to correlate
22 Mil and a bandpass between 30and 35 000Hz.
Nerve activity was monitored with a loudspeaker inversely with heart rate (Jewett, 1964; Inoue,
and an- oscilloscope (Tektronix type 565). The Samodelov and Arndt, 1980), are considered to be
spikes were shaped to standard pulses (5 V, 0.5 ms cardioinhibitory. Type B activity decreased with induration) with a Schmitt trigger to trigger reliably a creasing arterial pressure. Type C activity remained
digital counter of our own design which produced a unchanged in spite of increasing arterial pressure.
spike count at 2.5- or 5-s intervals. To calculate the
Types B and C are non-cardiac, although their
average discharge rate (spikess"1)) the 2.5- or 5-s target organs were not identified.
values were averaged for periods of 10-30 s. The
Evaluation of the drug effects. The drug effects on
technical details of the spike processing system have type A fibres were evaluated in two different ways:
been described in detail (Arndt, Morgenstern and (l)From the time-course of average discharge rate
Samodelov, 1977).
following drug injections either independently of
Parameters measured. Arterial pressure was meas-arterial pressure or at arterial pressures kept at or
ured electromanometricaUy (Statham P 37 B) with a greater than the pre-injection values by inflation of
fluid-filled catheter advanced into the thoracic aorta the aortic balloon. (2) By comparing pressurefrom a femoral artery and heart rate with a car- response curves determined before and 2 min after
drug injections. These pressure-response
diotachometer triggered by the e.c.g.
All data were recorded continuously oil a mul- curves were derived by relating average discharge
tichannel pen-recorder (Beckmann type RM dyno- rates with various arterial pressures increased or
decreased relative to the control pressure by inflatgraph recorder).
TIME SCALE (•)
ARTERIAL
PRESSURE
Aortic
SPIKES
Occlusion
l ! i l l i t i l|
EFFERENT
VAGAL
DISCHARGE
RATE
(Spikes/2.5s)
HEART
RATE _
(beotmin"1)
Typ. B
Typ. C
FIG. 1. Responses of various vagal efferents to an inHii™-H hypertension. Original recordings from three cats
nitrous oxide in oxygen anaesthesia. The transient increase in arterial pressure by aortic occlusion i
to an increase (type A), decrease (type B) or no rtungr in fibre discharge (type C).
VAGAL DISCHARGE AND HEART RATE IN CATS
ing or by rapidly deflating the aortic balloon (fig. 1).
Responses of non-cardiac type B and type C
efferents to the drugs were evaluated qualitatively
and judged as activation, no change or inhibition.
The following doses were used: methohexitone
2.0mgkg-', Althesin O.lmlkg- 1 , ketamine
S.Omgkg"1 and etomidate 0.8mgkg-'. They were
found to be equipotent according to pilot experiments in awake cats.
Experimental procedure. The experiments were
started at least 1 h after surgery when nerve activity,
arterial pressure and heart rate were in a steady state
and when several pressure-response curves were
identical. Each drug was administered within 3 s
through a catheter placed in the right atrium. The
drugs were administered in random sequence and
sufficient time, usually 45min, was allowed between each injection for complete recovery of the
variables studied.
XX
200
XX
1107
In the experiments for the evaluation of the
chronotropic effects of the agents in anaesthetized
cats, each drug was given in the same way as above,
but at least Smin after the injection of suxamethonium to avoid interference with cardiovascular effects of the muscle relaxant.
Data analysis. To demonstrate the time-course of
the drug effects on discharge rate of cardioinhibitory
vagal efferents the data are expressed as percentages
of the values before injection for each individual
fibre.
The pressure-response curves were constructed
for each individual fibre before and after drug injection. The discharge rates and corresponding arterial
pressures were averaged to derive the average
pressure-response curves.
The data are presented in means + SEM except
for the time-course of the drug effects. The differences between values before and after injection were
200
Methohexitone
(2 0mg kef1)
Althesin
(0 1ml kg'1)
150
/7=6
/7=6
LU
100
•J-
/ /
t-
cc
tr 200
J-
_l
10
10
°
L
l_l
0
200 r
10
y
UJ
i
150
100
Ketamine
l5 0mg kg"1)
150
Etomidate
IO8mg kg"1)
n-1
100
10
TIME
0
(mm)
FlG. 2. Heart rates after i.v. injections of the four anaesthetics in awake cats (mean ± SEM). Significance test
between the controls and postinjection values: x P < 0 . 0 5 ; x x P < 0 . 0 1 .
10
BRITISH JOURNAL OF ANAESTHESIA
1108
tested with Student's ttest for paired samples, since
Drug effects on cardiac vagal efferents in anaestheteach cat served as its own control. Differences were ized cats. The discharge rates of cardioinhibitory
vagal efferents always decreased with methohexconsidered significant when P<0.05.
itone, Althesin and ketamine, but their responses to
etomidate were unpredictable. As shown in original
RESULTS
recordings (fig. 3), the average discharge rates are
Hypnotic and chronotropic effects of the drugs in awake much less after than before the injection of
cats. The doses used were found to be equipotent in methohexitone, Althesin and ketamine, but there
their hypnotic effects by pilot studies on awake cats. was hardly a response to etomidate.
Awake cats lay down, closed their eyes, and lost
To exclude the initial, transient decrease in arteritheir righting reflexes within 5-25 s after injection al pressure seen in figure 3 as a possible factor for a
and woke up 4-6 min later as judged by their ability baroreflex-mediated vagal inhibition, the decrease
to raise their heads and open their eyes.
in pressure was prevented by balloon occlusion of
As is seen in figure 2, this was accompanied by an the descending aorta in some experiments.
abrupt increase in heart rate by about 40 beat min-1
In the example shown in figure 4, vagal discharge
within 30 s after injection of methohexitone and rate clearly decreased following methohexitone in
Althesin. With ketamine, the increase in heart rate spite of constant arterial pressure and with Althesin
by about 20 beat min-1 developed gradually and and ketamine even when arterial pressure was inreached its maximum 2 min after injection. Etomi- creased. The last is worth stressing because indate had no consistent effect except for a transient creased arterial pressure by itself in the absence of
increase immediately after the injection.
anaesthetics activates vagal discharge of type A
T I M E SCALE
(*)
ARTERIAL
PRESSURE
200
H kPtO
200
20
100
10
0
0
100
1
SPIKES
EFFERENT
VAGAL
DISCHARGE
RATE
(Spik*i/S»)
20
0
Methohexitone
(2.0 mg kg-1|
Althesin
(01ml kg'1)
TIME SCALE (»)
(mmHo) (kPo)
ARTERIAL
200
PRESSURE
L20
100
"U
SPIKES
EFFERENT
VAGAL
DISCHARGE
RATE
20
(Spikts/St)
Ketamine
l5 0mg kg"1)
Etomidate
10 8 mg kg"1!
FIG 3. Effects of the four anaesthetics on discharge rates of cardioinhibitory vagal efferents. Original
recordings from four cats under nitrous oxide in oxygen anaesthesia.
VAGAL DISCHARGE AND HEART RATE IN CATS
1109
ARTERIAL
PRESSURE
SPIKES
EFFERENT
VAOAL
DISCHARGE
RATE
(Spikm/Ss)
—'-jttm
Etomidate
(0.8 mg kg"1)
FIG 4. Effects of the four anaesthetics on discharge rates of cardioinhibitory vagal efferents with constant or
slightly increased arterial pressure. Original recordings from three cats under nitrous oxide in oxygen
anaesthesia. The initial decrease in arterial pressure seen in figure 3 was prevented here by controlled balloon
occlusion of the descending aorta.
fibres (fig. 1). Such an activation, in fact, is seen
with etomidate in figure 4.
Methohexitone, Althesin and ketamine had similar effects in all experiments, as is seen in figure 5.
Irrespective of whether the early decrease in arterial
pressure was prevented, discharge rate decreased
without exception during the first 5 min after injections of these three agents and returned gradually to
the controls during the following 30 min. In contrast
to this, etomidate did not produce regular changes
in discharge rates, irrespective of the arterial pressure. The differences in the time courses of vagal
activity are also of interest. After injections of
methohexitone and Althesin, discharge rates attained their minimum rapidly during the 1st min,
but more slowly within 2 min following ketamine.
We considered it therefore appropriate to compare
the inhibitory action of these agents for their values
2 min after injections, particularly since, at this
time, arterial pressure had reached the pre-injection
values in all experiments.
For quantitative analysis of the fibre response,
pressure-response curves were determined for each
cardioinhibitory fibre before and 2 min after drug
injections. The original recording in figure 6 shows
how these response curves were derived. In the
control, nerve discharge rate increased above the
preocclusion value when arterial pressure was increased for about 25 s by inflating the aortic balloon
and decreased below the preocclusion value when
the balloon was deflated. Clearly, 2 min after the
injection of ketamine, average discharge rate was
less for each arterial pressure value which was of the
same magnitude as during the control. Thus,
ketamine inhibits nerve activity independently of
arterial pressure.
Figure 7 was obtained by relating discharge rates
and the corresponding pressure values before and
2 min after injections for each fibre. Except for
etomidate, the pressure-response curves are dis-
1110
BRITISH JOURNAL OF ANAESTHESIA
200
EFFERENT
VAOAL
OISCHAROE
RATE
MEAN
ARTERIAL
PRESSURE
Methohexitone
(2.0mgkg' 1 )
200
150
150
100
100
50
50
0
0
130
130
100
100
Althesm
(0.1 ml kg'1)
•J:-.-.-.~.~,.-t
(H)
70
EFFERENT
VAOAL
OISCHAROE
RATE
200
70 L
W/Ketamine (5.0 mg kg'1)
(00
" /\
Etomidate (0.8 mgkg'1)
150
100
50
0
MEAN
ARTERIAL
PRESSURE
130
100
70 >-
»
i5 20
Time (min)
25 30
5
10
15
20
25
30
Time (min)
FIG S. Time course of the discharge of cardioinhibitory vagal efferents foUowingithe injection of the four
^anaesthetics. Data from 19 cats under nitrous oxide in oxygen anaesthesia. The initial decrease in arterial
pressure was either not prevented (continuous lines) or was prevented by aortic occlusion (dotted lines).
placed to lower activity and their slopes are reduced.
Methohexitone, Althesin and ketamine not only
inhibit vagal discharge independently of arterial
pressure but, in addition, they also inhibit the pressure-dependent fibre response as indicated by the
reduced slopes.
Taking the average discharge rate at the control
pressures (centre point of the curves) as 100, the
activity is reduced by 90, 73 and 55% for Althesin,
methohexitone and ketamine, respectively. Thus,
for equipotent doses, the extent of the pressureindependent, central inhibition of vagal cardioinhibitory efferents is different for various agents. It
is most marked with Althesin, followed by
methohexitone and ketamine, whereas etomidate
has no effect.
Drug effects on non-cardiac vagal efferents in anaes-
thetized cats. Non-cardiac fibres responded less uniformly to the anaesthetics than the cardiac. According to table I, inhibition prevailed with methohexitone and Althesin which, however, had no effect on
about one-third of type C fibres. This nonuniformity was more pronounced with ketamine. It
inhibited only a minority of non-cardiac fibres, had
no effect in about half of them and even activated
some. The response-pattern of non-cardiac fibres
agreed with that of the cardiac only in case of
etomidate. Thus, the same anaesthetic may act differently on different neurones (type A, B and C)
whereas the particular cardioinhibitory type A
VAGAL DISCHARGE AND HEART RATE IN CATS
1111
Control
TIME SCALE (»)
(mmHg) (kPo)
ARTERIAL
200
PRESSURE
SPIKES
EFFERENT
VAGAL
DISCHARGE
RATE
(Splk»»/2S«)
0
2min after Kttamin* I5mg kg"1iv)
TIME SCALE (*)
(mmHgMkPa)
gMk
ARTERIAL
2
PRESSURE
1oo
,.,
i.o
o-L
o-L o
SPIKES
EFFERENT
VAOAL
DISCHARGE
RATE
(Splk*i/2Si)
40
20
0
FIG 6. The discharge of a cardioinhibitory vagal fibre at three different arterial pressures before and 2 min
after injection of ketamine. Original recording from a cat under nitrous oxide in oxygen anaesthesia. Arterial
pressures were altered by controlled occlusion of the descending aorta by a balloon.
neurone is inhibited by various anaesthetics
(methohexitone, Althesin and ketamine).
etomidate. These effects correspond, by and large,
with our observation in awake cats shown in
Chronotropic effects of the agents in anaesthetized figure2.
cats with intact cardiac vagal innervation. The
chronotropic effects could not be analysed in these
experiments because of the atropine-like action of
pancuronium and the disruption of the vagal nerves
in the course of fibre dissection. Therefore, it was
necessary to evaluate the heart rate responses to the
agents in cats with an intact vagal innervation, but
otherwise under similar conditions.
According to table II, the heart rate increased
2 min after injections of methohexitone, Althesin
and ketamine by 36, 52 and 23 beatmin"1, respectively, and there was on average no change with
DISCUSSION
Our experiments were primarily designed to study
the effects of anaesthetics on cardiac vagal drive and
a central question is if the fibres of which responses
were tested here, do innervate the heart. In general,
it is difficult to identify the organ specificity of vagal
efferents. Such differentiation has been attempted
according to their response to variations in arterial
pressure and lung mechanics. In spontaneously
breathing dogs, Jewett (1964) discriminated seven
BRITISH JOURNAL OF ANAESTHESIA
1112
15
15
Althesm
(01ml kg*1)
Methohexitone
l2 0mg kg'1
10
10
n=6
1
10
DC
50
100
150
200
5 0 1 0 0 1 5 0 2 0 0 2 5 0
250
<
O 15
15
Ketamine
15.0 nig kg'1
Etomidate
(08mg kg'1)
10
10
30 (kPo)
100
150
200
250
50
100
MEAN ARTERIAL PRESSURE
150
200
250
(mmHg)
FIG. 7. Pressure-response curves of cardioinhibitory vagal efferents in the control (O) and 2 min after the
injection ( • ) of the four anaesthetics. Results from cats under mtroui oxide in oxygen anaesthesia
(mean±SEM). Significance test between the controls and postinjection values. x P < 0 . 0 5 ; x x P < 0 . 0 1 .
different fibre groups. His type I fibres were activated only during expiration, their discharge increased with increasing arterial pressure and correlated inversely with heart rate. In Jewett's view,
which was later adopted by several others (Katrona
et al., 1970; Hakumaki, 1972; Davidson, Goldner
and McCloskey, 1976) these fibres are cardioinhibitory. Since we worked with ventilated and paralysed
cats, neither lung mechanics nor the heart rate
response which was blocked by the vagolytic action
of the muscle relaxant, could be taken into consider-
ation. Nevertheless, our type A fibres conform to
Jewett's type I in one important point, in that they
were not only activated by an increase in arterial
pressure, but their discharge followed without delay
the induced arterial pressure change and correlated
closely with the arterial pressure as shown by the
pressure-response curves in figure 7. By these
criteria, the type A fibres the discharge rate of which
has previously been shown to correlate with heart
rate (Inoue, Samodelov and Arndt, 1980), could be
distinguished clearly from non-cardiac vagal fibres.
VAGAL DISCHARGE AND HEART RATE IN CATS
1113
TABLE I. Effects of the four anaesthetics on acttmties of various vagal efferents
Methohexitone
2.0mgkg" 1
Althesin
0.1 ml kg"1
Ketamine
O.Smgkg"1
Inhibition
Activation
No change
8/8
6/6
7/7
3/7
3/7
1/7
TypeB
Inhibition
Activation
No change
5/5
3/3
2/4
1/4
1/4
2/4
2/4
TypeC
Inhibition
Activation
No change
11/16
12/17
5?16
5/17
3/13
3/13
7/13
4/11
2/11
5/11
Fibre
Response
Type A
Etomidate
TABLE II. Heart rate (beat mtn~l) after injections of the four anaesthetics (mean 1 SEM). *P < 0.05, **P < 0.01
Tune after injection (min)
Drug
0.25
Methohexitone
2.0mgkg" 1
(«=6)
158±8
Althesin
0.1 ml kg"1
(» = 6)
0.5
177±9
*
*
195±3
*
*
155114
180112
197113
Ketamine
159110
188112
**
Etomidate
161112
173111
n.s.
10
194±5
*
*
193±5
*
*
204113
206113
207113
207113
192117
180112
*
183111
*
182111
*
181111
*
179111
**
176112
n.s.
173112
n.s.
168113
n.s.
164113
n.s.
162114
n.s.
160114
n.s.
161111
n.s.
Our non-cardiac type B and C fibres which were
either inhibited or not affected by the induced arterial pressure change, contained a variety of fibres.
Since we were only interested to observe how these
non-cardiac fibres would respond to anaesthetics in
comparison with cardioinhibitory type A fibres, no
further attempts were made to identify their target
organs.
The atropine-like action of pancuronium and
vagal dissection in the course of the nerve filamentation blocked the effects on heart rate which were
seen after drug injection in conscious and anaesthetized cats with intact vagal innervation. Irrespective
of the actual heart rate response, the type A fibres
are cardioinhibitory and their activity may be taken
as a neurophysiological correlate of cardiac vagal
tone.
Nitrous oxide, which renders cats analgesic with-
*
194±4
*
*
191 ± 5
*
184±5
*
out impairing evoked potentials in the brain, has
been advocated as the most suitable anaesthetic for
neurophysiological work (Venes, Collins and Taub,
1971). It was preferred also because there is evidence that nitrous oxide does not alter the heart rate
effects of other anaesthetics. In man, the heart rate
increased little (2.65%) when nitrous oxide was
added to light halothane anaesthesia (0.8-1.2% in
oxygen) and by even less (0.82%) when nitrous
oxide was added to deep halothane anaesthesia
(1.2-2.0% in oxygen) (Smith et al., 1970). Finally,
in dogs, addition of nitrous oxide to halothane
anaesthesia (0.5-2.5% in oxygen), elicited the same
degree of bradycardia found with halothane in oxygen (Smith and Corbascio, 1966). It appears
reasonable to interpret the described responses of
the type A fibres as the drug action perse rather than
as a consequence of their additive action with nitr-
1114
ous oxide.
Methohexitone, Althesin and ketamine, but not
etomidate, inhibited without exception cardioinhibitory vagal efferents. These fibres originate
from the vagal nuclei in the medulla, the nucleus
ambiguus and vagalis dorsalis (Spyer, 1980), and
their discharge constitutes the neurophysiological
correlate of cardiac vagal tone and thus of heart rate
(Jewett, 1964). In the dose range used in this study,
none of these agents exerts an atropine-like
peripheral action (McGrath, MacKenzie and Millar,
1975; MacKenzie et al., 1976). All have a negative
chronotropic effect on the isolated heart (Reynolds,
Chiz and Pasquet, 1970; Fischer, 1973; Fischer and
Marquort, 1977) and, with the exception of
ketamine, all inhibit efferent sympathetic drive
(Millar etal., 1970; Skovsted, Price and Price, 1970;
MacKenzie et al., 1976; Skovsted and Sapthavichaikul, 1977). The positive chronotropic actions
of these agents are therefore the consequence of an
inhibition of cardiac vagal drive. This applies also to
ketamine, which activates efferent sympathetic
drive (Niederstrasser, 1981) but the action of which
in producing tachycardia is nevertheless blocked by
atropine rather than by propranolol (Traber, Wilson
and Priano, 1970a, b).
In our neurophysiological studies, the drug effects on heart rate could not be identified. When
cardiac vagal innervation was intact, the heart rate
responded similarly in the conscious state and under
nitrous oxide anaesthesia. Under both conditions,
the tachycardia, in correspondence with the degree
of vagal inhibition, was most pronounced with
Althesin followed by methohexitone and ketamine
whereas etomidate had no effect. It seems permissible, therefore, to consider the responses of cardiac
vagal efferents to these agents as a principal cause of
their heart rate effects.
The inhibition of vagal efferents was shown to be
independent of arterial pressure as it occurred at
constant and even at increased pressure, which usually activates these fibres. This conclusion is also
supported by the clear-cut displacement of the
pressure-response curves to lower activities with all
agents except etomidate. Pressure-dependent effects via arterial baroreflexes cannot, therefore, explain the fibre responses.
Also probably excluded are drug-induced
changes in baroreceptor activity which, in the presence of constant arterial pressure, might have altered afferent baroreceptor drive. Methohexitone,
for example, excites baroreceptors (Schumacher
BRITISH JOURNAL OF ANAESTHESIA
and Arndt, 1978). This, however, should activate
cardiac vagal efferents but not inhibit them.
Ketamine has no effect on baroreceptors (Slogoff
and Allen, 1974; Hagenau, Pietsch and Arndt,
1976), but nevertheless inhibits vagal efferents. A
peripheral event via the afferent discharge of arterial
baroreflexes is therefore an unlikely causal factor for
the inhibitory action of these agents on cardiac vagal
tone. Hence one can conclude that, contrary to the
widely held view, the vagolytic action of certain i.v.
anaesthetics is of central origin and independent of
arterial pressure and baroreflex function.
This conclusion does not, however, deny the
importance of baroreflexes in anaesthesia. In fact,
the well-known impairment of baroreflex function
(Morrison, Walker and Richardson, 1950; Bristow
et al., 1969; MacKenzie et al., 1976) is seen also in
our experiments in the reduced slopes of the
pressure-response curves of cardioinhibitory vagal
efferents, which are particularly pronounced with
methohexitone and Althesin. This shows that these
agents, in addition to their central vagolytic effects,
also attenuate the baroreflex-mediated, pressuredependent control of heart rate. Hence, the action of
anaesthetic agents on the cardiac vagus has two
different aspects. They exert a central vagolytic
action which is independent of arterial pressure and
which determines heart rate. They also attenuate the
pressure-dependent responsiveness of cardiac vagal
tone and thereby the body's capability to stabilize
reflexly its arterial pressure against challenges such
as blood loss and orthostatic stress by the appropriate heart rate responses.
Although the neurophysiological evidence is lacking at present, it is presumably the central vagolytic
action of anaesthetics that determines the heart rate
response in other species. First, heart rate is dominated physiologically by vagal rather than sympathetic influences (Bishop, Peterson and Horwitz,
1976). Second, in animals, most i.v. anaesthetics
inhibit efferent sympathetic drive which was demonstrated for thiopentonc in man also (Wallin and
Konig, 1976). Third, the heart rate responses to the
agents studied correspond roughly with those found
in other species. Whereas etomidate affects heart
rate little in dogs as well as in man, the others elicit
pronounced tachycardia in both species (Patschke et
al., 1977; Arndt and Zindler, 1978). In nonpremedicated man, for example, heart rate increases
by 20 beatmin"1 or 30% on average for recommended clinical doses of barbiturates, Althesin and
ketamine, and by 45 beat min~' after complete
VAGAL DISCHARGE AND HEART RATE IN CATS
1115
carotid sinus reflex. Am. J. Phynol., 218, 1030.
Inoue, K., Samodelov, L. F., and Amdt, J. O. (1980). Fentanyi
activates a particular population of vagal efferent* which are
cardioinhibitory. Naunyn Schmudtbtrg's Arch. Pharmacol.,
312, 57.
Jewett, D. L. (1964). Activity of single efferent fibres in the
cervical vagus nerve of the dog, with special reference to
possible cardioinhibitory fibres. / . Physiol. (Land.), 175, 321.
McGrath, J. C , Mackenzie, J. E., and Millar, R. A. (1975).
Effects of ketamine on central sympathetic discharge and the
baroreceptor reflex during rfnrhflTvr*q* ventilation. Br. J.
Anaath., 47,1141.
MacKenzie, J. E., McGrath, J. C , Tetrault, J. P., and Millar,
R. A. (1976). The effects of Althesin and thiopentone on
sympathetic and baroreflex activity. Can. Anaath. Soc. / . , 23,
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Millar, R. A., Warden, J., Cooperman, L. H., and Price, H. L.
(1970). Further studies of sympathetic actions of anaesthetics
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Morrison, J. L., Walker, H. A., and Richardson, A. P. (1950).
The effect of pentobarbital on response of cardiovascular
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Int. Pharmacodyn., 82, 53.
Niederstrasser, D. (1981). Vergjeich der Wirkung von Ketamin
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physiologically relevant information regarding systemic blood
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pressure encoded m the carotid sinus baroreceptor discharge
intravenous induction agents (thiopentone, methohexitone,
pattern. / . Physiol. (Land.), 268, 775.
propanidid, Althesin, ketiunine, piritramide and etomidate) on
Zindler.M. (1978). Effects of intravenous anesthetics on the
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Bnstow, J. D . , Prys-Roberts, C , Fisher, A., Pickering, T. G.,
and Sleight, P. (1969). Effects of anesthesia on baroreflex
Robinson, B. F., Epstein, S. E., Beiser, G. D . , and Braunwald,
control of heart rate in man. Antsthawlogy, 31,422.
E. (1966). Control of heart rate by the autonomic nervous
system. Cm. Res., 19,400.
Davidson, N. S., Goldner, S., and McCloskey, D. I. (1976).
Respiratory modulation of baroreceptor and chemoreceptor
Schumacher, I. G., and Amdt, J. O. (1978). Der Effekt von
reflexes affecting heart rate and cardiac vagal efferent nerve
Methobexital, Fentanyi, Dehydrobenzperidol sowie von
activity. / . Phynol. (Loud.), 259, 523.
Chloralose auf die Aktivitat der Barorezeptoren des Aortenbogens decerebrierter Katzen. Anaesthesist, 27,10.
Fischer, K. (1973). Vergleichende tierexperimentelle UnterSkovsted, P., Price, M. L., and Price, H. L. (1970). The effects
suchungen zum Finflnft verschiedener Narkotica auf das Herz;
of short-acting barbiturates on arterial pressure, preganglionk
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Sapthavkhaikul, S. (1977). The effects of etomidate on
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Marquort, H. (1977). Experimental investigations on the
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Etomidate—An Intravenous Hypnotic Agtnt(cd. A. Doemcke), Slogoff, S., and Allen, G. W. (1974). The role of baroreceptors in
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effects of nitrous oxide during halothane anesthesia in the dog.
von Halothan und Enfhirane sowie von Propanidid und KetaAnesthestology, 27, 560.
min auf die Aktivitat der Barorezeptoren des Aortenbogens
Eger, E. I., n, Stoelting, R. K., Whayne.T. F.,Cullen, D.,
decerebrierter Katzen. Anaesthetist, 25,331.
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pathomimetic responses to the addition of nitrous oxide to
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Spyer, M. (1980). Neural organisation and control of barorecepKatona, P. G., Poitras, J. W., Barnet, G. O , and Terry, B. S.
tor reflex. Rev. Physiol. Biochem. Pharmacol., 88,24.
(1970). Cardiac vagal efferent activity and heart period in the
vagolysis with atropine 0.04mg kg"1 (Robinson et
al., 1966). The estimate based on this comparison
agrees fully with the neurophysiologically
documented vagal inhibition in case of ketamine,
but is smaller for Althesin and methohexitone. Yet,
considering the dose-dependency of the heart rate
effects (Patschke et al., 1977) and the problem of
comparing equipotency of doses between species,
not much emphasis can be put on these differences.
It is presumably, therefore, the central vagolytic
action which determines the heart rate response to
these agents in man also.
The central inhibition of cardiac vagal neurones
was- demonstrated here neurophysiologically and
found to be independent of baroreflex function and
to differ in degree for equihypnotic doses of Althesin, methohexitone and ketamine. Etomidate had
no consistent effect on cardiac vagal drive.
BRITISH JOURNAL OF ANAESTHESIA
1116
Trabcr, D. L., Wilson, R. D , and Priano, L. L. (1970s). The
effect of beta-adrenergic blockade on the cardiopulmonary
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(1970b). A Hftail>H study of the cardiopulmonary
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RESPONSE VAGALE EFFERENTE ET FREQUENCE
CARDIAQUE APRES INJECTION DE
METHOHEXITONE, D'ALTHESIN, DE
KETAMINE ET D'ETOMIDATE CHEZ LE CHAT.
EFFERENTE VAGUSENTLADUNG UND
HERZFREQUENZ NACH METHOHEXITAL,
ALTHESIN, KETAMIN UND ETOMIDATE
BEI KATZEN
ZUSAMMENFASSUNG
Die chronotropen Effekte von Methohexital, Althesin, Ketamin
und Etomidate auf die FntlaHnng riner Faser des efferenten
Herzvagus und auf die Herzfrequenz wurde an Katzen untersucht. Der efferente Herzvagus wurde ausgepragt und regelmafiig durch aquipotene Dosen von Methohexital (S.Omgkg"1)
Althesin (O.lmlkg" 1 ) und Ketamin (5,0mgkg~ l ), aber nkht
durch Etomidate (O.Smgkg"1) inhibiert. Diese inhibitorachen
Effekte waren nnahhangig vom arteriellen Druck und spiegelten
den Anstieg der Herzfrequenz, die durch die ersten drei Substanzen ausgeldst worden war, wkder. Etomidate beeinflufite weder
die Entladung des Herzvagus noch die Herzfrequenz. So inhibieren also Metohexital, Althesin und Ketamin den efferenten
Herzvagus durch ihre zentrale Wirkung unabhangig von der
Funktkra der Baroreflex-Funktion. Diese zentrale Vagolyse ist
wahrscheinlich die Ursache ihres positiven chronotropen Effektes.
DESCARGA VAGAL EFERENTE Y RTTMO
CARDlACO EN RESPUESTA A METOHEXITONA,
ALTESINA, QUETAMINA Y ETOMIDATO EN
LOS GATOS
RESUME
SUMAJUO
Nous avons etudie les effets chronotropes de la methohexitone,
de 1'Althesin, de la ketamine et de l'etomidate sur la
decharge d'une fibre unique des efferents cardiaques vagaux
et sur la frequence cardiaque chez le chat. Les efferents
cardiaques vagaux etaient inhibes de facon marquee et
reproductible pour des doses equihypnotiques de methohexitone
(2,0mgkg-') d'Althcsin (O.lmlkg"1) et de ketamine
(S.Omgkg"1) mais pas d'etomidate (0,8mgkg~')- Ces effets mhibiteurs etaient independants de la pression arterielle et refletaient les augmentations de frequence cardiaque induites par
les trois premiers agents. L'etomidate n'avait reguliirement pas
d'eifets stir la decharge cardiaque vagale ou la frequence cardiaque. Ainsi la methohexitone, 1'Althesin et la ketamine inhibent la
transmission vagale cardiaque efferente par leur action centrale
independemment du baroreflexe. Cette vagolyse centrale est
probablement la cause de leurs effets chronotropes positifs.
Se llevaron a cabo estudios sobre los efectos cronotropicos de la
metohexitona, la altesina, la quetamina y el etomidato en la
descarga de fibra unica de los eferentes vagales cardiacos y en el
ntmo cardiaco. Los eferentes vagales cardiacos fueron inhibidos
de manera marrada y regular por dosis equihipnoticas de
metohexitona (2,0mgkg~ 1 ), de Altesina (0,1 ml/kg"1) y de
quetamina (5,0 mg/kg"), perono fue asi por las de etomidato
(0,8 mg/kg" 1 ). Dichos efectos inhibitorios fueron independientes
de la presion arterial y reflejaron los aumentos del ritmo cardiaco
producidos por los tres pnmeros agentes. El etomidato no afecto
la descarga vagal cardiaca ni tampoco el ritmo cardiaco, y eso de
manera uniforme y constante. Entonces, la metohexitona, la
Altesina y la quetamina inhiben el impulso vagal cardiaco
eferente por su accidn central, independientemente de la funcion
de baroreflejo. Esta vagblisis central constituye probablemente la
causa de sus efectos cronotropicos posirivos.