Download cardiovascular effects of ketamine in the pithed rat, rabbit and cat

Br.J. Anaesth. (1976), 48, 935
CARDIOVASCULAR EFFECTS OF KETAMINE IN THE
PITHED RAT, RABBIT AND CAT
A. S. CLANACHAN, J. C. MCGRATH AND J. E. MACKENZIE
SUMMARY
The effects of i.v. ketamine on arterial pressure and heart rate were examined in pithed rats, rabbits
and cats. In all three species ketamine caused a brief decrease in arterial pressure and heart rate. In
the rat, but not in the other two species, this initial decrease in arterial pressure was followed by a
pressor response which was resistant to oc-adrenoceptor blockade, depletion of tissue noradrenaline
stores and adrenalectomy. It is concluded that the peripherally mediated pressor response found in
the pithed rat is specific to this species, is not a result of liberation of peripheral catecholamines and
does not explain the pressor effect of ketamine found in mnn and several animal species.
Ketamine increases arterial pressure and heart rate in
man and in several animal species (Domino, Chodoff
and Corssen, 1965; McCarthy et al., 1965) by effects
exerted via the autonomic nervous system (Traber
and Wilson, 1969; Schwartz and Horwitz, 1975).
However, it has also a direct negative inotropic action
on the myocardium (Dowdy and Kaya, 1968; Fischer,
1973; Treese, Niemezyk and Reuther, 1973; Schwartz
and Horwitz, 1975), so that its effect on arterial
pressure may consist of an increase, a decrease, or a
biphasic effect according to the experimental conditions and dose employed (McCarthy et al., 1965;
Dowdy and Kaya, 1968; Traber and Wilson, 1969;
McGrath, MacKenzie and Millar, 1975).
In a study designed to eliminate the influence of the
central nervous system, Chang, Chan and Ganendran
(1969) found that ketamine 2 mg/kg i.v. caused an
increase in arterial pressure in the pithed rat which
was decreased by the a-blocker phentolamine,
reserpine pretreatment or adrenalectomy, and which
they attributed to a release by ketamine of catecholamines from the peripheral sympathetic nervous
system. In a more recent study of the effects of
ketamine on peripheral autonomic neurotransmission
in the pithed rat (Clanachan and McGrath, 1975),
ketamine caused a biphasic change in arterial pressure.
The present work was designed to investigate this
response further and extend the study to two further
species, the rabbit and cat.
METHODS
The animals used were Sprague-Dawley rats
(200-250 g), New Zealand White rabbits (3.03.5 kg) and cats (3—4 kg). The animals were pithed
under halothane anaesthesia—rats and cats by the
method of Gillespie, MacLaren and Pollock (1970),
rabbits by the method of McGrath and MacKenzie
(1976). Rats were given pancuronium bromide
2 mg/kg, rabbits and cats gallamine 1 mg/kg, and
respiration with 100% oxygen (Harvard ventilator)
was adjusted to give an end-tidal carbon dioxide
concentration of 4% (Beckman LB2 medical gas
analyser).
A. S. CLANACHAN,* B.SC., PH.D.; I. C. MCGRATH, t B.sc.,
PH.D.; J. E. MACKENZIE, B.SC., PH.D., M.P.S.J University
The left carotid artery was cannulated for measurement of arterial pressure (Bell and Howell transducer).
Heart rate was derived from the arterial pressure
pulse with a Devices ratemeter and displayed,
together with arterial pressure, on a Devices MX4 or
M19 recorder. Therightjugular vein was cannulated
for the administration of drugs. Stimulation of the
sympathetic outflow, where appropriate, was accomplished using the tip of the pithing rod, placed in
the appropriate region of the spinal canal, and an
indifferent electrode placed under the skin (Devices
gated pulse generator and isolated stimulator, 1-ms
pulses, supramaximal voltage (nominal 70-100 V) at
the frequencies indicated in the text). The rectal
temperature of the rats was maintained at 37 + 1 °C
using a tungsten lamp, and of the rabbits and cats at
38 + 0.5 °C by means of a Palmer homoeothermic
blanket.
Department of Anaesthesia, Royal Infirmary, Glasgow
G4 0SF.
Present addresses:
* Department of Pharmacology, University of Alberta,
Edmonton, Alberta, Canada.
•f Institute of Physiology, University of Glasgow,
Glasgow G12 8QQ.
Acute adrenalectomy was performed in three rats
through an abdominal incision, following pithing. One
rat was pithed having been obtained commercially
after adrenalectomy had been performed (Scientific
Products, Margate).
936
BRITISH JOURNAL OF ANAESTHESIA
Statistical comparisons were made using a paired
Student's t test.
Drugs used were: gallamine triethiodide (Flaxedil,
May & Baker), halothane (Fluothane, I.C.I.),
ketamine hydrochloride (Ketalar, Parke Davis),
pancuronium bromide (Pavulon, Organon), pentobarbitone sodium (Nembutal, Abbott), phentolamine
mesylate (Rogitine, CIBA), reserpine, tyramine
hydrochloride (Sigma Laboratories). With the exception of halothane and reserpine, all drugs were
administered i.v.
(•> BAT
Ktort
(B) RABBIT
RESULTS
Lo
Pithed rat
Ketamine 2-50 mg/kg produced a biphasic effect on
arterial pressure, an initial transient (15-s) depressor
response, followed by a pressor response which
reached a peak at approximately 1 min after injection
and decreased to control values by 3—4 min after
injection (fig. 1A). The pressor response was maximal
at 5 mg/kg, whereas the depressor response increased
with increasing dose up to 50 mg/kg. The heart rate
was decreased also in a dose-related manner up to
50 mg/kg (table I).
The pressor response to ketamine 2,5 and 10 mg/kg
was unaffected by phentolamine 2 mg/kg or by
pretreatment of the rats with reserpine 2 mg/kg daily
i.p. for 3 days (table II). Tyramine 200 j^g/kg, which
increased arterial pressure and heart rate in untreated
rats, had no effect in these reserpinized animals.
400
Haort
Eott
(C) CAT
nHj
0
-200
H«ort
Kaf«
FIG. 1. Effects of ketamine 5 mg/kg i.v. on the arterial
pressure of the pithed rat, rabbit and cat. (A) Rat. Note that
time scale differs from (B) and (c) below, (B) Rabbit. Event
marker indicates electrical stimulation of the upper lumbar
sympathetic outflow (10 Hz, 20 s). (c) Cat. Event marker
indicates electrical stimulation of the upper lumbar
sympathetic outflow (10 Hz, 20 s). Note delayed increase in
heart rate resulting from release of adrenal catecholamines
following sympathetic stimulation.
TABLE I. The maximum depressor, pressor and heart rate responses produced by ketamine in pithed animals. P values
indicate significance of the difference from pre-injection control values calculated by paired t test
Maximum depressor response
Systolic
pressure
Ketamine
dose
Species (mg/kg)
n
Rat
2
9
5
15
10
18
Rabbit
20
21
50
19
5
6
%of
control
93.8
±2.7
93.8
±1.4
0.05
893
0.001
±1.4
85.9
±1.4
68.6
±3.3
75.5
±2.1
Cat
5
2
>P
76
74
0.001
0.001
0.001
0.001
Diastolic
pressure
%of
control
95.1
±1.9
89.6
±2.1
80.8
±2.2
71.0
±1.7
49.5
±2.4
83.2
±3.9
77
74
>P
0.05
0.001
0.001
Maximum pressor response
Systolic
pressure
%of
control
%of
>P
122.0 0.001
±4.5
132.8 0.001
±6.3
130.2 0.001
±3.1
0.001
0.001
0.001
Diastolic
pressure
123.4 0.001
±3.1
124.5 0.001
±5.7
control
>P
131.2
±4.8
145.5
±7.9
147.5
±4.9
135.5
±5.0
135.9
±63
—
0.001
0.001
0.001
0.001
0.001
Heart: rate
response
%of
control
83.3
±2.7
79.8
±2.1
73.2
±2.3
68.6
±2.7
53.2
+ 2.8
89.0
±2.1
90
87
>P
0.001
0.001
0.001
0.001
0.001
0.001
937
CARDIOVASCULAR EFFECTS OF KETAMINE
TABLE II. TTie effect of phentolamine 2 mglkg and of pretreatment with rescrpine 2 mglkg i.p. daily for 3 days on the pressor
response to ketamine 2-10 mglkg in the pithed rat. P values indicate significance of the difference from control group calculated by
paired t test. Neither phentolamine nor reserpine pretreatment made any significant difference to the values of control arterial
pressure, (n.s. = not significant)
Control
dose
(mg/kg)
Systolic
% control
Diastolic
% control
2
122.0
±4.5
132.8
131.2
+ 4.8
145.5
±6.3
±7.9
5
10
130.2
147.5
±3.1
±4.9
Phentolamine 2 mg/kg
n
Systolic
% control
Diastolic
% control
9
118.3
±3.2
133.4
129.1
+ 5.4
143.6
±5.2
±6.8
15
18
128.7
+ 3.5
In one rat which had been adrenalectomized
chronically and in three which were adrenalectomized
acutely, ketamine 5 mg/kg produced pressor responses
similar to those obtained in the control
Pithed rabbit
Ketamine 5 mg/kg produced a short-lived depressor
response which was maximal within 30 s and had
returned to control values within 2 min. Heart rate
was depressed transiently, also. The direct vasopressor response to stimulation of the sympathetic
outflow was unaffected 2 min after ketamine 5 mg/kg
(table I,fig.1B).
Pithed cat
As in the rabbit, in two cats studied, ketamine
5 mg/kg produced only a short-lived depressor
response and a transient depression of heart rate
(table I, fig. lc). Stimulation of the lumbar sympathetic outflow in the cat produced both a direct vasopressor response as a result of stimulation of vasoconstrictor nerves and a delayed response as a result
of release of catecholamines from the adrenals which
increased both arterial pressure and heart rate.
Ketamine 5 mg/kg failed to enhance these responses
(fig. lc).
DISCUSSION
These results demonstrate that ketamine can increase
arterial pressure by a direct peripheral mechanism in
the rat, but not in the rabbit or cat. In each of the
latter two species, however, ketamine can produce a
pressor effect in the presence of an intact central
nervous system (Wong and Jenkins, 1974; McGrath,
MacKenzie and Millar, 1975). The occurrence of a
pressor effect following ketamine in the pithed rat,
therefore, points to a particular sensitivity of this
species rather than a general explanation of the
78
143.7
±6.8
Reserpine pretreatment
n
P
Systolic
% control
Diastolic
% control
3
n.s.
117.9
135.8
+ 6.2
160.0
±10.2
146.2
±5.0
3
3
n.s.
n.s.
±2.9
154.2
±10.8
124.8
±1.5
n
P
3
n.s.
5
n.s.
3
rus.
mechanism by which ketamine increases arterial
pressure in several species.
Although the mechanism of the pressor effect of
ketamine in the pithed rat is not defined closely by
this study, we cannot confirm the suggestion of
Chang, Chan and Ganendran (1969) that ketamine
releases peripheral catecholamines since, in the
experiments described here, the pressor response
was unaltered by (1) the a-adrenoceptor blocker
phentolamine in a dose sufficient to abolish the
response to injected catecholamines or sympathetic
nerve stimulation (Gillespie, MacLaren and Pollock,
1970), (2) reserpine pretreatment sufficient to decrease
peripheral tissue noradrenaline concentrations to less
than 2% (Gillespie and McGrath, 1974) and prevent
the indirect sympathomimetic action of tyramine,
and (3) adrenalectomy, both chronic and acute. In
addition, the heart rate was not increased as it would
have been in the presence of increased concentrations
of circulating catecholamines (Gillespie, MacLaren
and Pollock, 1970).
In each of the three species examined, ketamine
caused a decrease in arterial pressure and heart rate
immediately following injection. This is in accord
with the direct negative inotropic and chronotropic
effect which ketamine exerts on the myocardium
(Dowdy and Kaya, 1968) and which is responsible
for the initial decrease in arterial pressure commonly
preceding the pressor effect in intact animals
(McCarthy et al., 1965; Dowdy and Kaya, 1968;
McGrath, MacKenzie and Millar, 1975). In the
pithed cat and rabbit this transient decrease of both
arterial pressure and heart rate was the only discernible
effect of ketamine, while in the rat it was followed by
the pressor effect. While these initial depressant
effects in the rat were dose-related up to 50 mg/kg,
the subsequent pressor effect was maximal at 5 mg/kg.
938
BRITISH JOURNAL OF ANAESTHESIA
This indicates that the pressor effect of ketamine is
independent of the depressor effect and that at doses
in excess of 5 mg/kg the depressant effects predominate.
Taken alone, these results do not explain the
mechanism of the pressor effect of ketamine in intact
animals They do, however, indicate the absence of a
direct peripheral component in the rabbit and cat.
Similar results have been demonstrated in dogs
during extradural anaesthesia (Traber and Wilson,
1969), and in patients with irreversible post-traumatic
coma (du Cailar, 1972). Also, it has been suggested
from in vitro experiments that ketamine may cause an
indirect peripheral potenuation of the effects of
sympathetic nerve stimulation by blockade of the
uptake of noradrenaline into sympathetic nerve
terminals (Montel et al., 1973; Nedergaard, 1973). In
vivo, however, ketamine does not potentiate the
effects of sympathetic nerve stimulation or noradrenaline in the rat (Clanachan and McGrath, 1975) or the
rabbit (McGrath and MacKenzie, unpublished
observations). Therefore, this indicates that ketamine
exerts its pressor effect by a central rather than a
peripheral mechanism in agreement with the findings
of Schwartz and Horwitz (1975).
ACKNOWLEDGEMENTS
Excellent technical assistance was provided by Mr G. M.
McCreaddie. We are grateful to Professor J. S. Gillespie
and Professor R. A. Millar for their advice and support.
J. C. McG. and A. S. C. were respectively in receipt of a
fellowship and a scholarship from the Wellcome Trust and
J. E. M. of an M.R.C. fellowship.
Gillespie, J. S., and McGrath, J. C. (1974). The effect of
pithing and of nerve stimulation on the depletion of
noradrenaline by reserpine in the rat anococcygeus muscle
and vas deferens. Br. J. Pharmacol., 52, 585.
MacLaren, A., and Pollock, D. (1970). A method of
stimulating different segments of the autonomic outflow
from the spinal column to various organs in the pithed cat
and rat. Br. J. Pharmacol., 40, 257.
McCarthy, D. A., Chen, G., Kaump, D. H., and Ensor, C.
(1965). General anesthetic and other pharmacological
properties of 2-(0-chlorophenyl)-2-methylaminocyclohexanone H a (CI-581). J. New Drugs, 5, 21.
McGrath, J. C , and MacKenzie, J. E. (1976). A pithed
rabbit preparation for stimulation of different segments of
the autonomic outflow. Br. J. Pharmacol, (in press).
Millar, R. A. (1975). Circulatory response to
ketamine: dependence on respiratory pattern and background anaesthesia in the rabbit. Br. J. Anaesth., 47,
1149.
Montel, H., Starke, K., Gorlitz, B.-D., and Schumann,
H. J. (1973). Tierexperimentelle Untersuchungen zur
Wirkung des Ketamins auf periphere sympathische
Nerven. Anaesthetist, 22, 111.
Nedergaard, O. A. (1973). Cocaine-like effect of ketamine
on vascular adrenergic neurones. Eur. J. Pharmacol., 23,
153.
Schwartz, D. A., and Horwitz, L. D. (1975). Effects of
ketamine on left ventricular performance. J. Pharmacol.
Exp. Ther., 194, 410.
Traber, D. L., and Wilson, R. D. (1969). Involvement of
the sympathetic nervous system in the pressor response
to ketamine. Anesth. Analg. (Cleve.), 48, 248.
Treese, N., Niemezyk, H., and Reuther, P. (1973).
Tierexperimentelle Untersuchungen iiber die myokardiale
und zentralnervos ausgeloste Wirkung von Ketamin auf
das Herz-Kreislauf-System. Anaesthetist, 22, 117.
Wong, D. H. W., and Jenkins, L. C. (1974). An experimental
study of the mechanism of action of ketamine on the
central nervous system. Can. Anaesth. Soc. J., 21, 57.
REFERENCES
du Cailar, J. (1972). The effects in man of infusion of
Althesin with particular regard to the cardiovascular
system. Postgrad. Med. J. (Suppl.)—Steroid Anaesthesia,
p. 72.
Chang, P., Chan, K. E., and Ganendran, A. (1969). Cardiovascular effects of 2-(0-chlorophenyl)-2-methylaminocyclohexanone (CI-581) in rats. Br.J. Anaesth., 41, 391.
Clanachan, A. S., and McGrath, J. C. (1975). Effects of
ketamine on the peripheral sympathetic nervous system
of the rat. Br. J. Pharmacol., 55, 245P.
Domino, E. F., Chodoff, P., and Corssen, G. (1965).
Pharmacologic effects of CI-581, a new dissociative
anesthetic in man. Chn. Pharmacol. Ther., 6, 279.
Dowdy, E. G., and Kaya, K. (1968). Studies of the
mechanism of cardiovascular responses to CI-581.
Antsthetiology, 29, 931.
Fischer, K. (1973). Vergleichende tierexperimentelle
Untersuchungen zum Kinfluss verschiedenen Narkotica
auf das Herz; in Ketamin—Nene Ergebmsse in Forschung
und Klmik. (Anaesthetiology and Resuscitation, 69) (eds
M. Gemperle, D. Langrehn and H. Kreuscher), p. 11.
Berlin: Springer-Verlag.
EFFETS CARDIOVASCULAIRES DE LA
KETAMINE SUR LES RATS, LAPINS ET CHATS
AYANT ETE SOUMIS A UNE ENERVATION
RESUME
On a etudie les effets de la ketamine administree par voie
intraveineuse sur la tension arterielle et la frequence cardiaque de rats, lapins et chats ayant ete soumis a une enervation. Sur ces trois types d'animaux, la ketamine a provoquc
une breve diminution de la tension arterielle et de la frequence cardiaque. Chez le rat, mais pas chez les deux autres
especes, cette baisse initiate de la tension arterielle a etc
suivie par une reponse vasomotrice qui a resiste au blocus
de l'adrenorecepteur alpha, a l'epuisement des reserves de
la noradrenaline des tissus et a l'adrenalectomie. On en a
conclu que la reponse vasomotrice peripherique que Ton a
trouvee chez le rat enerv6 est specifique a cette espice,
qu'elle n'est pas le resultat du degagement de catecholamines peripheriques et qu'elle n'explique pas l'effet vasomoteur de la ketamine que Ton trouve chez l'homme et
chez plusieurs especes d'animaux.
939
CARDIOVASCULAR EFFECTS OF KETAMINE
KARDIOVASKULARE WIRKUNGEN VON
KETAMIN AUF RATTEN, KANINCHEN UND
KATZEN MIT AUSGEBOHRTEM RUCKENMARK
EFECTOS CARDIOVASCULARES DE LA
KETAMINA EN RATAS, CONEJOS Y GATOS
DESCEREBRADOS
ZUSAMMENFASSUNG
SUMARIO
Diese MRirkxingen von Ketamin auf den arteriellen Druck
und das Herzminutenvolumen bei Ratten, Kaninchen und
Kfltzen mit ausgebohrtem Ruckenmark wurden untersucht.
Bei alien drei Spezies kam es zu einem kurzen Abfall des
arteriellen Drucks und des Minutenvolumens. Bei Ratten,
aber nicht bei den anderen Spezies, war dieser anfangliche
Druckabfall von einer Druckreaktion gefolgt, die gegen
alpha-Adrenozeptorblockierung resistent war, ferner von
einer Verringerung der Noradrenalin-Vorrate im Gewebe
und von Adrenalektomie. Es wird geschlossen, dass die
peripher vermittelte Druckreaktion speziflsch fur Ratten ist,
nicht das Ergebnis der Freisetzung peripherer Katecholamine darstellt, und nicht den Druckeffekt von Ketamin
erklart, der beim Menschen und in verschiedenen Tierarten
fastgestellt wurde.
Se examinaron los efectos de ketamina i.v. en la presion
arterial y frecuencia cardiaca en ratas, conejos y gatos
descerebrados. En las tres especies la ketamina produjo un
breve descenso en la presion arterial y frecuencia cardiaca.
En la rata, pero no en las otras dos especies, este descenso
initial en la presion arterial fue seguido de una respuesta
presora que resistio al bloqueo adrenoceptor-a, la depletion
de reservas de noradrenalina histica, y adrenalectomia. Se
conduye que la respuesta presora mediada perifericamente
hallada en la rata descerebrada es espetifica a esta especie, no
es resultado de liberation de catecolaminas perifericas, y no
explica el efecto presor de la ketamina hallado en el Hombre
y en diversas especies animales.