EUROPEAN JOURNAL OF PHARMACOLOGY 11 (1970) 332-341.

NORTH-HOLLANDPUBLISHING COMPAN~

MECHANISM OF SELECTIVE CARDIAC VAGOLYTIC ACTION

OF PANCURONIUM BROMIDE. SPECIFIC BLOCKADE OF
CARDIAC MUSCARINIC RECEPTORS

Pramod R. SAXENA * and Ivan L. BONTA *

Pharmacological Research Department,
N. V. Organon, Oss The Netherlands

Recewed 24 February 1970 Accepted 22 April

P.R. SAXENA and I.L. BONTA, Mechanism of selective cardiac vagolytic action of pancuronium bromide: S~
blockade of cardiac muscarinie receptors, European J. Pharmacol. 11 (1970) 332-341.
The selective vagolytic action of the potent steroidal neuromuscular blocker, pancuronium on the hem
analysed in cats, dogs and in isolated tissues of guinea-pigs. The compound not only suppressed the inhil
effects of vagal stimulation, but also selectively antagonised the negative inotropic and chronotropic actic
parasympathomimetic compounds without appreciably modifying their vascular effects or the respon~
potassium chloride. Antagonism of the above compounds was competitive and was more selective on spontam
beating auricles than on the ileum when compared with atropine. Thus, pancuronium possessed a more Sl:
blocking action on the muscarinic receptors of the heart. These receptors, in analogy with the cardiac
adrenergic receptors, may be different from muscarinic receptors present elsewhere.
Study of the cardiovascular actions of pancuronium in dogs indicated that the compound was well toleratec
in relatively high doses. This lack of adverse cardiovascular effects has already been demonstrated in several cl
reports.

Pancuronium Parasympatholytic Neuromuscular block

Heart Muscarinic receptor Autonomic nervous system

1. INTRODUCTION sponses to peripheral stimulation of the v~

Among a series of bisquaternary steroids, pancuro-
nium bromide was found to be a potent non-depolar-
izing neuromuscular-blocking agent having several
times the potency of d-tubocurarine (Buckett,
Marjoribanks, Marwick and Morton, 1968). In sub-
sequent papers (Bonta and Goorissen, 1968; Bonta,
Goorissen and Derkx, 1968; Bonta and Buckett,
1969), the pharmacological profile of the compound
was further delineated and it was shown that while
pancuronium entirely blocked the circulatory re-
* Present address: Department of Pharmacology, Medical
Faculty, Rotterdam, The Netherlands
it did not inhibit the fall in blood presst
exogenous acetylcholine. Further, the corn
not markedly affect contractions of gu
bladder, or nictitating membrane elicite
stimulation of, respectively, the vagus, pel
ganglionic cervical sympathetic nerves.
mogenic response of the guinea-pig ileum
choline or nicotine was only weakly supl
pancuronium (Bonta et al., 1968; Buc~
1968). Thus it was suggested that pancuron
have a selective vagolytic action on the cal
terminals (Bonta et al., 1968). In this
cation, we report studies on the mechani~
selective vagolytic action of the drug
 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade
demonstrated that pancuronium may specifically
block the cardiac muscarinic receptors. The results
are indicative of subtle differences between the car-
diac muscarinic receptors and the muscarinic recep-
tors present in some other organs.
2. METHODS
2.1. Cardiovascular responses in.cats
Experiments were performed on a total of 12 cats
(2-3.8 kg) of either sex anaesthetized with pento-
barbital sodium (35 mg/kg, i.p.) and given positive
pressure ventilation. Blood pressure was measured
with a Statham P23Ac transducer by attaching it to a
polyethylene cannula inserted in a femoral artery.
The tone of the nictitating membrane was recorded
semi-isometrically with a Grass FT 03 transducer. The
heart rate was registered with a Grass tachograph
preamplifier (7P4A), triggered by ECG signals. In
some experiments, the intravesicular pressure was
recorded with a Statham P23Bc transducer by a
cannula introduced into the urinary bladder through
urethra. All events were recorded on a model 7 Grass
polygraph. The drugs were injected i.v. through a
cannulated femoral vein. Supramaximal stimuli of
1 msec duration and 25/sec frequency derived from a
model $4 Grass stimulator were delivered for 15 sec
to the preganglionic cervical sympathetic nerve or to
the peripheral stump of the sectioned vagus nerve.
2.2. Cardiovascular responses in dogs
2.2.1. Cardiovascular effects of pancuronium
Ten dogs ( 1 0 - 1 6 kg), not selected by breed or
sex, were anaesthetized with a mixture of 5% chlo-
ralose with 25% urethane in physiological saline
(2 ml/kg, i.v.). The animals were ventilated with room
air by means of a Palmer pump connected to a
tracheal cannula. Blood pressure was recorded as
mentioned in 2.1. while the heart rate was monitored
with a Grass 7P4A amplifier triggered by blood
pressure signals. The chest was opened between the
left fourth and fifth intercostal spaces, and the right
ventricular contractile force was measured with a
Walton-Brodie strain gauge arch (Boniface, Brodie
and Walton, 1953). Blood flow in the ascending aorta
(i.e. cardiac output minus coronary flow) was record-
333
ed with a sine-wave electromagnetic flow meter
(Skalar, Delft) after placing a calibrated flow probe
around the above vessel. All these parameters were
recorded on a Grass model 7 polygraph. A cardiostat
(Siemens) was used to register various leads of ECG
intermittantly. Cumulative doses (1A log 10 sequence
starting with 50 pg/kg) of pancuronium were injected
i.v. every 15 rain through a cannula introduced in a
femoral vein. Effect of pancuronium was observed on
the above parameters and compared with the control
readings in the individual experiments.
2.2.2. Effect of pancuronium on the cardiovascular
responses to cholinergic drugs
Fifteen dogs ( 8 - 1 5 kg), of either sexes were
anaesthetized either with pentobarbital sodium
(35 mg/kg, i.v.) or with a mixture of urethane and
chloralose (see 2.2.1.). Blood pressure, heart rate and
right ventricular force of myocardial contraction were
registered as described in 2.2.1. Effect of pancuro-
nium was studied on the negative inotropic and
chronotropic, and hypotensive effects of the choliner-
gic drugs (acetylcholine, methacholine and carba-
chol).
2.3. Perfused guinea-pig heart
The effects of pancuronium and atropine were
studied on 12 hearts perfused with Meyler's fluid
(Meyler, Offerijns, Willebrands and Groen, 1959)
equilibrated with 5% CO2 and 95% 02 at 37°C using
essentially the technique of Langendorff (Langen-
dorff, 1895). Contractile force was measured by a
Grass FT 03 transducer, while the heart rate was
registered by Grass tachograph preamplifier (7P4A)
being triggered with contractile force signals. Perfu-
sion outflow was recorded with a Grass PT5 volume-
tric transducer as described elsewhere (Saxena, 1970).
The records were traced on a model 7 Grass poly-
graph. Responses to acetylcholine (10/.tg), metha-
choline (5 ~g) and carbachol (5 ~g), injected through
a rubber tube directly into the aorta, were elicited.
The effect of pancuronium (2.5 and 5 X 10 -6 g/ml)
and atropine (1 and 2 × 10-~ g/ml) was studied on
the negative inotropic and chronotropic, and
coronary vasodilator response elicited by the choline
esters.
334 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade
2.4. Isolated spontaneously-beating guinea-pig auri-
cles
Sixteen spontaneously-beating guinea-pig auricles
were suspended in a 25 ml bath containing tyrode
solution equilibrated with 5% CO2 and 95% 02 at
29°C. The contractions of the auricles were recorded
on a Harvard recorder via an isotonic transducer.
Cholinomimetic drugs (acetylcholine, methacholine
and carbachol), which inhibit the auricles by a
muscarinic action, were administered into the bath in
cumulative doses (½ log 10 sequence) according to
the method of van Rossum (1963). The response
obtained with the individual doses was calculated as a
percentage of the maximum effect elicited by the
respective compounds. The action of pancuronium
and atropine was studied on the dose-response curves
of the agonists. Data were analysed (van Rossum,
1963) to determine the pD2 and pA2 of the agonists
and antagonists, respectively.
2.5. Isolated guinea-pig ileum
Twenty-four guinea-pig ileum preparations were
set up in a 5 ml bath containing tyrode solution
equilibrated with 5% CO2 and 95% 02 at 37°C. The
contractions of ileum were registered isotonically on
a smoked drum via a lever arrangement. Cumulative
dose-response curves to the choline esters were made
as described above (see 2.4.) and the effects of
pancuronium and atropine were evaluated. The pD2
of the agonists and pA2 of the antagonists were
calculated (van Rossum, 1963).
2.6. Drugs
Acetyl-/3-methylcholine chloride (methacholine); ace-
tylcholine chloride; adrenaline bitartrate; atropine
sulphate; carbamylcholine chloride (carbachol); 1,1-
dimethyl-4-phenylpiperazinium iodide (DMPP); 4-(m-
chlorophenyl-carbamoyloxy)-2-butynyltrimethylam-
monium chloride (McN-A-343, Mc Niel); N',N',N"-
trimethyl-N'-(5-cyano-5,5-diphenyl)ethylene-l-ammo-
nium-2-morpholinium dichloride (BW 139C55); pan-
curonium bromide (2/3,16/3-dipiperidino-5c~-andros-
tane-3a, 17/3-diol diacetate dimethobromide, Pavulon)
and potassium chloride. All compounds were dis-
solved in 0.9% saline or in the appropriate physiologi-
cal fluid for isolated tissue experiments. The doses
mentioned are those of the corresponding salts.
3. RESULTS
3.1. Studies in cats
3.1.1. Effect on the response to adrenaline, I
glionic cervical sympathetic nerve stimulatic
peripheral vagal stimulations.
In 7 experiments, pancuronium (up to 11
did not appreciably affect the pressor respc
tachycardia to adrenaline (5/ag/kg), nor did it 1
the contraction of the nictitating membrane
by preganglionic cervical sympathetic nerve s
tion. However, bradycardia and hypotensio
duced by peripheral vagal stimulation were in]
by pancuronium (0.1 to 0.5 mg/kg).
3.1.2. Effect on the responses to DMPP
In 2 cats, DMPP (25-50/ag/kg) produced a
intravesicular pressure and arterial blood p
together with tachycardia preceeded by trl
bradycardia. Pancuronium (0.1 mg/kg) did nol
responses to DMPP except for the initial brad3
(due to parasympathetic ganglion stimulation
reflex vagal activity) which was abolished.
The results presented so far confirm
findings (Buckett et al., 1968; Bonta et al., 196
show that not only the cardio-inhibitory effi
vagal stimulation but also that of DMPP wa;
ished by pancuronium.
3.1.3. Effect on the responses to McN-A-343
Specificity of the action of pancuronium ol
was studied on the pressor effect, tachycard
nictitating membrane contraction caused
muscarinic ganglionic stimulant, McN
(Roszkowski, 1961) in 3 cats pretreated
BW 139C55 (1.5 mg/kg), a long-acting nicotin
glion blocker (Green, 1956). Pancuronium (
0.25 mg/kg) did not appreciably affect the res
elicited by McN-A-343 (25-100/ag/kg) whi
extremely sensitive to the action of atropine
kowski, 1961).
3.2. Studies in dogs
3.2.1. Cardiovascular actions of pancuronium
The effect of pancuronium was studied
number of cardiovascular parameters in dog
results presented in table 1 show that lower do
to 1.5 mg/kg) of pancuronium caused a con
 Table 1
Effect of cumulative doses o f pancuronium on some cardiovascular parameters (mean values -+ S.E.M.) in dogs.

Values (% o f control), 5 min after pancuronium (mg/kg)

Parameters Control
values
0.05 0.15 0.50 1.50 5.00 1500 50.00

Systolic blood
pressure 143.6 -+ 3.7 99.5 -+ 1.1 96.5 + 2.2 97.3 + 3.0 93.0 -+ 2.9 77.8 + 5.6 57.5 + 4.2 51.6 + 3.6
(mm Hg) (10)* (10) (10) (10) (9) (9) (6) (6) e~

Diastolic blood
pressure 92.7 + 4.3 102.3 + 1.8 102.5 +- 3.4 101.3 + 3.6 99.8 -+ 4.7 84.3 + 9.2 64.9 + 5.0 56.8 -+ 1.7
t'~
(ram Hg) (10) (10) (10) (10) (9) (9) (6) (6)

Heartrate 146.4+10.8 108.5-+2.0 111.1-+2.8 117.3 + 3.3 111.9-+ 4.5 107.9 -+ 5.9 103.6 + 6.8 109.3 + 11.6
per rain (10) (10) (10) (10) (9) (9) (6) (6)
Ascending aorta
flow 126.3-+15.9 104.0-+2.1 105.8+1.9 111.8+ 5.6 105.4 + 5.0 94.4 -+ 8.2 87.7 + 10.6 81.3 + 6.5
(ml/min/kg) (6) (6) (6) (6) (6) (6) (4) (4)

Perepheral resis- 69.4 -+ 21.8 95.6 + 2.0 92.9 + 1.9 92.0 + 4.4 94.8 -+ 4.8 95.6 + 9.2 74.7 + 8.7 73.7 + 9.2
tahoe** (6) (6) (6) (6) (6 ~ (6) (4) (4)
Right ventricular
myocardial con- 100% 99.1 + 3.7 107.9 + 9.0 122.2 + 17.6 110.8 + 17.3 93.3 + 20.8 68.4 + 12.6 82.3 + 25.2
tractility*** (10) (10) (10) (10) (9) (9) (6) (5)

* Number of animals.
** Calculated by dividing the mean blood pressure in mm Hg by ascending aorta flow in 1/min.
*** Not calibrated and thus taken as 100% in the control period.
336 P.R. Saxena and 1.L. Bonta, Cardiac muscarinic blockade
but moderate increase in heart rate. There was also a
slight concomitant increase in blood flow in the
ascending aorta (i.e. cardiac output minus coronary
flow); blood pressure was not significantly changed.
Higher cumulative doses (5 to 50 mg/kg) produced
hypotension, a consequence of a fall in peripheral
resistance and a decrease in ascending aorta blood
flow. No abnormalities in the ECG were detected.
These results demonstrated that pancuronium in
amounts up to approximately 100-200 times that of
a neuromuscular blocking dose (15/lg/kg) in dogs
(Buckett et al., 1968) did not produce any cardio-
vascular effects other than marginal tachycardia.
3.2.2, Effect of pancuronium on cardiovascular re-
sponses to cholinergic drugs
The effect of pancuronium was observed on the
cardiovascular responses elicited by acetylcholine
(20 200 /~g/kg), carbachol (1.5 6/ag/kg) and meta-
choline (2.5--800/ag/kg). The effect of pancuronium
(300/ag/kg) on the decrease in myocardial contractil-
ity, heart rate and blood pressure caused by carbachol
300
200f
100 If-
20of
100
0 Fig. 2. Effect o f cumulative doses o f p a n c u r o n i u m on th~
Cacbe-chol Carb:chol
15 ~g/kg 1.5 ,,tag/kg
Pancuronium
0 3 mg/kg
Fig. 1. Effect o f p a n c u r o n i u m on the negative inotropic,
negative chronotropic and hypotensive actions of carbachol.
Dog 10.5 kg, c~. Records from above downwards: Force o f
myocardial contraction, time mark 10 ~ c , heart rate per min
and blood pressure ( m m Hg). P a n c u r o n i u m completely
blocked the depressant effects o f carbachol on heart while its
bypotensive response was only minimally counteracted.
(1.5 pg/kg) is shown in fig. l. The depressor effect ot
carbachol was only slightly reduced whereas its nega.
tive chronotropic and inotropic actions were com-
pletely blocked by pancuronium suggesting that pan-
curonium specifically blocked cholinergic receptors in
heart. Similar results were obtained with acetyl.
choline instead of carbachol. The effect of cumulative
doses of pancuronium was studied on the responses
to increasing concentrations of metacholine (see
fig. 2). This figure, apart from confirming the select-
ive blocking action of pancironium on the heart also
turn Hg a b
I
mm Hg c d
200 r ~ r
;o ;o ~ a'o
mm Hg • f
;60 [
80 L
,'o 8"o a'o
cardiovascular responses to methacholine. Dog 16 kg,
Records from above downwards: blood pressure, time marl
5 sec, force o f myocardial contraction and heart rate per rain
Methacholine was injected at d o t s and the n u m b e r s below thq
dots indicate the dose in pg/kg. Doses of p a n c u r o n i u n
(pg/kg) employed: 50 between a and b, 150 between b and c
500 between c and d, 1500 between d and e, and 5001
between e and f. P a n c u r o n i u m caused a more selectivq
s u r m o u n t a b l e blockade (see text) of the negative inotropi,
and chronotropic effects o f methacholine. The hypotensivq
responses due to m e t h a c h o l i n e were only slightly reduce(
because of the blockade of the effects on heaxt.
 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade 337

demonstrated the surmountable nature of this block. ( 1 - 2 × 1 0 - S g / m l ) not only caused approximately
Higher amounts of metacholine overcame the anti- equal blockade of the parasympathomimetic drugs on
muscarinic action of pancuronium but an increase in heart, but also suppressed their response on the
the dose of pancuronium re-established blockade. coronary outflow (fig. 4). However, atropine ap-
peared to have more than 250 times the activity of
3.3. Perfused guinea-pig heart pancuronium on weight basis. As expected, the car-
In perfused guinea-pig heart, acetylcholine (10/ag), diac inhibitory effects of KC1 were unaffected by
methacholine (5/~g), carbachol (5/~g) and KC1 (5 rag) atropine.
inhibited heart rate and force of contraction but
increased perfusion outflow because of coronary 3.4. Isolated guinea-pig auricles and ileum
vessel dilatation. Pancuronium (2.5-5 X 10 -6 g/ml), The effects of pancuronium and atropine on the
"although itself without appreciable effect on heart dose-response curves of acetylcholine, methacholine
rate or contraction, prevented or even reversed the and carbachol on guinea-pig auricles are shown in
negative chronotropic and inotropic effects of fig. 5. There was a parallel shift of the curves to the
cholinergic drugs. It did not markedly influence right indicating competitive antagonism by both
coronary vasodilatation induced by these drugs. drugs. Similar results were obtained on guinea-pig
Moreover, the responses to KC1 were not modified, ileum except that the antagonism between atropine
establishing that the site of action of pancuronium and carbachol was found to be non-competitive. The
was not directly the heart muscle itself, but was on pDz values for the above cholinergic drugs and pA2
muscarinic receptor sites. One such experiment is values of atropine and pancuronium are shown in
presented in fig. 3. In similar circumstances, atropine table 2. Pancuronium was a much weaker antagonist

:::::::::::::::::::::::::::::::::::: =============================== t . . . ~

2OO
--~--
,llttll l/,,
:t::t::::::: :::::::::::::::::::::::::::: ::::::::::::::::::::::::::::::::::: :::::::::::::::::::::::::::::::::::::

Acetyl:holine Idethl~holine Clrb~chol

IOhtg 5)4g 5~g 5n~
Fig. 3. Effect of pancuronium on the cardiac inhibition and increase in coronary perfusion outflow caused by acetylcholine,
metacholine, carbachol and KCI on isolated perfused guinea-pig heart. Records from above downwards: force of myocardial
contraction, time mark 10 sec, heart rate per min, and coronary perfusion outflow. Upper panels, control responses; lower panels,
responses in the presence of pancuronium (5 X 10-~'g/ml). Note that pancuronium abolished the negative inotropic effect of
cholinergic drugs more selectively than their coronary vasodilator response which was only slightly reduced. The effects of KCI
remained essentially unchanged.
338 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade

o f muscarinic receptors in ileum than

However, in auricle preparations the dill
300 r tween the antagonistic activities o f at~
pancuronium was much less. This conf
pancuronium blocked the auricular musca
100 tors more specifically than those in the gu
opposite was true for atropine. The effect (
nium was more easily removed by washing
than that o f atropine.

Fig. 4. Effect of atropine on the cardiac in]

increase in coronary perfusion outflow caused b:
drugs on isolated perfused guinea-pig heart. R
300 [ above downwards: force of myocardial contr
mark 10 sec, heart rate per min, and corona:
outflow. Upper panels, control responses; lowe
I00L ~ ~ sponses in presence of atropine (10-ag/ml). No
pine not only suppressed the negative inotropic
tropic effects of methacholine and carbach~
markedly reduced their coronary vasodilator r~
responses to acetylcholine both on the heart a
vessels were only partially blocked by this dose
Higher doses (2 X 10-Sg/1) blocked the effecl
tong 5~g 5pg choline completely.

'30

80!

10 5 10 ¢' 10"] 10-2 10-7 I0 6 )0 "s 10 "/" 10I] 10"2 1Oq ~0 I 7 10 6 10 5 1014 I 01 ] ~0

c~ ao
6O

aS

2C

q
. . . . , , , , t

'0[6 I0 ~ I0 4 I0 3 I0 2 10 7 I0 6 I0 5 I0 ~ 10 ,3 I0 7 I0 6 I0 5 i0-4 i0-]

ACETYLCHOLINE (M) METHACHOLINE

(M) CARSACHOL (M)

Fig. 5. Influence of atropine (upper panels) and pancuronium (lower panels) on the dose response curves o f the negal
action of acetylcholine, methacholine, and carbachol on the spontaneously beating guinea-pig auricles. Molar conc,
atropine:(~ ~ 4 0; []-- -q~, 10-6; H , 1.5 X 10-6 , A ; ~ , 3 X 10-6; and ~ 4, 10-5 . Molar conce
pancuronium: o - - ~ , 0; ~ - - ~ , 10-s;o-----O, 2 X 10-s; ~ ' ~ , 3 X 10-5; A ~ , 5 X 1 0 - s ; 0 - - - - - 0 , 10 --4
3 X 10--4. No~e the parallel shift o f the curves to the right showing a competitive antagonism by atropine and pancur
effects of the cholinergic drugs on guinea-pig auricles.
 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade 339

Table 2
pD2 Values of parasympathomimetic agents, and pA2 values of their antagonists (atropine and pancuronium) on guinea-pig auri-
cle and ileum.

Agonists. Mean pD2 -+S.E.M. Antagonists. Mean pA2 +-S.E.M.

Auricle Ileum
Compound Auricle Ileum
Atropine Pancuronium A t r o p i n e Pancuronium

Acetylcholine 5.25 +-0.10 (14)* 6.33 -+0.10 (6) 6.98 + 0.15 (6) 5.52 + 0.11 (6) 8.37 + 0.09 (5) 4.96 + 0.05 (6)
Metacholine 5.12 + 0.11 (12) 6.02+-0.07 (6) 6.69 +-0.10 (6) 5.39 + 0.05 (6) 8.17+-0.11(6) 4.72+-0.03(6)
Carbachol 5.86 +-0.08 (10) 6.34 + 0.11 (8) 6.80 + 0.17 (4) 5.44 +-0.07 (6) 7.12 ** -+0.09 (11) 4.80 + 0.06 (6)

* number of observations.
** non-competitive antagonism.

4. DISCUSSION nomic ganglia were not affected by pancuronium

Blockade of the cardiac vagus by the neuromuscu-
lar blocking agents, d-tubocurarine (Mautner and
Luisada, 1941) and gallamine (Bovet et al., 1949;
Jacob and Depierre, 1950), is well-known although its
mechanism is poorly understood. The demonstration
by Bonta et al. (1968) that pancuronium possessed a
similar selective cardiac vagolytic action aroused
interest in the mechanism. Theoretically, suppression
of the action of the cardiac vagus could be due to
paralysis of ganglia, inhibition of acetylcholine-release
or blockade of muscarinic receptors. No evidence has
been found so far for alteration of acetylcholine
release and/or by pancuronium. The ganglion-block-
ing action of the compound is weak and is not
observed following doses which are vagotytic (Buck-
ett et al., 1968; Bonta et al., 1968). The results
obtained in cats in the present study confirmed the
above statement. The conclusion that pancuronium
exhibited a selective cardiac vagolytic action by virtue
of a more specific blockade of myocardial muscarinic
receptors is indicated from findings in dogs and in
perfused guinea-pig heart where the vascular (even the
coronary vasodilatation) effects of cholinergic drugs
were not apparently modified by doses of pancuron-
ium that blocked their negative inotropic and chrono-
tropic actions. Since the responses to KC1 were not
modified, it must be assumed that pancuronium acted
on muscarinic receptors rather than directly on the
myocardium. The muscarinic receptors on the auto-
since responses to McN-A-343 were not suppressed.
This specificity of action was further supported by
the more marked competitive antagonism between
pancuronium and the parasympathomimetics on
auricles than on ileum. Atropine presented the oppo-
site picture.
Selective and competitive blockade of muscarinic
receptors of heart by pancuronium suggested that
these inhibitory muscarinic receptors may be dif-
ferent from those present in smooth muscles. An
analogous situation is already known for the heart,
since its/3-adrenergic receptors also differ from those
at other sites and can be selectively spared (Levy,
1966; 1967) or blocked (Dunlop and Shanks, 1968)
Further support for the above statement is provided
by gallamine and some other neuromuscular-blocking
agents which may also specifically block the cardiac
muscarinic receptors. This is indicated from several
previous publications (Mautner and Luisada, 1941;
Riker and Wescoe, 1951; Della Bella, Rognoni and
Gopal, 1961; Bouman, 1962; Laity and Garg, 1962;
Buckett and Saxena, 1969). The muscarinic receptors
in heart appear to possess some characteristics com-
mon to the two types of cholinergic receptors in the
smooth and skeletal muscles. Indeed, it is well-known
that cardiac muscle has some structural features of
both involuntary and voluntary muscles.
The cardiovascular actions of pancuronium in dogs
indicated that the compound was a well tolerated
neuromuscular-blocking agent. While d-tubocurarine
 P.R. Saxena and LL. Bonta, Cardiac muscarinic blockade
: n o w n t o cause a p r e c i p i t o u s fall in b l o o d pressure
m u c h l o w e r doses, p a n c u r o n i u m (in a m o u n t s 100
es t h a t o f n e u r o m u s c u l a r - b l o c k i n g d o s e ) p r o d u c e d
effect other than a moderate tachycardia which
y be d u e to its cardiac vagolytic a c t i o n . T h e l a t t e r
ion o f p a n c u r o n i u m is n o t likely to play a n y
lificant role in clinical s i t u a t i o n s since t h e mus-
inic r e c e p t o r s are usually paralysed b y a t r o p i n e ,
n m o n l y used in p r e - m e d i c a t i o n . I n d e e d , t h e lack
c a r d i o v a s c u l a r side e f f e c t s w i t h p a n c u r o n i u m h a s
n d o c u m e n t e d in several clinical studies ( B a i r d a n d
d, 1967; Baird, 1 9 6 8 ; Sellick, 1 9 6 8 ; K o m e s a r o f f
[ Field, 1 9 6 9 ; S t o j a n o v , 1969).
'KNOWLEDGEMENTS
The authors wish to thank Prof. E. Noach, Department of
• macology, University of Leiden, Leiden, for his valuable
aments. The skilled technical assistance of Messrs. H.
erenburg, P. van Houwelingen and B. de Blank is grateful-
acknowledged. McN-A-343 and BW 139C55 were kindly
plied by Mc Neil Labs, and Burrough Wellcome Co. Ltd.,
~ectively.
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NOTE ADDED IN PROOF:
In a recently published paper, Brown and Crout (J.
Pharmacol. Exptl. Therap. 172 ( 1 9 7 0 ) , 2 6 6 - 2 7 3 com-
pared the anti-acetylcholine action of gallamine and
atropine on the electrically-driven auricle and ileum
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muscarinic receptors. The above authors arrived at a
similar conclusion that the muscarinic receptors of
341
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the heart appear to be different from those present in
other tissues. In addition, Brown and Crout (1970)
reported that gaUamine has on the heart an unique
indirect sympathomimetic action which probably
provides the best explanation for the tachycardia and
the increase in cardiac output occurring immediately
after its i.v. injection in man. Whether or not pan-
curonium has a similar sympathomimetic action re-
mains to be seen.