Download The role of the autonomic nervous system in the

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CIinicalScience(1987)7 2 , 239-244
The role of the autonomic nervous system in the resting
tachycardia of human hyperthyroidism
BENEDITO C. MACIEL, LOURENCO GALLO, JR,JOSg A. MARIN NETO,
U A M. Z. MACIEL, MARIA L. D. ALVES, GLORIA M. F. PACCOLA AND NASSIM IAZIGI
Department of Medicine, Medical School of Ribeirrio Preto, Universityof Srio Paulo, Ribeirrio Preto, State ofScio Paulo,
Brazil
(Received 16 May/3 September 1986; accepted 10 September 1986)
Summary
1. The mechanisms that control resting heart
rate in hyperthyroidism were evaluated in six
patients before and after treatment with propylthiouracil.
2. The patients were subjected to pharmacological blockade under resting conditions in two experimental sessions: first session, propranolol (0.2
mg/kg body weight); second session, atropine (0.04
mg/kg body weight) followed by propranolol (0.2
mg/kg body weight). All drugs were administered
intravenously.
3. Resting heart rate was significantly reduced
from 100 k 6.5 beats/min to 72 f 2.5 beats/&
(P<0.005) after clinical and laboratory control of
the disease. After double blockade, intrinsic heart
rate was reduced from 105 f 6.8 beats/& before
treatment to 98 f6.0 beats/& after treatment
(P<0.025). The reduction in heart rate caused by
propranolol was not significantly different before
( - 13f 1.4 beats/&) and after ( - 9 f1.0 beats/
min) propylthiouracil. In contrast, atropine induced
a higher elevation of heart rate after treatment
(45k 8.6 beats/&) than before treatment (26 st 4.0
beats/&).
4. The present results suggest no appreciable
participation of the sympathetic component of the
autonomic nervous system in the tachycardia of
hyperthyroidism, at least under the conditions of
the present study. The small change observed in
intrinsic heart rate, although significant, seems to
indicate that this is not the most important mechanism involved in this tachycardia.
Correspondence: Dr Benedito Carlos Maciel, Departamento de Clinica MBdica, Faculdade de Medicina de
Ribeirlo Preto, 14049-Ribeirlo Preto, SP, Brazil.
5. Our results suggest that an important reduction in the efferent activity of the parasympathetic
component participates in the mechanisms that
m o d e resting heart rate in hyperthyroidism.
Key words: autonomic nervous system, heart rate,
hyperthyroidism, intrinsic heart rate, tachycardia.
Abbreviations: T3,tri-iodothyronine; T4,thyroxine.
Introduction
Increased resting heart rate is one of the most outstanding clinical characteristics among the signs and
symptoms of hyperthyroidism. Increased intrinsic
heart rate of the sinus node, increased sympathetic
autonomic activity and reduced parasympathetic
tonus over the heart may potentially participate in
the genesis of this tachycardia by acting separately
or in combination. Many doubts exist, however,
with respect to the relative contribution of these factors. The notable similarities between the clinical
manifestations of hyperthyroidism and the clinical
manifestations caused by adrenergic hyperactivity
have stimulated intensive studies of the possible
interactions between thyroid hormones and the
sympathetic nervous system. Although there are
many clues that support this hypothesis [l-71, the
precise nature of this inter-relationship has not been
fully elucidated [6, 71. On the one hand, there is
evidence indicating that sympathetic stimulation
may influence the secretion of thyroid hormones [8],
that the number of /3-adrenoceptors is increased in
hyperthyroidism [9,10] in the rat; moreover the use
of /3-adrenoceptor blockers may influence the
peripheral conversion of thyroxine (T4)to tri-iodothyronine (TJ [ll], in addition to producing con-
240
B. C. Maciel et al.
siderable symptomatic improvement accompanied
by a significant reduction in heart rate [l, 12, 131.
On the other hand, studies have been published
which have reported reduction of plasma noradrenaline levels in hyperthyroidism [14, 151, controversial results with respect to the number of
p-adrenoceptors in the lymphocytes of human
hyperthyroid patients [16, 171 and with respect to
cardiovascular sensitivity to circulating catecholamines [2, 5, 181. Today, definite evidence of the
existence of hyperactivity of the sympathetic system
in thyrotoxicosis is still lacking [6,19].
The contribution of a higher frequency of
intrinsic depolarization of the sinus node associated
with the direct effect of thyroid hormones on the
heart has also been proposed to explain the tachycardia occurring in hyperthyroidism [20-221. The
possible modification of parasympathetic activity
has not been extensively investigated. However,
studies carried out in animals [23, 241 and in man
[25] have reported results that are consistent with
reduced parasympathetic activity.
The present study was designed to re-evaluate
the relative contribution of neural factors and of
intrinsic heart rate as mechanisms determining the
occurrence of tachycardia in human hyperthyroidism. To our knowledge, this is the first time that a
group of patients has been studied under both
thyrotoxicosis and euthyroid (after clinical treatment) conditions using pharmacological blockade
of the efferent divisions of the autonomic nervous
system.
Methods
Six patients (all women), aged 25-37 years
(31f 1.9 years, mean fSEM), with hyperthyroidism
were studied after having freely given informed
consent to participate in the investigation. The
study was camed out before and after clinical control of the disease with propylthiouracil. The
diagnosis of thyrotoxicosis was based on clinical
parameters, on the elevation of serum T4levels and
of T3levels and on the excessive 1311 uptake by the
thyroid. The patients showed no signs or symptoms
of heart failure. Radiological examination showed
that the dimensions of the heart rate were normal
and the two-dimensional echocardiogram showed
no morphological or dynamic abnormalities.
Electrocardiography showed the presence of sinus
rhythm in all patients. After treatment (follow-up
range: 2-6 months) with propylthiouracil, all
patients showed considerable symptomatic
improvement and normalization of T4and T3levels.
During the two phases of the study (before and
after treatment), each individual participated in two
experimental sessions held at the same time of day
and spaced at least 24 h apart, in postabsorptive
state after a light meal. During each experimental
session, the patients lay in supine decubitus in a
comfortable bed, with room temperature stabilized
around 22°C. The drugs were injected through an
intravenous butterfly cannula maintained patent
with 0.9% NaCl solution and positioned in a superficial vein of the arm. Heart rate was continuously
monitored and recorded through a cardiotachometer (C model, Hewlett-Packard) coupled to an
electrocardiogram channel.
After a 20 min rest in the supine position, drug
administration was started. During the first session,
four identical doses of propranolol (0.05 mg/kg
body weight) were administered at 3 min intervals,
During the second session, the patients initially
received four identical doses of atropine sulphate
(0.01 mg/kg body weight) at 3 min intei-vals. Five
minutes after the last dose, propranolol was administered as during the first session. Thus, we administered total doses of propranolol equivalent to 0.2
mg/kg body weight and total doses of atropine
equivalent to 0.04 mg/kg body weight, which are
known to be able to produce full efferent blockade
of the components of the autonomic nervous
system of the heart under resting conditions [26]
and also to permit the evaluation of intrinsic heart
rate [27].
The same procedure was carried out before and
after clinical control of the disease, with administration of the antithyroid drug being maintained during re-evaluation in the second phase. The changes
observed in heart rate were compared by Student’s
(-test for paired samples, with the level of significance set at 5%. Heart rate values are expressed as
the mean of the values obtained at 30 s intervals
during the different phases of the study.
Results
Resting heart rate significantly decreased
( P < 0.005) after clinical and laboratory control of
the disease from 100f 6.5 beats/& (mean fS E M )
to 72 f2.5 beats/&.
Fig. 1 shows the mean variations in heart rate
after pharmacological blockade before and after
clinical control of the disease. The individual heart
rate values obtained under the different conditions
employed in this study are shown in Tables 1 and 2.
The heart rate responses to the different doses of
the blocking agents before and after treatment
showed sharp flattening of the curve from the third
dose, indicating that additional doses would not
have been likely to cause further significant changes
in heart rate.
The intrinsic heart rate observed after double
blockade decreased from 105 f6.8 beatslmin
Tachycardia of hyperthyroidism
140 1
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before treatment to 98 f6.0 beatslmin after treatment ( P <0.025). The reduction in heart rate produced by propranolol was not significantly different
before ( - 13 f 1.4 beats/min; - 13.0%) and after
( - 9 f 1.0 beats/min; - 12.5%)propylthiouracil. In
contrast, atropine induced a more marked increase
in heart rate after treatment (45 f8.6 beats/min;
61.5%) than before (26 f 4 . 0 beats/min; 26.0%).
Fig. 2 summarizes these variations in heart rate.
Discussion
In the present study, the contribution of the components of the autonomic nervous system to the
genesis of resting tachycardia observed in human
hyperthyroidism was evaluated using selective
pharmacological blockade of both autonomic
divisions. The drug doses utilized were sufficient to
block the neural activity existing under resting conditions, both on the basis of the experience reported
in the literature [27, 291 and of the analysis of the
shape of the dose-response curves, which showed
no perceptible variations in heart rate after the third
dose of atropine or propranolol. The methodology
used to obtain intrinsic heart rate, although different from that originally described when the two
drugs were administerd simultaneously [26], should
produce equivalent results, considering that the two
drugs are administered within a period of time in
which their effectivenessis maintained [27-291.
Treatment with an antithyroid drug produced
notable symptomatic improvement of the patients
and was accompanied by normalization of the
24 1
B. C. Maciel et al.
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FIG.2. Mean resting heart rate changes observed in
six patients, when hyperthyroid (0)and euthyroid
(o), induced by clinical treatment (basal condition)
and after autonomic pharmacological blockade.
Values represented correspond to -total dose of
atropine (0.04 mg/kg) and propranolol(O.2 mg/kg).
Vertical bars indicate standard error of the mean.
NS, Not significant.
serum levels of thyroid hormones as well as by a
notable reduction of resting heart rate.
The results obtained during administration of
propranolol to patients with thyrotoxicosis or in the
euthyroid condition were superimposable. These
data are not compatible with the existence of
increased sympathetic activity in hyperthyroid individuals, under resting conditions, and agree with
previous observations [30, 311 showing that the
reductions of heart rate evoked by intravenous
administration of propranolol were comparable in
normal and hyperthyroid individuals.
Furthermore, clinical control of the patients
induced a significant reduction in intrinsic heart
rate. This observation demonstrates the contribution of a non-autonomic mechanism, which probably depends on the direct action of thyroid
hormones on the sinus node, in determining the
Tachycardia of hyperthyroidism
resting tachycardia of hyperthyroidism. However, in
the present investigation, the magnitude of the
variation in intrinsic heart rate was not sufficient to
explain the important reduction in resting heart rate
observed .after clinical control of the disease.
Studies conducted on animals [20-221 have
reported results compatible with higher depolarizing frequency of the sinus node in experimental
hyperthyroidism. This possibility was also considered in man [32, 331 on the basis of the determination of intrinsic heart rates, which were higher
than expected from the regression lines obtained in
normal individuals.
The contribution of the parasympathetic component to the tachycardia occurring in thyrotoxicosis
has not been extensively evaluated. Studies carried
out on hyperthyroid animals [22-241 have demonstrated that the negative chronotropic response of
the heart during electrical stimulation of the vagus
was considerably lower than in euthyroid controls.
In man, Heimbach & Crout [25] observed that the
administration of increasing doses of atropine produced a lower elevation in heart rate in hyperthyroid patients as compared with a group of
normal individuals. The results of the present study
in the same subjects, before and after control of
hyperthyroidism, agree with these previous observations. Atropine caused a greater increase in resting heart rate after clinical control (euthyroid state)
than before clinical control (thyrotoxic state). These
data indicate that a lower efferent activity of the
cardiac parasympathetic system may exist in hyperthyroidism which contributes to inducing the resting tachycardia occurring in this disorder.
Taken as a whole, the results of the present investigation indicate that the resting tachycardia
occurring in hyperthyroidism is mainly mediated by
a reduction of the parasympathetic activity on the
sinus node and, to a certain extent, by an increase in
intrinsic heart rate. Under the conditions used here,
it was not possible to document an increase in
adrenergic activity. The mechanisms that cause this
reversible modification of the vagal efferent activity
in hyperthyroidism have not been fully elucidated.
They do not seem to depend on increased acetylcholinesterase activity in the heart or even on decreased sensitivity of cardiac receptors to
acetylcholine [24]. It is possible that the amount of
acetylcholine released at the vagal nervous endings
is reduced in hyperthyroidism, but this still awaits
direct demonstration.
Acknowledgment
This work work was supported in part by Conselho
Nacional de Desenvolvimento Cientifico e Tecnol6gico (Roc. 302389-82).
243
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