CATECHOLAMINE SENSITIVITY IN HYPERTHYROIDISM AND HYPOTHYROIDISM

Transcription

1 Br. J. clin. Pharmac. (1978), 6, CAECHOAINE SENSIIVIY IN HYPERHYROIIS AN HYPOHYROIIS.G. cevi,j.g. RIE,.R. HAEN &.A.. ONGOERY epartment of herapeutics and Pharmacology, he Queen's University of Belfast, and etabolic 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 hese results indicate that sensitivity to catecholamines is not altered in thyroid dysfunction and, in particular, that hypersensitivity does not occur in spontaneous hyperthyroidism. Introduction he 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 (urner, 1974; urner, 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 (evey, 1971). In addition, adequately designed studies in both animals (Van der Shoot & oran, 1965; argolius & Gaffney, 1965; Cravey & Gravenstein, 1965; Cairoli & Crout, 1967) and man (Wilson, heilin, Hege & Valenca, 1966; Aoki, Wilson, heilin, ukensmeyer & everton, 1967) of catecholamine receptiveness in artificially induced hyperthyroidism have failed to demonstrate hypersensitivity. espite 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 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. 20 ethods Eight hyperthyroid and eight hypothyroid patients were studied. hey 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 interpolation. When each patient became clinically and biochemically euthyroid, the isoprenaline sensitivity test was repeated under identical experimental conditions. patients taking carbimazole were asked to discontinue their therapy 48 h prior to the study; hypothyroid patients did not discontinue -

2 298. G. cevi, J. G. RIE,. R. HAEN &. A.. ONGOERY a b C c co Cu Representative dose-response curves in three hyperthyroid patients are shown in igure 1. hese demonstrate (a) no alteration in catecholamine sensitivity from the hyperthyroid to the euthyroid state (Patient ) (b) catecholamine hypersensitivity in hyperthyroidism (Patient E) and (c) catecholamine hyposensitivity in hyperthyroidism (Patient G). he 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. hese results are shown in able 2. It can be seen that in three hyperthyroid patients and in two hypothyroid patients the dose-.0-0 Cu 20k I I I Isoprenaline (pg/kg) Ai igure 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 -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). 0.1 thyroxine treatment. he 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. 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. he initial clinical and biochemical findings for the remaining seven patients are shown in able 1. able 1 ean ±s.e. mean observations on seven hyperthyroid and seven hypothyroid patients Sex Age Weight Heart rate 3* 4t../. (years) (kg) (beats/min) (% uptake) (n mol/l) 6, ± , ±4.8 ±4.2 ±3.4 ±4.5 ±3.0.S.H. (mu/l) < ±9.6 Normal ranges: * % uptake t n mol/i t mu/i

3 CAECHOAINE SENSIIVIY IN HYPER- AN HYPOHYROIIS 299 response curve shifted significantly with treatment. he direction of the shift is shown by the mean response adjusted to a common isoprenaline dose within each patient before and after treatement (able 2). In the hyperthyroid group, the before treatment curve lay to the left of the euthyroid curve in one patient (E) (indicating hypersensitivity to isoprenaline) and to the right in two patients (C and G) (indicating hyposensitivity). In the two hypothyroid patients ( and N) the shift indicated decreased sensitivity in the disease state. hese mean responses cannot be compared between patients or between groups because adjustment is not made to a common dose between patients. In addition, comparision of slopes of dose-response lines between patients before and after treatment was made in each separate group (able 3). his indicated dissimilarity of slopes for hypothyroid patients and for hyperthyroid patients when euthyroid and invalidates calculation of a pooled line for these groups. A comparision of all hyperthyroid with all hypothyroid patients or of all patients within either group before and after treatment cannot be made. Results for calculation of the dose of isoprenaline required to produce a fixed response (I20) are shown in able 3. Patient 1 has again been excluded because of the non-parallelism of dose-response curves, but her inclusion would not have altered the overall results. It can be seen that in neither the hyperthyroid nor the hyporthyroid patients was the I20 significantly different after treatment from that obtained before. Variation in response was obtained, with some patients appearing more sensitive to isoprenaline in the disease state than when euthyroid and others less sensitive. his was true for both forms of thyroid disease and, in the hyperthyroid group, there was no evidence that the type of treatment influenced this variation. he mean I20 in the hyperthyroid and the two euthyroid groups appeared similar (around 0.02 gig/kg). In contrast, even though the difference was not significant, the mean I20 in the hypothyroid group was twice that calculated in the hyperthyroid group. However, the individual results show that one hypothyroid patient (N) with an I20 of jg/kg differed markedly from others in that group, for no obvious reason. If her result is excluded, the mean I20 of the hypothyroid group becomes jg/kg which is comparable to the means of the other three goups. Apart from the anticipated cardiovascular and respiratory symptoms, no untoward side-effects of the isoprenaline injections occurred in any patient and no test had to be discontinued before its completion. able 2 (a) Comparison of before and after treatment dose-response regressions within each patient. (b) ean response adjusted to a common dose within each patient before and after treatment. Patient and Group a P values for the comparison of Slopes Positions b Adjusted mean response (beats/min) Before After treatment treatment (Euthyroid) A BC E G H I J K N < 0.05 < (i).. indicates that positions cannot be compared because before and after treatment regressions differ significantly (at P<0.05) in slope. (ii) Adjusted mean responses above cannot be compared between patients or between groups because adjustment is not made to a common dose between patients. (iii) Significant difference in positions indicates a significant difference between adjusted mean responses.

4 300. G. cevi, J. G. RIE,. R. HAEN &. A.. ONGOERY iscussion he results of these studies in patients with spontaneous hyperthyroidism suggest that catecholamine hypersensitivity is not present in this disease. his finding is in agreement with the conclusions of similar investigations of triiodothyronine-induced hypermetabolism both in animals and in man (Van der Shoot & oran, 1965; argolius & Gaffney, 1965; Cravey & Gravenstein, 1965; Wilson, et al, 1966; Aoki et al., 1967). able 3 Comparison of slopes of dose-response lines between patients before and after treatment separately Euthyroid (Hyper) Euthyroid (Hypo) P values for comparison of slopes In addition if hypersensitivity existed in hyperthyroidism, patients with hypothyroidism should be less sensitive to catecholamines. However, in the present study, responsiveness to isoprenaline did not differ significantly either in patients when hypothyroid compared to when they became euthyroid or between groups of hyperthyroid and hypothyroid patients. Apparent variations in the mean I20 between these groups were contributed to principally by one hypothyroid individual whose 120 was more than twice that found in any other patient. he reasons for this difference were not known but without this result the groups were not dissimilar, allowing for biological variation. hus from the balance of evidence from this study, it would appear that alterations in thyroid hormone concentrations do not affect responsiveness to catecholamines. In support of this, Aoki, Wilson & heilin (1972), infusing graded doses of noradrenaline and adrenaline intravenously into five patients both when they were spontaneously hyperthyroid and again when euthyroid, found no indication of augmented haemodynamic responses to these drugs in hyperthyroidism. able 4 Calculated isoprenaline dose (tg/kg) required to increase heart rate by 20 beats/min (120) in hyperthyroid and hypothyroid patients before and after treatment. Patient Sex Age (years) reatment A BC E G ean s.e. mean H J K N ean s.e. mean R=Radio-iodine therapy: =rug therapy: =hyroxine. -Before treatment v after treatment -Before treatment v after treatment before treatment v hypothyroid before treatment R R RR Before treatment (gg/kg) After treatment (Euthyroid) p >0.6 >0.2 >0.1

5 CAECHOAINE SENSIIVIY IN HYPER- AN HYPOHYROIIS 301 he 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, ollery, enyvesi & George, 1973) and that prolonged infusion may produce tolerance (Conolly, avies, ollery & 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, enyvesi, Briant & ollery, 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 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 References AOKI, V.S., WISON, W.R. & HEIEN, E.O. (1972). Studies on the reputed augmentation of the cardiovascular effects of the catecholamines in patients with spontaneous hyperthyroidism. J. Pharmac. Exp. her., 181, AOKI, V.S., WISON, W.R., HEIIN, E.O., UKENSEYER, W.W. & EVERON, P.E. (1967). he effects of tri-iodothyronine on hemodynamic responses to epinephrine and norepinephrine in man. J. Pharmac. exp. her., 157, BRIAN, R.H. OERY, C.., ENYVESI,. & GEORGE,.. (1973). Assessment of selective,-adrenoceptor blockade in man. Br. J. Pharmac., 49, CAIROI, VJ. & CROU, J.R. (1967). Role of the autonomic nervous system in the resting tachycardia of experimental hyperthyroidism. J. Pharmac. exp. her., 158, CEAVEAN, C.R., RANGNO, R.E. & SHAN,.G. (1972). A standardised isoproterenol sensitivity test. Arch. int. ed., 130, CONOY,.E., AVIES,.S., OERY, C.. & GEORGE, C.. (1971). Resistance to P-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br. J. Pharmac., 43, CRAVEY, G.. & GRAVENSEIN, J.S. (1965). he effect of thyroxin, corticosteroids and epinephrine on atrial rate. J. Pharmac. exp. her., 148, GEORGE, C.., CONOY,.E., ENYVESI,., BRIAN, R. & OERY, C.. (1972). Intravenously administered isoproteronol sulphate dose-response curves in man. Arch int. ed., 130, 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. hese variations did not correlate with thyroid status, type of treatment or duration between the two tests. he 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 (cevitt, 1977) must be sought. We would like to thank r J.A. Weaver for allowing his patients to participate in this study. We are grateful also to r J.. errett for help with the statistical analysis. Requests for reprints to.g. cevitt, epartment of herapeutics and Pharmacology, Whitla edical Building, 97 isburn Road, Belfast B9 7B. HARRISON,.S. (1964). Adrenal medullary and thyroid relationships. Physiol. Rev, 44, EVEY, G.S. (1971). Catecholamine sensitivity, thyroid hormone and the heart: A re-evaluation. Am. J. ed., 50, cevi,.g. (1977). P-adrenoceptor blockade in hyperthyroidism. In In Advanced edicine opics in herapeutics 3, edited by R.G. Shanks, pp ondon: Pitman edical. ARGOIUS, H.S. & GANEY,.E. (1965). Effects of injected norepinephrine and sympathetic nerve stimulation in hypothyroid and hyperthyroid dogs. J. Pharmac. exp. her., 149, URNER, P. (1974).,-adrenergic receptor blocking drugs in hyperthyroidism. rugs, 7, URNER, P. (1976). Beta-adrenoceptor blockade in hyperthyroidism and anxiety. Proc. Roy. Soc. ed., 69, VAN ER SHOO, J.B. & ORAN, N.C. (1965). An experimental evaluation of the reported influence of thyroxine on the cardiovascular effects of catecholamines. J. Pharmac. exp. her., 149, WAENSEIN, S.S. (1966). hyroid-catecholamine interrelations. Ann. Rev. ed., 17, WISON, W.R., HEIIN, E.O., HEGE, J.H. & VAENCA,.R. (1966). Effects of beta-adrenergic receptor blockade in normal subjects before, during and after triiodothyronine induced hypermetabolism. J. clin. Invest., 45, (Received August 5, 1977)