European Journal of

Clinical Pharmacology

Eur J Clin Pharmacol (1982) 23 : 15-20

Springer-Verlag 1982

Sympathomimetic Effects of Amezinium on the Cardiovascular System

and Plasma Catecholamines in Man
G. G. Belz 1, P. E. Aust I, G. Belz 1, E. Appel 2, and D. Palm 2
l Institut fiir Kardiovaskul~ire Therapie, Wiesbaden and 2Zentrum der Pharmakologie, Klinikum der Universit~it Frankfurt,
Frankfurt, Federal Republic of Germany

Summary. The cardiovascular effects of the sympathomimetic agent amezinium were investigated in a
double-blind, placebo-controlled, randomized trial in
six volunteers. Before and 2 h after oral administration of amezinium 30 mg or placebo the cardiovascular responses to orthostatic stress, induced by 80 passive head-up tilt, were assessed by recording blood
pressure, systolic time intervals, and echocardiogram.
Plasma catecholamines were also determined. After
amezinium treatment, the average supine systolic
blood pressure was increased by +30 mm Hg and
after tilting it remained above both the pre-treatment
and placebo values. Compared to placebo, amezinium elicited only minor changes in heart rate and diastolic blood pressure. The effect of amezinium on the
pre-ejection period corrected for heart rate (PEPc)
and mean velocity of fiber shortening (VcFmean) indicated positive inotropic properties. Its effects were
distinctly more pronounced during tilt than with the
subjects supine. Plasma concentrations ofnoradrenaline and adrenaline were not influenced by amezinium during rest or tilt. From these results and previous
research it is concluded that amezinium induces its
sympathomimetic effects by preferentially inhibiting
the re-uptake of noradrenaline which is released by
the drug itself, or by sympathetic activation during
tilt. This mechanism of action might explain the pronounced sympathomimetic effects of the drug, especially during orthostatic stress.
Key words: amezinium; sympathomimetic effects,
catecholamines, echocardiography, systolic time intervals, orthostatic stress, inhibition of noradrenaline
uptake
Amezinium (4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulphate) exerts pronounced and long
lasting sympathomimetic effects in animals and man
[4, 9, 14, 15, 16, 17, 31, 35]. The bioavailability of the
drug is high at 50~57% [12, 29, 31]. In animal experi-

ments a- and fl-adrenoceptor blocking drugs antagonized the elevation of blood pressure and positive
inotropic and chronotropic effects of amezinium [15,
16, 17]. In animal organs depleted of nerve terminal
noradrenaline (NA), the sympathomimetic actions of
amezinium were abolished [17, 24].
Therefore, the drug can be characterized as acting
by an indirect mechanism dependent on the neuronal
store of NA. Amezinium has some properties typical
of indirect acting sympathomimetic amines (e. g. tyramine as a prototype; [10]), but it also has others that
are distinctly different. Like other indirectly acting
sympathomimetics, amezinium is transported into
the noradrenergic nerve endings via the NA-uptake
mechanism, thereby inhibiting uptake and re-uptake
of NA itself [25, 28, 30]. The inhibition of NA-uptake
is much more pronounced than that caused by tyramine. The transport of amezinium leads to a considerable intraneuronal accumulation of the substance.
This accumulation is the pre-requisite for its relatively
selective and reversible inhibition of intraneuronal
monoamine oxidase (MAO), which is not observed
with the classical indirectly acting sympathomimetic
amines [24]. Furthermore, in contrast to tyramine,
amezinium itself is not a sub strate of MAO. It releases
small amounts of NA from the nerve endings into the
synaptic cleft, but at a lower rate than tyramine [25,

301.
The aim of the present study was to investigate the
cardiovascular effects of amezinium in man after oral
administration. The quantitative measurements were
performed exclusively by non-invasive techniques. In
addition, plasma catecholamines were measured in
order to elucidate its mechanism of action in man.

Material and Methods

Subjects
There were 6 volunteers, 4 females and 2 males, average age 23.8 years (21-26 years), average height
168 cm (160-175 cm), and average bodyweight 56.4 kg
0031-6970/82/0023/0015/$01.20

16

G.G. Belzet al.: CardiovascularEffectsof Amezinium

=

;7" 11C
,E
lOC

._~_
._.9.E

Time Sequence
(min)

t
I
-30

Bodyeosition

I ""J

~'
~I'i~ii
" 0 +10

30
I

I'[I

Plasma Catecho[amines
Registrations

9c

,+

60
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90
I

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~,
"50 40

II

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6C

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10~1os

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II

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140

I
Actual Time a.m. 8r--~-E~._
is
8 8a5 8ss

g 13o

Fig. 1. Schematic presentation of daily study protocol. Body position is indicatedas supine or 80 head-uptilt by the symbols.One

~ 120

tiltingexperimentwas performedwithoutdrug administrationand

another 120 min followingtreatmentwith placebo or amezinium.
+ indicatestimepointsof collectionof blood for determinationof
plasma catecholamines and measurement of the various parameters of cardiovascularfunction

N 110
I~ 100
90

Techniques
The echocardiogram, electrocardiogram (Lead II
ECG), impedance cardiogram (ICG) and phonocardiogram were recorded simultaneously using a Kontron Medical IREX II ultrasonic unit. Five consecutive heart cycles from each recording were averaged
to obtain a mean value. The impedance cardiogram
was obtained with a Minnesota Impedance Cardiograph Model 400. Cardiograph Electrode Tape (Instrumentation for Medicine Inc., Greenwich, USA)
was applied as described elsewhere [3, 13]. Pre-ejection period (PEP) was measured from the Q-wave in
the ECG to the intersection of the d Z / d t curve with its
standard zero-line [2], and was corrected for heart rate
according to Weissler et al. [32] and Weissler and
Schoenfeld [33], resulting in PEPc. Left ventricular
ejection time was measured from the end of PEP to
the first high frequency components of aortic closure
[2, 31.
A 2.25 MHz transducer, 13 mm outside diameter,
medium focus, was used to obtain the echocardiograms. Echocardiography was performed by standard techniques to obtain a simultaneous record of the
interventricular septum and the epicardium and endocardium of the posterior wall of the left ventricle,

II

I"-[~
100

(48-62 kg). The volunteers did not have any disease or

a history of disease of the heart, lung, kidneys, or liver.
On examination four weeks prior to the test, all volunteers had signs of sympathicotonic dysregulation according to the criteria of Thulesius [27]. In each subject a clear echocardiogram of the left ventricle was
made in the supine and head-up positions. The subjects did not take any other drug during the trial period. Written informed consent was obtained from
each volunteer.

-!

II

~11~- [_ --,t

i"
I

II

90
80
70

60
k5

50

II

01

10

30

60

90

It

1201

10(min)

Fig.2. Time course of heart rate and systolicand diastolicblood

pressures in experimentswith oral administrationof placebo (PL)
(Q~---O) or amezinium30 mg (AM)(A
A). AM or PLwas
given afterthe end of the firsttiltingexperiment * p < 0.05compared to PL; mean +_SEM
just below the tip of the anterior leaflet of the mitral
valve [8]. The distances between the endocardial surfaces of the left ventricular posterior wall and the interventricular septum were measured at end-diastole
(R-wave in ECG) and end-systole.
The mean velocity of circumferential fibre shortening (VcFmean) was calculated from Vc~ mean =
(EDD-ESD)
The end-diastolic (VED) and endEDD x LVET"
systolic (VES) volumes were calculated according to
the formula of Teichholz et al. [26].
Stroke volume (SV) was taken by subtracting VES
from VED. Cardiac omput was calculated by SV x
HR. Total peripheral resistance was calculated assuming brachial artery mean pressure (BAPm):
BAPm = BPdiastolic + (BPsystolic-BPdiastolic) x 0.43 (Wezler and B6ger [341). Brachial artery
blood pressure was measured using an ordinary mercury manometer.

Plasma Catecholarnines
Venous blood samples (5 ml) taken without venous
congestion from an antecubital vein into heparinized

G, G. Belz et al.: Cardiovascular Effects of Amezinium

3.2

2.8

~ 2A

u_
~ 2.o

PL_

1.6
t.2

Jk

0.8

5.2

oJ
-,~

4.8

-6 4,0

h~
LIJ

3.6
3,2

~, 28
2.4

2.0
1.6

-5

0 I

10(min)

Fig.3. Velocity of mean circumferential fibre shortening (Vcvmean)

and end-systolic and end-diastolic diameters of the left ventricle
during the second tilting experiment 120 rain (= 120 rain on the
time axis) following administration of placebo (PL) (0--------0) or
amezinium 30 mg (AM) (
). (For details see Fig. 2)

syringes were immediately transferred into Eppendoff reaction vessels containing 20 ~1 of a freshly prepared, ice cold solution of 95 mg EGTA and 60 mg reduced glutathione per ml, adjusted to pH 6.5. Plasma
was immediately separated in a refrigerated centrifuge and was stored at - 70 C until analysis. Quantitative determinations of noradrenaline and adrenaline in plasma were performed essentially according
to the method described by Appel et al. [1].
Stud), Protocol and Measurements
Each of the volunteers was studied twice over a period of 7 days. On each study day the volunteers received, in a double-blind, randomized sequence,
ameziniummetilsulfate 30 mg (3 tablets of Regulton ,
10 mg each) or an equivalent number of placebo
tablets. During the days preceding the study, the volunteers were required to adhere to the following, instructions: from noon no excessive physical activity
or sport, and no coffee, china tea, cola drinks, smoking, alcohol or drugs were allowed; from 10:00 p.m.
the volunteers had to rest in bed and to fast.
On the study days the fasting volunteers arrived at
the laboratory at 7:30 a.m. A Vygoflon T persistent
Teflon venous needle was inserted in an antecubital

17

vein in the left arm. The electrodes for ECG and ICG
and the microphone for the phonocardiogram were
applied. The electrodes for the ICG remained in place
during the entire study period for each day.
The subject rested for 15 rain in the supine position on a tilt table.
After the resting period, two basic recordings were
made 5 min apart. Thereafter, the subjects were tilted
to 80 head-up position within 10 sec, and records
were made 1, 5, and 10 min after tilting. When at 80
tilt, 20% of the volunteer's weight was supported by
padded arm supports under the axilla and he sat on a
bycicle seat, while his legs dangled unsupported. The
subject was returned to the supine position and the
medication was given with 100 ml water according to
the randomization plan. Repeated recordings of the
parameters and venous blood samples in the supine
position were made at 30, 60, 90,115 and 120 min after
drug administration. Following this, the second tilting
experiment was done according to the protocol of the
first one, with blood sampling after 1, 5, and 10 min of
tilting. The complete plan of each study day is depicted in Fig. 1.
Statistical Evaluation
The arithmetic means and univariate 95%-confidence
intervals were calculated for each time point. 'Statistically significant' differences (differences with confidence limits not including '0') between amezinium
and placebo are marked on the graphs by * '. Data
shown in the figures are mean values + SEM (n = 6).

Results

Effects o f Tilt and A mezinium on Heart Rate (HR)

and Blood Pressure
As expected, tilt increased HR. At the end of 10 min
tilting, the rise was 20 and 40 beats/min, respectively,
compared with the values before and after placebo
administration (Fig.2). The decrease in systolic and
diastolic blood pressures was more pronounced during tilting following than before placebo administration. These variations could be explained by increased orthostatic sensitivity of the volunteers due to
the 120 min resting period in supine position. Amezinium did not change resting HR, and only slightly increased HR above placebo value during tilt. Systolic
blood pressure was continuously enhanced by amezinium, reaching + 30 mmHg by 120 min after administration (Fig.2). Although the decrease in systolic
blood pressure during tilt was more pronounced after
amezinium than as placebo, its level became stabilized above its pre-treatment level, and was about
+ 20 mmHg above the corresponding placebo value.
Similar behaviour after amezinium was observed in

18

G.G. Belz et al.: Cardiovascular Effects of Amezinium

"~ +40

3.5

Z,,0

Z..5

u +30

a_ * 2 0
*10
0
-10
-20
-30
-40

3.0

5.0
5.5
EDD (cm)

Fig.4, End-diastolic diameter of the left ventricle (EDD; abscissa)

versus pre-ejection period corrected for heart rate (PEPc; ordinate). Mean values immediately before and 1 rain after tilting are
shown for 4 experiments: O
O before and ~
120 rain
following placebo; A
A before and
120 rain following amezinium 30 mg (For details see Fig.2)
800

Effects of Tilt and Amezinium

on Systolic Time Intervals'

g
o

PL N,t

600

AM]

o
(,.9

400
o

{,9

200

E
I

30

60

90

..........

120 1

10

turn secondary to a shift of blood into the caudal venous system [18, 20]. The changes in EDD remained
almost unaffected by amezinium as compared to
placebo. ESD in the placebo phase was progressively
diminished by 10 min of tilting, from 3.1 to 2.2 cm.
ESD under the influence of amezinium during tilt
rapidly fell from 3.0 to 1.8 cm, and then began to approach end values similar to those measured 10 rain
after tilt during placebo.
Compared to placebo, amezinium did not affect
cardiac output (average 4100 ml/min) during the
120 min resting period (results not shown). During tilt
under placebo, there was a rapid initial drop in cardiac output of 1440 ml/min (to 2660 ml/min), followed by gradual stabilization of output. However,
amezinium limited the reduction in cardiac output to
670 ml/min (to 3430 ml/min) and generally maintained the output at that level.
Neither tilt nor the drug induced any significant
change in total peripheral resistance (results not
shown).

(min)

Fig.5. Plasma catecholamines following oral administration of

placebo (PL; O, O) and amezinium 30 mg (AM; A, A). Mean
values _+ SEM for noradrenaline (NA) and adrenaline (A) are
shown

the diastolic blood pressure, but the changes were

smaller and were not notably different from those of
placebo.

Effects of Tilt and Amezinium on Variables Determined

by Means of Echocardiography
Throughout the 120 min for which the volunteers remained in the supine position after treatment with
placebo and amezinium, no change was observed in
EDD, ESD, or in Vcv mean (Fig.3). Elevation of
Vcvmean did occur during the 80 tilt after placebo or
amezinium, but, the rate and extent of the changes differed. After placebo, the VcFmean increased from 1.2
to 2.t s -1 after 10 min, whereas the increase during
amezinium was sudden and larger from 1.3 to 2.4 s -1
in 1 min (Fig. 3). After both treatments EDD was reduced following tilt, due to a decrease in venous re-

Recent studies have shown that before and during tilt

amezinium can induce distinct, significant shortening
of the systolic time intervals corrected for heart rate
[4]. These results (not depicted) were confirmed and
extended in the present investigation. When values of
EDD (compare Fig.3) as a measure of preload were
correlated with the simultaneously determined PEPc,
as a measure of cardiac performance, the result was
part of a cardiac function curve. This curve may give
insight into changes in the inotropic state. As depicted
in Fig. 4, in the supine position amezinium markedly
reduced PEPc by - 15 ms (p < 0.05) in relation to the
controls, whereas EDD was not affected. When the
subjects were placed under orthostatic stress by tilting, two changes occurred:
1. Compared to placebo there was some additional decrease in EDD following amezinium.
2. Despite this decrease in preload, during amezinium the PEPc under tilt was lengthened by only
30 msec, whereas during placebo its prolongation was
approximately 50 ms.Compared to the placebo phase
during tilt, PEPc was 30 ms shorter, whereas in the supine position the difference due to the effect of the
drug was only 15 ms.

Effects of Tilt and A mezinium on Plasma

Catecholamines
As expected [21], a pronounced increase in noradrenaline concentration in plasma (mean values from
267 ng/l to 619 ng/1) was found 10 min following tilt
(Fig. 5). Adrenaline concentration remained almost
unaltered. Up to 120 min after administration, amezi-

G.G. Belzet al.: CardiovascularEffectsof Amezinium

nium had not affected catecholamine concentrations
at rest. During tilt, too, amezinium did not affect plasma noradrenaline (Fig. 5).

Discussion
The main results of this placebo-controlled, doubleblind study indicate that amezinium, in subjects in supine position, has a long-lasting effect of increasing
blood pressure, especially its systolic component. In
addition, it is a positive inotropic drug in man. The
cardiac effects of amezinium are clarified by the significant shortening of the pre-ejection period corrected for heart rate (PEPc; Fig.4). In the supine position,
cardiac output, EDD, ESD, and VcFmean showed
only minor changes. More pronounced drug effects
(with the exception of actions on blood pressure, see
below) compared to placebo were observed after tilting stress was induced. Cardiac output remained enhanced relative to placebo, the cardiac performance
in terms of Vcvmean, PEPc, and SV (which is indicated by the relation of ESD to EDD) was distinctly increased above the level during placebo, and also partly above the values before tilting.
PEPc as a measure of cardiac performance is influenced by HR (this influence is eliminated by
Weissler's equations), preload, diastolic blood pressure, and cardiac contractility. At any inotropic level,
the PEPc is most sensitive to change in preload [7]. In
normal hearts, provided the ventricle is not overloaded, according to the Frank-Starling principle a
decrease in preload will lead to a decrease in cardiac
performance and vice versa. Several techniques have
been shown to alter preload; those which decrease
preload (and therefore lengthen PEPc) are tilting [22,
23], haemodialysis [5], nitroglycerin [7], and furosemide [6]. Buch et al., using EDD from echocardiograms as a measure of preload [6, 19], were the first to
combine EDD and PEPc for derivation of cardiac
function curves. Note that in Fig. 3 there are distinct
reductions in EDD induced by tilting. Tilt-induced
reduction in preload, when correlated with prolongation of PEPc, allows comparison of cardiac performance under two different preload situations. Amezinium as compared to placebo did not influence preload,
rather there was a slight diminution of EDD 1 min
after tilting (see Figs. 3 and 4). Therefore, the shortening of PEPc by the drug observed here was not induced by a change in preload. The behaviour of diastolic blood pressure [11] has also to be taken into consideration in relation to PEPc. Since, after amezinium
administration, these values were not lower than
those during placebo, the changes may not be responsible for the observed shortening of PEPc. We can
conclude that, following amezinium, increased cardiac performance is not due to change in ventricular

t9
load, but rather, it is the inotropic level that is enhanced.
It should be noted that, despite the distinct increase in systolic blood pressure in the supine position, a pronounced decrease in systolic pressure still
occurred after tilting, even though the level remained
distinctly above the control level. The latter may be
due to enhanced cardiac output and increased contractility.
In experiments with dogs an increase in peripheral resistance and a redistribution of blood volume
from peripheral compartments has been found [15]
after amezinium. A positive inotropic effect has also
been demonstrated. In contrast, the present study in
man suggests that the cardiac effects predominate under our conditions.
Mechanism of Action
Animal experiments have shown that amezinium
elicits its sympathomimetic effects indirectly, namely
via endogenous noradrenaline (NA). An increase in
NA in plasma was expected to accompany the pronounced increase in systolic blood pressure in the
present investigation (Fig. 2), as has previously been
shown for tyramine [10]. However, this has not been
observed (Fig. 5).
It can be deduced from the results of Steppeler et
al. [25], that after amezinium administration much less
release of NA is required than after tyramine to induce equieffective sympathomimetic effects in isolated perfused rabbit hearts.
In contrast to tyramine, amezinium is one of the
most potent inhibitors of NA-uptake into the nerve
ending; and, it is not a substrate of intraneuronal
MAO but rather it inhibits this enzyme [25, 28]. Thus,
amezinium may act by releasing only a small amount
of catecholamines, which would be prevented from
inactivation by MAO, as well as by the re-uptake into
the neuron. Based on the latter mechanism, it is conceivable why amezinium is pharmacologically effective, especially when NA release is triggered by the orthostatic reflex mechanisms: the most pronounced effects were seen when body position was changed
from the supine into the tilted position (compare
Figs. 3 and 4). A drug with such a mechanism of action
appears not to have been available until now. This
type of drug is not only of theoretical interest, but
might also be of therapeutic value, especially for treatment of hypotensive a n d / o r orthostatic disorders.

Acknowledgements. The statistical analysis evaluation

was kindly done by the Biometric Group of Clinical
Research and Development, Operating Division
Pharma, BASF Aktiengesellschaft, Ludwigshafen,
FRG.
Ameziniummetilsulfate and placebo tablets were
provided by courtesy of Dr. Oloff, Clinical Research

20

and Development, Operating Division Pharma,

BASF Aktiengesellschaft, Ludwigshafen, FRG.
We are grateful to the Dr. Robert Pfleger Stiftung
for its donation of the liquid scintillation spectrometer.
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Received: December 19, 1981

accepted in revised form: January 22,1982

Prof. Dr. med. Gustav G. Belz

Institut ftir Kardiovaskul~ire Therapie
Wilhelmstral3e 16
D-6200 Wiesbaden, Federal Republic of Germany