Br. J. clin. Pharmac. (1978), 6, 297-301
CATECHOLAMINE SENSITIVITY IN HYPERTHYROIDISM AND HYPOTHYROIDISM D.G. McDEVITT,J.G. RIDDELL, D.R. HADDEN & D.A.D. MONTGOMERY Department of Therapeutics and Pharmacology, The Queen's University of Belfast, and Metabolic Unit, Royal Victoria Hospital, Belfast, Northern Ireland
1 Catecholamine sensitivity in hyper- and hypothyroidism has been studied using a standardised isoprenaline sensitivity test. 2 Seven patients with hyperthyroidism and seven with hypothyroidism were tested both when showing evidence of thyroid dysfunction and again when euthyroid. 3 No significant differences were seen in heart rate responses to isoprenaline when patients became euthyroid compared to their response when either hyperthyroid or hypothyroid. 4 These results indicate that sensitivity to catecholamines is not altered in thyroid dysfunction and, in particular, that hypersensitivity does not occur in spontaneous hyperthyroidism.
Introduction The relationship between the sympathetic nervous system and thyroid hormones has been a matter of controversy for many years. Prior to 1960, the hyperdynamic circulatory state of hyperthyroidism was ascribed to catecholamine hypersensitivity said to occur in this disease (Harrison, 1964; Waldenstein, 1966) and the existence of such hypersensitivity is still widely believed and quoted (Turner, 1974; Turner, 1976). However, the investigations on which this concept was based have been criticised because they were largely uncontrolled and because they failed to examine concentration - response relationships to catecholamines, essential to conclusions regarding sensitivity (Levey, 1971). In addition, adequately designed studies in both animals (Van der Shoot & Moran, 1965; Margolius & Gaffney, 1965; Cravey & Gravenstein, 1965; Cairoli & Crout, 1967) and man (Wilson, Theilin, Hege & Valenca, 1966; Aoki, Wilson, Theilin, Lukensmeyer & Leverton, 1967) of catecholamine receptiveness in artificially induced hyperthyroidism have failed to demonstrate hypersensitivity. Despite this, the possibility that patients with spontaneous hyperthyroidism might react differently to catecholamines from subjects with induced-disease have resulted in continued support for the original
Methods Eight hyperthyroid and eight hypothyroid patients were studied. They were selected by the physicians responsible for their clinical care and voluteered after full explanation of the procedures involved. Patients had to have no evidence of other disease, and a normal electrocardiogram, to show biochemical confirmation of the diagnosis and to be taking no drug therapy. Approval for the study was obtained from the local ethical committee. Studies were commenced at 9 am after a light breakfast. Patients lay supine and an isoprenaline sensitivity test was carried out according to the method of Cleaveland, Rangno & Shand (1972). A Butterfly needle was placed in a forearm vein and a slow intravenous infusion of saline commenced. Heart rate was recorded from an electrocardiograph, using the three shortest consecutive R-R intervals. Small, single injections of isoprenaline were administered into a fast-running drip and the increase in heart rate determined from ECG tracings before and after each injection. A log dose-response curve was constructed from isoprenaline dose and heart rate increase for each patient and the dose required to increase resting heart rate by 20 beats/min (I20) was estimated by in-
hypothesis. We have, therefore, studied catecholamine sensitivity in patients with spontaneous thyroid dysfunction, both when they were hyperthyroid or hypothyroid and again when they had become euthyroid.
biochemically euthyroid, the isoprenaline sensitivity test was repeated under identical experimental conditions. Hyperthyroid patients taking carbimazole were asked to discontinue their therapy 48 h prior to the study; hypothyroid patients did not discontinue L-
20
terpolation.
When each patient became clinically and
D. G. McDEVITT, J. G. RIDDELL, D. R. HADDEN & D. A. D. MONTGOMERY
298
b
a
C
c co
20k - -
--
20
Cu
.00 Cu
10 I
10
I
L
L
I
0.001
0.01
0.1
L
0.001
0.01
0.1
Ai
0.001
0.1
0.01
Isoprenaline (pg/kg) Figure 1 Representative isoprenaline doseheart rate response curves in three of the hyperthyroid patients, before (A) and after (0) treatment. W shows the points at which the isoprenaline concentration required to increase heart rate by 20 beats/min (120) were measured. (a) Patient D-no change in dose-response curve from hyperthyroid to euthyroid state. (b) Patient E-hyperthyroid curve shifted to the left of euthyroid curve (indicating catecholamine hypersensitiviity in hyperthyroidism). (c) Patient G-hyperthyroid curve shifted to the right of euthyroid curve (indicating catecholamine hyposensitivity in hyperthyroidism).
thyroxine treatment. The interval between the two tests ranged from 3 to 18 months (mean 10.4 months). Statistical analysis was carried out using least squares regression analysis, Student's paired and unpaired t-tests and analyses of covariance. Results are expressed as the mean + s.e. mean.
Representative dose-response curves in three hyperthyroid patients are shown in Figure 1. These demonstrate (a) no alteration in catecholamine sensitivity from the hyperthyroid to the euthyroid state (Patient D) (b) catecholamine hypersensitivity in hyperthyroidism (Patient E) and (c) catecholamine hyposensitivity in hyperthyroidism (Patient G). The I20 is also shown for each curve. Examination of the slopes of the dose-response curves within each patient by analysis of covariance showed that in only one hypothyroid patient (a) was there a significant difference between the before and after treatment regressions. Her results were excluded, therefore, from the subsequent analysis of position of the dose-response curves. These results are shown in Table 2. It can be seen that in three hyperthyroid patients and in two hypothyroid patients the dose-
Results One patient from each group was not restudied because of failure to achieve biochemical euthyroidism-the hyperthyroid patient had a persistently elevated serum tri-iodothyronine and the hypothyroid one a raised thyroid stimulating hormone concentration. The initial clinical and biochemical findings for the remaining seven patients are shown in Table 1. Table 1
Mean ±s.e. mean observations on seven hyperthyroid and seven hypothyroid patients Sex
Hyperthyroid
Hypothyroid
6F,1 M 6F, 1M
Age
Weight
(years)
(kg)
39.9 + 3.5 43.7 +2.3
56.9 ± 3.8 68.0
Normal ranges: *95-122 % uptake
±4.8
Heart rate
T3*
T4t
(beats/min) (% uptake) (n mol/l) 110.6 + 5.6 61.6 ±4.2
t54-144 n mol/I
82.3
+4.2 126.9
±3.4 t51-142
214.7 + 19.0 8.4 ±4.5
§1.5-7.2 mu/I
F.T./.T
T.S.H.§
269.2
0.05 > 0.05 >0.05
>0.05 > 0.05 >0.05 >0.05 0.05 0.05 > 0.05 > 0.05 > 0.05
Hypothyroid H I J K L M N
0.05 >0.05 > 0.05 > 0.05 > 0.05
>0.05
0.05 0.2 >0.1
CATECHOLAMINE SENSITIVITY IN HYPER- AND HYPOTHYROIDISM
The use of graded infusions of catecholamines, particularly with isoprenaline, has been criticised on the grounds that alterations in vagal tone may occur with infusions of three minutes or more (Briant, Dollery, Fenyvesi & George, 1973) and that prolonged infusion may produce tolerance (Conolly, Davies, Dollery & George, 1971). In contrast, standardised isoprenaline sensitivity tests, based on the measurement of log dose/response curves to rapid intravenous injections of isoprenaline (Cleaveland et al., 1972; George, Connolly, Fenyvesi, Briant & Dollery, 1972), have been shown to be reproducible and consistent within subjects over a period of six months with a coefficient of variation of about 20%: they are also independent of sex, weight, surface area, resting heart rate or vagal activity in normal subjects. However, Cleaveland et al. (1972) cautioned that heart rate increases of greater than 30-35 beats/min or absolute heart rates of greater than 145 beats/min might result in the production of ventricular ectopics. In this present study, because of resting tachycardia in patients with hyperthyroidism, it was decided to aim at heart rate increases of only 20 beats/min, even though this may be less reliable than increases of 25 beats/min (Cleaveland et al., 1972): no ectopic beats were seen. In addition, isoprenaline dose concentrations were calculated on the basis of body
301
weight because of expected weight changes with treatment in both disease groups. With these modifications, considerable variations were seen in individual responses, with shifts in the dose-response curves to the left and to the right after treatment in both groups. These variations did not correlate with thyroid status, type of treatment or duration between the two tests. The subjects were, of course, largely untrained and it is possible that this, together with the interval between the two studies, may have accentuated the expected variations with this technique. Whatever the reasons, it would appear that catecholamine sensitivity is not altered in spontaneous hyperthyroidism and that alternative explanations for the peripheral manifestations of the disease and of their response to 5-adrenoceptor blockade (McDevitt, 1977) must be sought. We would like to thank Dr J.A. Weaver for allowing his patients to participate in this study. We are grateful also to Dr J.D. Merrett for help with the statistical analysis. Requests for reprints to D.G. McDevitt, Department of Therapeutics and Pharmacology, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL.
References AOKI, V.S., WILSON, W.R. & THEILEN, E.O. (1972). Studies on the reputed augmentation of the cardiovascular effects of the catecholamines in patients with spontaneous hyperthyroidism. J. Pharmac. Exp. Ther., 181, 362-368. AOKI,
V.S.,
WILSON,
W.R.,
THEILIN,
E.O.,
LUKENSMEYER, W.W. & LEVERTON, P.E. (1967). The effects of tri-iodothyronine on hemodynamic responses to epinephrine and norepinephrine in man. J. Pharmac. exp. Ther., 157, 62-68. BRIANT, R.H. DOLLERY, C.T., FENYVESI, T. & GEORGE,
D.F. (1973). Assessment of selective ,-adrenoceptor blockade in man. Br. J. Pharmac., 49, 106-114. CAIROLI, VJ. & CROUT, J.R. (1967). Role of the autonomic nervous system in the resting tachycardia of experimental hyperthyroidism. J. Pharmac. exp. Ther., 158, 55-65. CLEAVELAND, C.R., RANGNO, R.E. & SHAND, D.G.
(1972). A standardised isoproterenol sensitivity test. Arch. int. Med., 130, 47-52. CONOLLY, M.E., DAVIES, D.S., DOLLERY, C.T. &
GEORGE, C.F. (1971). Resistance to P-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br. J. Pharmac., 43, 389-402. CRAVEY, G.M. & GRAVENSTEIN, J.S. (1965). The effect of thyroxin, corticosteroids and epinephrine on atrial rate. J. Pharmac. exp. Ther., 148, 75-79. GEORGE, C.F., CONOLLY, M.E., FENYVESI, T., BRIANT, R.
& DOLLERY, C.T. (1972). Intravenously administered isoproteronol sulphate dose-response curves in man. Arch int. Med., 130, 361-364.
HARRISON, T.S. (1964). Adrenal medullary and thyroid relationships. Physiol. Rev, 44, 161-185. LEVEY, G.S. (1971). Catecholamine sensitivity, thyroid hormone and the heart: A re-evaluation. Am. J. Med., 50, 413-420. McDEVITT, D.G. (1977). P-adrenoceptor blockade in hyperthyroidism. In In Advanced Medicine Topics in Therapeutics 3, edited by R.G. Shanks, pp. 100-115. London: Pitman Medical. MARGOLIUS, H.S. & GAFFNEY, T.E. (1965). Effects of injected norepinephrine and sympathetic nerve stimulation in hypothyroid and hyperthyroid dogs. J. Pharmac. exp. Ther., 149, 329-335. TURNER, P. (1974). ,-adrenergic receptor blocking drugs in hyperthyroidism. Drugs, 7, 48-54. TURNER, P. (1976). Beta-adrenoceptor blockade in hyperthyroidism and anxiety. Proc. Roy. Soc. Med., 69, 375-377. VAN DER SHOOT, J.B. & MORAN, N.C. (1965). An experimental evaluation of the reported influence of thyroxine on the cardiovascular effects of catecholamines. J. Pharmac. exp. Ther., 149, 336-345. WALDENSTEIN, S.S. (1966). Thyroid-catecholamine interrelations. Ann. Rev. Med., 17, 123-132. WILSON, W.R., THEILIN, E.O., HEGE, J.H. & VALENCA,
M.R. (1966). Effects of beta-adrenergic receptor blockade in normal subjects before, during and after triiodothyronine induced hypermetabolism. J. clin. Invest., 45, 1159-1169.
(Received August 5, 1977)
CATECHOLAMINE SENSITIVITY IN HYPERTHYROIDISM AND HYPOTHYROIDISM D.G. McDEVITT,J.G. RIDDELL, D.R. HADDEN & D.A.D. MONTGOMERY Department of Therapeutics and Pharmacology, The Queen's University of Belfast, and Metabolic Unit, Royal Victoria Hospital, Belfast, Northern Ireland
1 Catecholamine sensitivity in hyper- and hypothyroidism has been studied using a standardised isoprenaline sensitivity test. 2 Seven patients with hyperthyroidism and seven with hypothyroidism were tested both when showing evidence of thyroid dysfunction and again when euthyroid. 3 No significant differences were seen in heart rate responses to isoprenaline when patients became euthyroid compared to their response when either hyperthyroid or hypothyroid. 4 These results indicate that sensitivity to catecholamines is not altered in thyroid dysfunction and, in particular, that hypersensitivity does not occur in spontaneous hyperthyroidism.
Introduction The relationship between the sympathetic nervous system and thyroid hormones has been a matter of controversy for many years. Prior to 1960, the hyperdynamic circulatory state of hyperthyroidism was ascribed to catecholamine hypersensitivity said to occur in this disease (Harrison, 1964; Waldenstein, 1966) and the existence of such hypersensitivity is still widely believed and quoted (Turner, 1974; Turner, 1976). However, the investigations on which this concept was based have been criticised because they were largely uncontrolled and because they failed to examine concentration - response relationships to catecholamines, essential to conclusions regarding sensitivity (Levey, 1971). In addition, adequately designed studies in both animals (Van der Shoot & Moran, 1965; Margolius & Gaffney, 1965; Cravey & Gravenstein, 1965; Cairoli & Crout, 1967) and man (Wilson, Theilin, Hege & Valenca, 1966; Aoki, Wilson, Theilin, Lukensmeyer & Leverton, 1967) of catecholamine receptiveness in artificially induced hyperthyroidism have failed to demonstrate hypersensitivity. Despite this, the possibility that patients with spontaneous hyperthyroidism might react differently to catecholamines from subjects with induced-disease have resulted in continued support for the original
Methods Eight hyperthyroid and eight hypothyroid patients were studied. They were selected by the physicians responsible for their clinical care and voluteered after full explanation of the procedures involved. Patients had to have no evidence of other disease, and a normal electrocardiogram, to show biochemical confirmation of the diagnosis and to be taking no drug therapy. Approval for the study was obtained from the local ethical committee. Studies were commenced at 9 am after a light breakfast. Patients lay supine and an isoprenaline sensitivity test was carried out according to the method of Cleaveland, Rangno & Shand (1972). A Butterfly needle was placed in a forearm vein and a slow intravenous infusion of saline commenced. Heart rate was recorded from an electrocardiograph, using the three shortest consecutive R-R intervals. Small, single injections of isoprenaline were administered into a fast-running drip and the increase in heart rate determined from ECG tracings before and after each injection. A log dose-response curve was constructed from isoprenaline dose and heart rate increase for each patient and the dose required to increase resting heart rate by 20 beats/min (I20) was estimated by in-
hypothesis. We have, therefore, studied catecholamine sensitivity in patients with spontaneous thyroid dysfunction, both when they were hyperthyroid or hypothyroid and again when they had become euthyroid.
biochemically euthyroid, the isoprenaline sensitivity test was repeated under identical experimental conditions. Hyperthyroid patients taking carbimazole were asked to discontinue their therapy 48 h prior to the study; hypothyroid patients did not discontinue L-
20
terpolation.
When each patient became clinically and
D. G. McDEVITT, J. G. RIDDELL, D. R. HADDEN & D. A. D. MONTGOMERY
298
b
a
C
c co
20k - -
--
20
Cu
.00 Cu
10 I
10
I
L
L
I
0.001
0.01
0.1
L
0.001
0.01
0.1
Ai
0.001
0.1
0.01
Isoprenaline (pg/kg) Figure 1 Representative isoprenaline doseheart rate response curves in three of the hyperthyroid patients, before (A) and after (0) treatment. W shows the points at which the isoprenaline concentration required to increase heart rate by 20 beats/min (120) were measured. (a) Patient D-no change in dose-response curve from hyperthyroid to euthyroid state. (b) Patient E-hyperthyroid curve shifted to the left of euthyroid curve (indicating catecholamine hypersensitiviity in hyperthyroidism). (c) Patient G-hyperthyroid curve shifted to the right of euthyroid curve (indicating catecholamine hyposensitivity in hyperthyroidism).
thyroxine treatment. The interval between the two tests ranged from 3 to 18 months (mean 10.4 months). Statistical analysis was carried out using least squares regression analysis, Student's paired and unpaired t-tests and analyses of covariance. Results are expressed as the mean + s.e. mean.
Representative dose-response curves in three hyperthyroid patients are shown in Figure 1. These demonstrate (a) no alteration in catecholamine sensitivity from the hyperthyroid to the euthyroid state (Patient D) (b) catecholamine hypersensitivity in hyperthyroidism (Patient E) and (c) catecholamine hyposensitivity in hyperthyroidism (Patient G). The I20 is also shown for each curve. Examination of the slopes of the dose-response curves within each patient by analysis of covariance showed that in only one hypothyroid patient (a) was there a significant difference between the before and after treatment regressions. Her results were excluded, therefore, from the subsequent analysis of position of the dose-response curves. These results are shown in Table 2. It can be seen that in three hyperthyroid patients and in two hypothyroid patients the dose-
Results One patient from each group was not restudied because of failure to achieve biochemical euthyroidism-the hyperthyroid patient had a persistently elevated serum tri-iodothyronine and the hypothyroid one a raised thyroid stimulating hormone concentration. The initial clinical and biochemical findings for the remaining seven patients are shown in Table 1. Table 1
Mean ±s.e. mean observations on seven hyperthyroid and seven hypothyroid patients Sex
Hyperthyroid
Hypothyroid
6F,1 M 6F, 1M
Age
Weight
(years)
(kg)
39.9 + 3.5 43.7 +2.3
56.9 ± 3.8 68.0
Normal ranges: *95-122 % uptake
±4.8
Heart rate
T3*
T4t
(beats/min) (% uptake) (n mol/l) 110.6 + 5.6 61.6 ±4.2
t54-144 n mol/I
82.3
+4.2 126.9
±3.4 t51-142
214.7 + 19.0 8.4 ±4.5
§1.5-7.2 mu/I
F.T./.T
T.S.H.§
269.2
0.05 > 0.05 >0.05
>0.05 > 0.05 >0.05 >0.05 0.05 0.05 > 0.05 > 0.05 > 0.05
Hypothyroid H I J K L M N
0.05 >0.05 > 0.05 > 0.05 > 0.05
>0.05
0.05 0.2 >0.1
CATECHOLAMINE SENSITIVITY IN HYPER- AND HYPOTHYROIDISM
The use of graded infusions of catecholamines, particularly with isoprenaline, has been criticised on the grounds that alterations in vagal tone may occur with infusions of three minutes or more (Briant, Dollery, Fenyvesi & George, 1973) and that prolonged infusion may produce tolerance (Conolly, Davies, Dollery & George, 1971). In contrast, standardised isoprenaline sensitivity tests, based on the measurement of log dose/response curves to rapid intravenous injections of isoprenaline (Cleaveland et al., 1972; George, Connolly, Fenyvesi, Briant & Dollery, 1972), have been shown to be reproducible and consistent within subjects over a period of six months with a coefficient of variation of about 20%: they are also independent of sex, weight, surface area, resting heart rate or vagal activity in normal subjects. However, Cleaveland et al. (1972) cautioned that heart rate increases of greater than 30-35 beats/min or absolute heart rates of greater than 145 beats/min might result in the production of ventricular ectopics. In this present study, because of resting tachycardia in patients with hyperthyroidism, it was decided to aim at heart rate increases of only 20 beats/min, even though this may be less reliable than increases of 25 beats/min (Cleaveland et al., 1972): no ectopic beats were seen. In addition, isoprenaline dose concentrations were calculated on the basis of body
301
weight because of expected weight changes with treatment in both disease groups. With these modifications, considerable variations were seen in individual responses, with shifts in the dose-response curves to the left and to the right after treatment in both groups. These variations did not correlate with thyroid status, type of treatment or duration between the two tests. The subjects were, of course, largely untrained and it is possible that this, together with the interval between the two studies, may have accentuated the expected variations with this technique. Whatever the reasons, it would appear that catecholamine sensitivity is not altered in spontaneous hyperthyroidism and that alternative explanations for the peripheral manifestations of the disease and of their response to 5-adrenoceptor blockade (McDevitt, 1977) must be sought. We would like to thank Dr J.A. Weaver for allowing his patients to participate in this study. We are grateful also to Dr J.D. Merrett for help with the statistical analysis. Requests for reprints to D.G. McDevitt, Department of Therapeutics and Pharmacology, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL.
References AOKI, V.S., WILSON, W.R. & THEILEN, E.O. (1972). Studies on the reputed augmentation of the cardiovascular effects of the catecholamines in patients with spontaneous hyperthyroidism. J. Pharmac. Exp. Ther., 181, 362-368. AOKI,
V.S.,
WILSON,
W.R.,
THEILIN,
E.O.,
LUKENSMEYER, W.W. & LEVERTON, P.E. (1967). The effects of tri-iodothyronine on hemodynamic responses to epinephrine and norepinephrine in man. J. Pharmac. exp. Ther., 157, 62-68. BRIANT, R.H. DOLLERY, C.T., FENYVESI, T. & GEORGE,
D.F. (1973). Assessment of selective ,-adrenoceptor blockade in man. Br. J. Pharmac., 49, 106-114. CAIROLI, VJ. & CROUT, J.R. (1967). Role of the autonomic nervous system in the resting tachycardia of experimental hyperthyroidism. J. Pharmac. exp. Ther., 158, 55-65. CLEAVELAND, C.R., RANGNO, R.E. & SHAND, D.G.
(1972). A standardised isoproterenol sensitivity test. Arch. int. Med., 130, 47-52. CONOLLY, M.E., DAVIES, D.S., DOLLERY, C.T. &
GEORGE, C.F. (1971). Resistance to P-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br. J. Pharmac., 43, 389-402. CRAVEY, G.M. & GRAVENSTEIN, J.S. (1965). The effect of thyroxin, corticosteroids and epinephrine on atrial rate. J. Pharmac. exp. Ther., 148, 75-79. GEORGE, C.F., CONOLLY, M.E., FENYVESI, T., BRIANT, R.
& DOLLERY, C.T. (1972). Intravenously administered isoproteronol sulphate dose-response curves in man. Arch int. Med., 130, 361-364.
HARRISON, T.S. (1964). Adrenal medullary and thyroid relationships. Physiol. Rev, 44, 161-185. LEVEY, G.S. (1971). Catecholamine sensitivity, thyroid hormone and the heart: A re-evaluation. Am. J. Med., 50, 413-420. McDEVITT, D.G. (1977). P-adrenoceptor blockade in hyperthyroidism. In In Advanced Medicine Topics in Therapeutics 3, edited by R.G. Shanks, pp. 100-115. London: Pitman Medical. MARGOLIUS, H.S. & GAFFNEY, T.E. (1965). Effects of injected norepinephrine and sympathetic nerve stimulation in hypothyroid and hyperthyroid dogs. J. Pharmac. exp. Ther., 149, 329-335. TURNER, P. (1974). ,-adrenergic receptor blocking drugs in hyperthyroidism. Drugs, 7, 48-54. TURNER, P. (1976). Beta-adrenoceptor blockade in hyperthyroidism and anxiety. Proc. Roy. Soc. Med., 69, 375-377. VAN DER SHOOT, J.B. & MORAN, N.C. (1965). An experimental evaluation of the reported influence of thyroxine on the cardiovascular effects of catecholamines. J. Pharmac. exp. Ther., 149, 336-345. WALDENSTEIN, S.S. (1966). Thyroid-catecholamine interrelations. Ann. Rev. Med., 17, 123-132. WILSON, W.R., THEILIN, E.O., HEGE, J.H. & VALENCA,
M.R. (1966). Effects of beta-adrenergic receptor blockade in normal subjects before, during and after triiodothyronine induced hypermetabolism. J. clin. Invest., 45, 1159-1169.
(Received August 5, 1977)
