Catecholamines and hyperthyroidism

7

Catecholamines and Hyperthyroidism LEWIS LANDSBERG

The participation of catecholamines in the pathogenesis of the hyperthyroid state has intrigued and puzzled clinicians and investigators for the last one hundred years. The evidence in favour of an interaction between catecholamines and thyroid hormones in producing some of the manifestations of hyperthyroidism is considerable; the precise nature of this interaction, however, has remained elusive. Although thyroid hormones and catecholamines have many features in common, they differ in many highly significant ways, as shown in Table 1. The most compelling reason for suspecting involvement of catecholamines in the expression of hyperthyroidism derives from common clinical experience: infusions of epinephrine produce physiological changes that resemble those seen in thyrotoxicosis. Patients with phaeochromocytomas may be mistaken for patients with hyperthyroidism since tachycardia, sweating, weight loss, palpitations and nervousness are common to both diseases. Furthermore, adrenergic blocking agents may profoundly modify the severity of some of the manifestations of hyperthyroidism. Although the way in which catecholamines influence the hyperthyroid state is not completely clear at present, much is known about the interaction of catecholamines and thyroid hormones. The complex literature on this subject will be considered in the following way (Table 2): The effect of catecholamines on thyroid hormone synthesis, release and metabolism; the effect of thyroid hormones on the activity of the sympatho-adrenal system; the effect of thyroid hormones on the sensitivity or responsiveness of various tissues to catecholamines; and, finally, the use of adrenergic blocking agents in the treatment of hyperthyroidism.

THE EFFECT OF CATECHOLAMINES ON BIOSYNTHESIS, RELEASE AND METABOLISM OF THYROID HORMONES Sympathetic Innervation of the Human Thyroid

Nerve fibres originating in the superior cervical ganglion and terminating in the thyroid gland have been recognized for over one hundred years. Although the function of these nerves is still not completely clear, current concepts of the importance of this sympathetic innervation have evolved considerably Clinics in Endocrinology and Metabolism - Vol. 6, No.3. November 1977.

697

698

LEWIS LANDSBERG Table 1. Catecholamines and thyroid hormones: some similarities and differences

Property

Catecholamines

Thyroid hormones

Phylogeny

Ancient and ubiquitous

Ancient and ubiquitous

Embryology

Neuroectoderm

Endoderm

Structure

Tyrosine derivative Low molecular weight amine Catechol group important Metabolites inactive

Tyrosine derivative Low molecular weight amino acid Iodine critical Some metabolites active (T.)

Storage

Large stores - great reserve Subcellular storage particles

Large stores - great reserve Extracellular colloid

Circulating form

Neurotransmitter as well as circulating hormone Freely soluble in plasma Partially bound to albumin t'/, in plasma probably less than I min

Strictly circulating hormone

Physiology

Under direct CNS control Influences most tissues and many processes Specific receptors at cell membrane Effects induced rapidly dissipated quickly Stimulates calorigenesis increases metabolic rate Increases heart rate and cardiac contractility Peripheral vasoconstriction

Regulation by CNS indirect Influences most tissues and many processes Specific intracellular receptors Effects induced slowly - long lasting

Phaeochromocytoma may resemble hyperthyroidism Adrenergic blockade specifically blocks effects of catecholamines

Hyperthyroidism may resemble phaeochromocytoma Adrenergic blockade modifies some of the effects of thyroid hormone

Clinically relevant observations

Sparingly soluble in plasma Tightly protein bound t'l, in plasma several days

Stimulates calorigenesis increases metabolic rate Increases heart rate and cardiac contractility Peripheral vasodilation

over the last decade. It was previously thought that sympathetic nerves were confined predominantly to the vasculature, and it was well known that sympathetic stimulation or infusion of catecholamines caused pronounced vasoconstriction in the thyroid. The physiological significance of this effect on the thyroid vasculature is uncertain, although it is clear that sympathetically mediated vasoconstriction decreases both the delivery of TSH (Melander

Table 2. Catecholamine-thyroid interactions of potential significance 1.

Effect of catecholamines on the biosynthesis, release and metabolism of thyroid hormones.

2.

Effect of thyroid hormones on the activity of the sympathetic nervous system and adrenal medulla.

3.

Effect of thyroid hormones on the sensitivity to catecholamines.

4.

Effect of adrenergic blocking agents on the manifestations of hyperthyroidism.

CATECHOLAMINES AND HYPERTHYROIDISM

699

and Sundler, 1972) and the thyroidal clearance of iodine (Ahn, Athans and Rosenberg, 1969). It is now recognized that the thyroid follicles as well as the vessels are innervated with sympathetic nerve endings; current histochemical fluorescent techniques (Melander et aI, 1974a) and electron microscopy (Tice and Creveling, 1975) have demonstrated adrenergic fibres in close proximity to the thyroid follicular epithelium. If catecholamines influence thyroid hormone biosynthesis or release in vivo, such an effect is presumed to result from the sympathetic innervation of the thyroid follicles and the stimulation of the thyroid follicular cells by locally released norepinephrine. The Effect of Catecholamines on Thyroid Hormone Biosynthesis and Release The effect of catecholamines on iodine uptake and organification has been studied in vitro in thyroid slices and isolated thyroid cells, thereby avoiding the confounding effect of catecholamines on thyroid blood flow. Stimulation of iodine uptake (Melander, Sundler and Westgren, 1973) and organification (Maayan and Ingbar, 1970) by catecholamines has been convincingly demonstrated in these in vitro preparations. The relationship of catecholamine-stimulated thyroid hormone biosynthesis to catecholamine-stimulated glycogenolysis in thyroid cells (Ahn, 1971) and the receptor involved in mediating these effects on the thyroid remain obscure. The effect of catecholamines on thyroid hormone release and secretion has been demonstrated in vivo in experimental animals with TSH secretion blocked by prior hypophysectomy or the administration of suppressive doses of thyroid hormone. Under these circumstances both sympathetic nerve stimulation (Melander, Nilsson and Sundler, 1972) and catecholamine infusions (Ericson et aI, 1970) result in thyroid hormone release, as demonstrated by colloid resorption and increased 131 1 blood levels from previously labelled intrathyroidal hormone stores. In intact animals without TSH suppression, surgical or chemical sympathectomy (Melander et aI, 1974b) or the administration of adrenergic blocking drugs (Coleoni, 1972) transiently reduces thyroid hormone secretion. Although there was some confusion about the adrenergic receptor involved in mediating these effects on thyroid hormone secretion, recent evidence implicates a beta-receptor mechanism (Melander et aI, 1975). The role of the sympathetic nervous system in normal thyroid function, however, remains uncertain. The effect of TSH is certainly overriding, and any catecholamine-induced changes in thyroid hormone synthesis and release would have to be short lived as long as the normal TSH mechanism is intact. It is conceivable that the sympathetic nerves are important in modulating short-term changes in thyroid function in response to certain physiological stimuli (see Chapter 6), but direct evidence for this is lacking. Similarly, the significance of catecholamine effects on the thyroid gland in relation to hyperthyroidism is unknown; it is conceivable that prolonged and intense sympathetic stimulation could enhance thyroid function sufficiently to suppress TSH and induce a hyperthyroid state. There is, however, no evidence that such a mechanism is involved in the initiation or maintenance of increased thyroid hormone output in hyperthyroidism.

700

LEWIS LANDSBERG

The Ef(ed

or Catecholamines on Thyroid Hormone Metabolism

Studies in animals have suggested that catecholamines may increase the rate at which thyroxine is deiodinated (Galton, 1965). More recent work, however, has failed to demonstrate such an effect in man (Hays and Solomon, 1969; Nicoloff, 1970). Since it is now recognized that thyroxine may be deiodinated to either the metabolically active triiodothyronine or the metabolically inactive reverse triiodothyronine, studies of the effect of catecholamines on the relative formation of active versus inactive metabolites will be of interest. However, it should be noted, that, in distinction to the situation in normal man where most of the circulating triiodothyronine is derived from peripheral deiodination of thyroxine, in hyperthyroid patients most of the circulating triiodothyronine is secreted from the thyroid gland itself. The quantitative significance, therefore, of any effect of catecholamines on peripheral conversion of thyroxine to triiodothyronine in hyperthyroidism would be questionable.

THE EFFECT OF THYROID HORMONES ON THE ACTIVITY OF THE SYMPATHO·ADRENAL SYSTEM The activity of the sympatho-adrenal system has been studied in thyrotoxic patients and in experimental animals made hyperthyroid by the administration of exogenous thyroid hormone, as well as in patients with myxoedema and animals made hypothyroid by thyroidectomy or 1111 administration. Contrary to what might be expected, there is no evidence that the sympathetic nervous system or adrenal medulla are overactive in hyperthyroidism. The turnover of cardiac norepinephrine, a measure of sympathetic activity in heart, has been reported to be normal (Beaven, Costa and Brodie, 1963) and, more recently, decreased (Beley, Rochette and Bralet, 1973), in animals made hyperthyroid. Patients with thyrotoxicosis excrete normal or low amounts of norepinephrine in urine (Kuschke, Wernze and Becker, 1960; Wiswell et aI, 1963; Bayliss and Edwards, 1971); plasma levels of norepinephrine are either low or normal (Christensen, 1972, 1973; Stoffer et ai, 1973) in hyperthyroid patients, and plasma levels of dopamine-fJ-hydroxylase (DBH) are depressed (Nishizawa et ai, 1974; Noth and Saulding, 1974). The urinary excretion of epinephrine (Wiswell et ai, 1963; Bayliss and Edwards, 1971), plasma epinephrine levels (Christensen, 1973) and epinephrine secretion rate (Coulombe et ai, 1976) are unchanged in patients with thyrotoxicosis. Conversely, in animals with experimental thyroid deficiency cardiac norepinephrine turnover is markedly accelerated (Landsberg and Axelrod, 1968) indicating increased sympathetic activity. In patients with hypothyroidism urinary norepinephrine excretion is either normal or increased (Kuschke, Wernze and Becker, 1960; Wiswell et aI, 1963; Bayliss and Edwards, 1971), plasma norepinephrine levels are significantly elevated (Christensen, 1972, 1973; Stoffer et ai, 1973), and plasma DBH activity is increased (Nishizawa et ai, 1974). Urinary epinephrine, plasma epinephrine levels, and epinephrine secretion are not significantly changed in hypothyroid subjects.

CATECHOLAMINES AND HYPERTHYROIDISM

701

The evidence, thus, is quite clear that in hyperthyroidism sympathetic activity is normal or slightly suppressed, while in hypothyroidism sympathetic activity is significantly enhanced. Adrenal medullary function is probably not altered in either hypo- or hyperthyroidism. Thus, the 'sympathomimetic' features of hyperthyroidism cannot be explained by simple overactivity of the sympatho-adrenal system, although, as discussed below, 'nonnal' sympathoadrenal activity may be inappropriately high for the patient with hyperthyroidism.

THE EFFECT OF THYROID HORMONES ON THE SENSITIVITY OF PERIPHERAL TISSUES TO CATECHOLAMINES General Considerations

Since catecholamines are apparently not produced in increased amounts in hyperthyroidism, the 'sympathomimetic' features of hyperthyroidism cannot be explained by increased concentration of catecholamines at adrenergic receptors. The suggestion, therefore, has been made that hyperthyroidism renders the peripheral tissues more 'sensitive' or 'responsive' to catecholamines. Such an increase in sensitivity implies that 'normal' amounts of catecholamines at effector cells would result in increased responses, thus producing an adequate explanation of both the sympathomimetic features of hyperthyroidism and the beneficial effects of adrenergic blocking drugs. It is worth stating at the outset that the literature in this area is complex, confusing and often contradictory. If responsiveness to catecholamines is enhanced in hyperthyroidism there should be a clear shift in dose-response relationship to the left with a concomitant decrease in either the threshold catecholamine concentration or the concentration required to give a halfmaximal effect in the system under study. Only the more recent studies have taken these criteria into account and have carefully sought to document changes in sensitivity to catecholamines, as opposed to additive direct effects of thyroid hormones and catecholamines. Thus, although the theory that hyperthyroidism potentiates the effects of endogenous catecholamines is attractive and widely believed, the evidence, as reviewed below, is certainly not in full support. Furthermore, although the sympathomimetic features of hyperthyroidism involve predominantly the cardiovascular system. it is in the realm of the metabolic effects that the evidence of thyroid potentiation of catecholamine responses is most convincing. Another aspect of the effect of thyroid hormones on the sensitivity to catecholamines deserves comment. If adrenergic responses are, in fact. potentiated in hyperthyroidism a sustained increase in adrenergic activity would require a concomitant alteration in the regulation of central sympa. thetic outflow in order for the potentiated responses to be sustained. Since sympatho-adrenal activity is entirely dependent on central sympathetic outflow, an increase in sensitivity to catecholamines at the periphery should result in suppression of central sympathetic outflow. As described above, some studies have shown slight suppression of the sympathetic nervous system in experimental hyperthyroidism and in patients with thyrotoxicosis. This, however, has not been consistently demonstrated, and when present is

702

LEWIS LANDSBERG

of far less magnitude than the increase in sympathetic activity that is noted to accompany the hypothyroid state. Since enhanced sensitivity to the effects of catecholamines would be expected to suppress the sympatho-adrenal system, failure of suppression implies that other, undefined factors related to the hyperthyroid state alter the suppressibility of the sympathetic nervous system. This is discussed more fully at the end of this chapter. Sensitivity to the Cardiovascular Effects of Catecholamlnes In Relation to the Thpold Status Studies In experimental animals Although a large number of studies over the last fifty years claim to show that thyroid hormones increase the sensitivity of the cardiovascular system to exogenous catecholamines (Harrison, 1964; Waldstein, 1966), it is doubtful that these studies have adequately addressed the question of sensitivity in a way that would be considered valid today. In general, these widely quoted studies have shown that the increase in heart rate in response to catecholamines is more marked in animals rendered hyperthyroid than in normal controls (Sawyer and Brown, 1935; McDonald et ai, 1935; Brewster et ai, 1956; Thierl Gravenstein and Hoffman, 1962; Cravey and Gravenstein, 1965) or that tolerance to the toxic effects of catecholamines is increased by antithyroid drugs and decreased by thyroid hormone administration (Rosenblum, Hahn and Levine, 1933; Raab, 1944). Only in more recent studies (Margolius and Gaffney, 1965; van der Schoot and Moran, 1965; Cairoli and Crout, 1967; Anton and Gravenstein, 1970; Brus, Hess and Jacobowitz, 1970) have careful dose-response relationships, designed specifically to answer the question of sensitivity to catecholamines in the presence of excess thyroid hormones, been performed. These studies, utilizing in vivo and in vitro preparations from rats, rabbits and dogs with induced hyperthyroidism, have examined the effect of catecholamine infusions and sympathetic nerve stimulation on heart rate, blood pressure and cardiac con. tractility. No significant displacement of the dose-response relationship was noted in any of these experiments. Taken as a group, these reports provide convincing evidence that experimental hyperthyroidism does not alter the sensitivity of the cardiovascular system to catecholamines. Two other recent studies (Wildenthal, 1972; Field, Janis and Tribble, 1973), however, did note an effect of thyroid on the sensitivity of isolated tissues to exogenous catecholamines. In one, tension produced in isolated rat aortic rings in response to different concentrations of norepinephrine was found to vary with the thyroid state of the animal (Field, Janis and Tribble, 1973); in the other, the norepinephrine dose-response relationship for heart rate of fetal mouse heart in organ culture was shifted to the left after incubation with triiodothyronine (Wildenthal, 1972). In another large study (Coville and Telford, 1970) the effect of thyroid pretreatment on the in vitro responses of isolated tissues from rats and guinea-pigs was more difficult to interpret. Although sensitivity to epinephrine and norepinephrine appeared to be increased by thyroid hormone when the isolated perfused heart was studied and heart rate was measured, the sensitivity to acetylcholine was increased as

CATECHOLAMINES AND HYPERTHYROIDISM

703

well (with a greater drop in heart rate at a given acetylcholine dose). Thyroid pretreatment diminished the effects of epinephrine and norepinephrine on aortic strip contractility in the same study and the effect of other agents such as histamine and serotonin was modified as well. These findings were interpreted as indicating a non-specific effect of thyroid pretreatment rather than a specific enhancement of catecholamine-mediated responses. The reason for the conflicting results in these animal studies is not completely clear. Subtle differences in techniques may be partially responsible. It seems fair to say at the present, however, that potentiated cardiovascular responses to catecholamines in the presence of thyroid hormone excess have not been easy to demonstrate in experimental animals. Cardiovascular responses to catecholamines In thyrotoxic patients The sensitivity of the cardiovascular system to catecholamines as a function of thyroid status has been much less well studied in man than in experimental animals. Several oft-quoted and time-honoured reports (Goetsch, 1918; Schneckloth, Kurland and Freedberg, 1953; Murray and Kelley, 1959) suggest an enhanced effect of catecholamines on heart rate and blood pressure in the presence of thyrotoxicosis with restoration to normal after treatment (Schneckloth, Kurland and 'Preedberg, 1953). More recent studies in spontaneous hyperthyroidism before and after treatment (Aoki, Wilson and Theilen, 1972) and in normal persons made hyperthyroid by T) administration (Aoki et aI, 1967) have failed to show significant changes in a variety of haemodynamic responses to epinephrine or norepinephrine in the hyperthyroid state. The reason for the different results in these studies is not clear. Direct effects of thyroid hormones on the heart In contrast to the confusion that surrounds the effects of thyroid hormone on sensitivity of the heart to catecholamines, the direct effect of thyroid hormones on heart rate and contractility are well established. Thyroid hormones increase the heart rate and contractility by mechanisms independent of catecholamines and the sympatho-adrenal system. The direct effects of thyroid hormone may be additive with those induced by catecholamines without implying an increase in sensitivity to the latter. The direct effect of thyroid hormones to increase heart rate has been shown in a number of ways. Chick embryo heart muscle in tissue culture, fetal mouse heart in organ culture and isolated rat hearts in vitro all beat more rapidly in the presence of thyroid hormones despite the absence of sympathetic nerves (Markowitz and Yater, 1932; Thier, Gravenstein and Hoffman, 1962; Wildenthal, 1971). Sympathetic ablation in rats and mice does not alter the heart rate response to T. and T 3 (Nemecek and Hess, 1974). Studies with autonomic blocking drugs in patients and animals are also consistent with a direct effect of thyroid hormones on heart rate (Thier. Gravenstein and Hoffman, 1962; Cairoli and Crout. 1967). Similarly, studies with isolated cat papillary muscles and in intact dogs have demonstrated a direct effect of thyroid hormones to enhance cardiac contractility (Buccino et aI, 1967; Taylor, Covell and Ross, 1969).

704

LEWIS LANDSBERG

The effects of catecholamines on cardiac contractility and heart rate are mediated via the beta receptor with subsequent stimulation of adenylate cyclase and the intracellular accumulation of cyclic AMP (see Chapter 3). The mechanism by which thyroid hormones increase heart rate and contractility is uncertain. Activation of adenylate cyclase by thyroid hormones in vitro has been demonstrated (Levey and Epstein, 1969) in homogenates of cat heart; cyclase activation in this system is additive with the activation produced by norepinephrine and is not blocked by beta blocking agents (Levey and Epstein, 1969). The role of adenylate cyclase as a mediator of the effects of thyroid hormone on the heart is, however, open to serious question for the following reasons: (1) The adenylate cyclase activity in hearts of animals made hyperthyroid by exogenous thyroxine does not differ from normal controls in basal levels or stimulation by norepinephrine (Levey, Skelton and Epstein, 1969; McNeill, Muschek and Brody, 1969; Sobel, Dempsey and Cooper, 1969); (2) the norepinephrine dose-response relationship for cyclase activation (as well as cardiac contractility) is identical in normal and hyperthyroid animals (Levey, Skelton and Epstein, 1969); (3) the cyclic AMP content in hearts of animals made hyperthyroid with triiodothyronine is similar to that of normal animals (Levey, Skelton and Epstein, 1969); and (4) the accumu1ation of cyclic AMP in response to catecholamines is normal in hearts of triiodothyronine-treated animals, as is cardiac contractility (McNeill, Muschek and Brody, 1969). It is, therefore, unlikely that adenylate cyclase activation mediates the cardiac effects of thyroid hormones. Interestingly, although the direct effects of thyroid hormone on the heart resemble those of catecholamines, the effects on the peripheral vasculature are strikingly different. Thyroid hormones produce vasodilation with lowering of the peripheral resistance (deGroot and Leonard, 1970), although it is possible that changes in tissue metabolism account for the vasodilation. Thus, the direct effects of thyroid hormones on heart rate and contractility may be additive with those of catecholamines; the evidence does not support (but does not definitely exclude) an effect of thyroid hormones on the sensitivity of heart to catecholamines. Sensitivity to the Metabolic and Calorigenic Effects of Catecholamines in Relation to Thyroid Status The evidence for a thyroid-induced increase in sensitivity to the metabolic effects of catecholamines is more convincing than the evidence that thyroid hormones enhance the cardiac effects of catecholamines. Thyroid hormones appear to potentiate the effects of catecholamines on lipolysis, glycogenolysis (in heart), and non-shivering thermogenesis. Studies on catecholamineinduced lipolysis in rat fat pads clearly show a leftward displacement of the dose-response relationship in thyroid-treated animals (Brodie et ai, 1966). Conversely, epinephrine-induced lipolysis is diminished in isolated fat cells from hypothyroid rats and patients (Ichikawa et ai, 1971; Rosenqvist, 1972a). Catecholamine-stimulated lipolysis involves adenylate cyclase and cyclic AMP, and increased adenylate cyclase activity in adipose tissue of thyroid-treated rats has been reported (Krishna, Hynie and Brodie, 1968),

CATECHOLAMINES AND HYPERTHYROIDISM

705

but the precise role of thyroid hormones in enhancing catecholamine-induced lipolysis is still not certain. Similarly, catecholamines and thyroid hormones appear to be synergistic in the stimulation of glycogenolysis in heart via an effect on phosphorylase-a (Hess and Shanfeld, 1965; McNeill and Brody, 1968). The role of adenylate cyclase in this system is unknown (Frazer, Hess and Shanfeld, 1969). An interaction between catecholamines and thyroid hormones also appears to be involved in cold acclimatization and the generation of heat from non-shivering thermogenesis. Thyroxine enhancement of the calorigenic effects of norepinephrine has been demonstrated in newborn mice and adult rats exposed to cold stress (Leblanc and Villemaris, 1970; Kaciuba-Uschilko, 1971; Steele and Wekstein, 1973). Additional indirect evidence that thyroid hormones may modify the sensitivity to catecholamines is provided by recent studies of plasma and urinary cyclic AMP. It appears that hyperthyroidism is associated with increased cyclic AMP levels in plasma and urine (Guttler et al. 1975a; Tucci and Kopp, 1976). Since plasma cyclic AMP may reflect the activation of adrenergic receptors (Brodows, Ensinck and Campbell, 1976), and since the level of sympatho-adrenal activity is not increased in hyperthyroidism (see above), these data are consistent with thyroid-induced enhancement of catecholamine-stimulated processes mediated by beta adrenergic receptors. Furthermore, epinephrine induces a greater rise in urinary and plasma cyclic AMP in hyperthyroid patients than in euthyroid controls, a rise that is blunted by beta blockers (Guttler et ai, 1975a, 1975b). Hypothyroid patients, in contrast, do not raise plasma cyclic AMP levels after epinephrine. The specificity of the response is, however, open to question since both glucagon and parathormone induce a greater rise in plasma cyclic AMP in hyperthyroid subjects than in euthyroid controls (Guttier et ai, 1975b). The site of origin of plasma cyclic AMP in these studies is also unknown. Further studies are required to determine the significance of these plasma cyclic AMP changes in hyperthyroid subjects. Thyroid Hormones and Adrenergic Receptors

The molecular basis of enhancement of adrenergic processes by thyroid hormones is unknown. Thyroid·dependent changes in sensitivity to catecholamines could result from changes in the adrenergic receptors themselves or from potentiation of membrane or intracellular reactions distal to receptor activation in the chain of events leading to an adrenergic response. Studies bearing on these questions are in their infancy, but certain intriguing ideas have emerged which merit brief consideration. One possible way in which thyroid hormones could increase sensitivity to catecholamines is by increasing the number of adrenergic receptors or increasing the affinity of the adrenergic receptors for catecholamines. Although sophisticated techniques have recently been employed in the characterization of adrenergic receptors (see Chapter 3), these techniques have not as yet been extensively employed in studying the modification of adrenergic receptors by thyroid hormones. One recent study reported an

706

LEWIS LANDSBERG

increase in the binding of labelled norepinephrine to a particulate fraction of rat heart from hyperthyroid animals and a commensurate decrease in binding in hearts from hypothyroid animals as compared with normal controls (Will-Shahab and Wollenberger, 1974). The kinetics of the interaction suggested enhanced affinity for catecholamines in the hyperthyroid state rather than an increase in the number of receptors. The binding of labelled norepinephrine to cardiac membranes in the study of the beta receptor, however, has been criticized as being insufficiently specific (see Chapter 3 and review by Haber and Wrenn, 1976), and the significance of this observation is, therefore. open to serious question. In a more recent report the binding of the potent beta-blocking agent, 3H-dihydroalprenolol, to cardiac membranes in hyperthyroid rats has been studied (Williams et aI, 1977). The results indicate that hyperthyroidism increases the number of binding sites for the labelled beta antagonist without changing the affinity of the membrane for the antagonist. These findings are consistent with an increase in the number of cardiac beta receptors in the hyperthyroid rat and, if confirmed, provide a possible biochemical basis for thyroid-induced changes in sensitivity to catecholamines. Another intriguing and related hypothesis involves the possible interconversion of alpha and beta receptors. An interesting body of literature is developing which suggests that the balance of alpha and beta receptors is dependent on the thyroid state of the animal (Kunos, Vermes-Kunos and Nickerson, 1974). Thus, rat atria. rabbit aorta, rat-tail artery and human adipose tissue, in the presence of hypothyroidism, display enhanced responsiveness to alpha-adrenergic agonists and diminished responsiveness to beta-adrenergic stimuli (Nakashima et al, 1971; Rosenqvist and Boreus, 1972; Rosenqvist, 1972b, 1972c; Kunos, Vermes-Kunos and Nickerson, 1974; Fregly et ai, 1975). It has been suggested that the changes in sensitivity represent a thyroid-induced allosteric change in a single adrenergic receptor. Increased binding of labelled phenoxybenzamine in atria from hypothyroid rats as compared with euthyroid controls has been cited in support of this theory (Kunos, Vermes-Kunos and Nickerson. 1974) since the increased binding of the alpha blocker is consistent with an increase in alpha receptors. The converse of this theory, recruitment of beta receptors with augmented beta responses in the tissues of hyperthyroid animals, has apparently not been demonstrated, but the recent study quoted above (Williams and Leftowitz, 1977), which demonstrates an increase in the number of beta receptors in the hearts of hyperthyroid rats, appears to be consistent with conversion of alpha receptors to beta receptors in hyperthyroid animals. Augmentation in the number of beta receptors should be expressed as an increase in sensitivity to the beta agonists in hyperthyroidism; as indicated above this has not been readily demonstrable. Nonetheless, this interesting hypothesis deserves further work. The effect of thyroid hormones on events distal to stimulation of the adrenergic receptor has been even less well studied. Some of the evidence bearing on the role of adenylate cyclase has been summarized above. In general, however, these studies do not afford clear differentiation from possible receptor effects linked to adenylate cyclase.

CATECHOLAMINES AND HYPERTHYROIDISM

707

Summarization of the Effects of Thyroid Hormones on Sensitivity to Catecholamines The evidence at present does not favour (but does not exclude) an effect of thyroid hormones to enhance the sensitivity of the heart to catecholamines. Direct effects of thyroid hormones to increase heart rate and contractility independent of catecholamines are well established, and these may be additive with the similar effects of catecholamines. The metabolic effects of catecholamines, on the other hand, appear to be enhanced by thyroid hormones. Lipolysis, glycogenolysis, and the generation of heat from nonshivering thermogenesis are all potentiated by thyroid hormones, and the increased free fatty acid turnover and increased heat production characteristic of hyperthyroidism may reflect, in part, a synergism between catecholamines and thyroid hormones. ADRENERGIC BLOCKING AGENTS IN THE MANAGEMENT OF HYPERTHYROIDISM Despite the uncertainty concerning the nature of the interaction between thyroid hormones and catecholamines, it is well established that adrenergic blocking agents modify some of the manifestations of the hyperthyroid state in man. Although there is some debate about the usefulness of anti-adrenergic agents in the treatment of patients with hyperthyroidism, most clinicians feel that adrenergic blocking drugs are useful adjuncts in the management of selected patients with thyrotoxicosis. It is worth emphasizing, however, that the use of these agents is clearly secondary to the usual forms of treatment that diminish excessive thyroid hormone production. Physiological Effects of Adrenergic Blockade in Hyperthyroidism The effects of adrenergic blockade on the manifestations of hyperthyroidism have been extensively studied and a summarization of the results of some of these studies is provided in Table 3. Adrenergic blockade does not alter the plasma level of thyroid hormones or the l3l1 uptake and does not effect the thyroidal iodine release or turnover of thyroxine in hyperthyroid patients (Wartofsky et aI, 1975). The basal metabolic rate is often reduced by adrenergic blockade, although not to normal levels (Gaffney, Braunwald and Kahler, 1961; Lee, Bronsky and Waldstein, 1962); decrease in weight loss and oxygen consumption in hyperthyroid patients has been noted in some studies following adrenergic blockade (Lee, Bronsky and Waldstein, 1962; Stout, Wiener and Cox, 1969; McLarty et aI, 1973; Georges et ai, 1975; Mazzaferri et aI, 1976), but the oxygen consumption is not restored to normal and the weight loss not completely abolished. Partial restoration of the negative nitrogen balance has been noted, but the increased urinary loss of calcium, phosphorus, and hydroxyproline was not affected by adrenergic blockade in one recent study of hyperthyroid patients (Georges et aI, 1975). In two recently reported patients with thyrotoxicosis propranolol reversed hypercalcaemia by a mechanism independent of parathyroid hormone (Rude et aI, 1976). Significant improvement in tremor, hyperreflexia, widened

708

LEWIS LANDSBERG

palpebral fissure, and excessive sweating usually occur in response to adrenergic blockade, but fall in skin temperature and amelioration of heat intolerance are less regularly noted (Shanks et aI, 1969; Grossman et aI, 1971a; Allen et aI, 1973; McLarty et aI, 1973; Mazzaferri et aI, 1976). Most studies show a significant decrease in heart rate, systolic blood pressure, pulse pressure and cardiac output with prolongation of the circulation time (Wilson, Theilen and Fletcher, 1964; Wilson et aI, 1966; Howitt et aI, 1968; Wiener, Stout and Cox, 1969; Grossman et aI, 1971b; Pietras et aI, 1972). The increased cardiac contractility that occurs in hyperthyroidism is not restored to normal (Grossman et al. 1971b; Pietras et aI, 1972). Table 3. Effects of adrenergic blockade in hyperthyroidism Manifestation

Effect

General Plasma T. level '''I uptake Nervousness Sweating Tremor Hyperreflexia Widened palpebral fissure Heat intolerance Skin temperature Weight loss

No change No change Usually improved Usually improved Usually improved Usually improved Usually improved Occasional1y improved Occasionally improved Occasionally improved

Cardiovascular Pulse rate Pulse pressure Palpitation Cardiac contractility

Usually improved Usually improved Usually improved Occasionally improved (not restored to normal)

Metabolic Basal metabolic rate Oxygen consumption Urinary nitrogen loss Hydroxyproline excretion Calcium excretion Elevated plasma calcium

Occasionally improved. (not restored to normal) Occasionally improved (not restored to normal) Improved (needs confirmation) No change (needs confirmation) No change (needs confirmation) Improved (needs confirmation)

The Clinical Use of Adrenergic Blocking Agents In Thyrotoxicosis General considerations It should be re-emphasized that the use of adrenergic blocking agents in the management of patients with thyrotoxicosis is secondary to the usual forms of treatment which reduce the increased levels of thyroid hormone. These agents do not alter the underlying disease process and should therefore be regarded as adjuncts to definitive treatment such as thyroid ablation by 131 1 or surgery or a prolonged course of a thionamide. Furthermore, adrenergic blockers should not be substituted for thionamides as a form of medical treatment since symptomatic control of hyperthyroidism is incomplete under

CATECHOLAMINES AND HYPERTHYROIDISM

709

these conditions. and the underlying progress of the disease with its concomitant alterations in metabolism is not corrected (McLarty et ai, 1973; Georges et ai, 1975), with potential long-term detriment to the patient. Nonetheless, when used as an adjunct to definitive treatment adrenergic blocking drugs have significantly improved the management of the thyrotoxic patient in a variety of clinical situations. Although some investigators have cautioned that the reduction of cardiac output that follows adrenergic blockade in hyperthyroid patients may be associated with decreased tissue perfusion and the risk of anoxic damage, these fears appear to be unwarranted; the increase in cardiac output in hyperthyroidism is far in excess of the increase in oxygen consumption, and untoward effects on tissue perfusion have rarely been noted clinically. The choice of an anti-adrenergic agent Three agents are of established benefit in the management of patients with hyperthyroidism: reserpine, guanethidine, and propranolol. Reserpine inhibits the intraneuronal storage of catecholamines, thereby depleting catecholamines in the central and peripheral sympathetic nervous system and reducing both central sympathetic outflow and the peripheral release of neurotransmitter. Guanethidine is a neuron-blocking agent that prevents norepinephrine release from the peripheral sympathetic nerve endings; it is without significant effects on the central nervous system. Propranolol is a competitive blocker of adrenergic beta receptors in peripheral tissues and in the central nervous system. Propranolol also possesses membrane stabilizing effects similar to local anaesthetic agents, but it seems clear that the beneficial effects of propranolol in hyperthyroidism are due to the betablocking properties; the D-isomer, which possesses the membrane stabilizing properties without beta-blocking activity, is less effective than propranolol in reducing the sympathomimetic features of hyperthyroidism (Howitt et al. 1968), and other beta blockers, which have no membrane effects, are quite effective in modifying the hyperthyroid state (Grossman et ai, 1971a). Although both reserpine (Canary et aI, 1957) and guanethidine (Mazzaferri and Skillman, 1969) have demonstrated effectiveness in the treatment of severe thyrotoxicosis. the usefulness of these agents is seriously limited by severe side effects and long duration of action. With reserpine pronounced sedation. mental depression. and gastrointestinal haemorrhage may cause problems, but the drug is occasionally useful in those cases in which the sedative effect is desirable, as when marked agitation accompanies severe thyrotoxicosis. Guanethidine is limited by the slow onset of its action and the side effects associated with high-grade sympathetic blockade. most notably orthostatic hypotension. Propranolol has a rapid onset and short duration of action, is relatively free of severe side effects and has been used extensively in the symptomatic management of thyrotoxicosis. It is the drug of first choice when the clinical situation requires the use of an anti-adrenergic agent. The major side effects of propranolol, when used in the doses required for severe thyrotoxicosis, include: (1) bronchospasm in patients with asthma or chronic pulmonary disease; (2) hypoglycaemic reactions in insulin-requiring diabetics; and (3)

710

LEWIS LANDSBERG

exacerbation of heart failure resulting from the negative inotropic effect consequent to withdrawal of adrenergic reinforcement, although, as noted below, improvement in heart failure from control of heart rate is the more usual response. These potential adverse effects of propranolol can be avoided by close observation of predisposed patients. Clinical situations in which adrenergic blocking agents may be useful Experience with adrenergic blocking drugs has accumulated in a variety of clinical situations related to the hyperthyroid state. In general the need for adrenergic blocking agents is greatest and the effect most striking in severe thyrotoxicosis, although the clinical utility of adrenergic blockade clearly transcends the treatment of thyroid storm. Some of the situations in which adrenergic blockade has been used in hyperthyroid patients are indicated in Table 4. Table 4. Clinical situations in which adrenergic blocking agents have been used Situation

Effect

Agent and dose

Thyroid storm

Very effective - may be critical

Propranolol (drug of choice) 40-80 mg p.o. every 6 hours 0.5-1 mg Lv. as needed Reserpine 2-5 mg Lm. every 4-6 hours Guanethidine SO-l00 mg p.o. every day

Mild to moderate thyrotoxicosis

Useful adjunct for symptom control

Propranolol 10 mg p.o. every 6 hours; titrate up as needed

Incompletely prepared for emergency surgery or 13'1 treatment

Very effective

Propranolol 40 mg p.o. every 6 hours

Allergy to thionamide pending definitive treatment (surgery or "'I)

Very effective

Propranolol 40 mg p.o. every 6 hours

Routine preoperative preparation as sole agent

Preliminary studies encouraging; needs funher evaluation

Propranolol 40 mg p.o. every 6 hours

Thyrotoxicosis in pregnancy

Safety needs confirmation

Anti-adrenergics not advised at present

Thyroid storm or severe thyrotoxicosis (Mazzaferri and Skillman, 1969; Das and Krieger, 1969; Mackin, Canary and Pittman, 1974). In these conditions the beneficial effects of adrenergic blockade are often striking and may be life-saving. Adrenergic blocking agents will usually control tachycardia (sinus or supraventricular), decrease pulse pressure, prolong circulation time (if the latter is accelerated) and increase cardiac output (by slowing the rate); slowing the pulse rate and diminishing the high output state may actually improve congestive failure despite the negative inotropic effect. Propranolol

CATECHOLAMINES AND HYPERTHYROIDISM

711

is the most useful anti-adrenergic agent because of the rapid onset and short duration of its action, thus allowing careful titration of dose and physiological response. The initial dose of 40 to 80 mg p.o. every six hours should be adjusted up or down to control the pulse rate and the manifestations of the hyperdynamic circulation. Repeated doses of 0.5 to 1.0 mg Lv. may be given as well. Reserpine, in doses of 2 to 5 mg Lm. every four to six hours, should be reserved for those cases in which sedation is required and guanethidine (SO to 150 mg orally every day) for those cases in which a long duration of action is desirable. The adrenergic blocking drugs provide symptomatic improvement and buy time while the other measures aimed at reducing thyroid hormone output become effective. Mild to moderate thyrotoxicosis. Where symptomatic relief is desirable, the tachycardia, palpitation, heat intolerance, sweating, nervousness and irritability can often be controlled with propranolol resulting in significant clinical benefit (Shanks et aI, 1969). The initial dose of propranolol in this setting may be considerably lower, in the range of 10 to 20 mg p.o. every six hours. Many patients respond well to these modest doses; those who do not can have the dose adjusted up as needed. The propranolol may be continued until the results of definitive treatment have taken effect and the thyroid hormone levels are reduced. Patients receiving anti-thyroid drugs may be treated with propranolol for the first four to six weeks, with gradual withdrawal after the euthyroid state is attained. Patients receiving 131 1 for thyroid ablation may be managed with propranolol alone or in combination with inorganic iodide while awaiting the development of the euthyroid state (Hadden et aI, 1968; Sterling and Hoffenberg, 1971). . Incompletely prepared patients undergoing emergency surgery or 131[ treatment. Propranolol is an important adjunct of medical management in these circumstances. Hyperthyroid patients who require emergency surgery for non-thyroidal disease, as well as hyperthyroid patients who are allergic to thionamides and require emergency thyroidectomy, may be satisfactorily managed by a combination of propranplol and inorganic iodide (Cook and Choddof, 1970; Pimstone and Joffe, 1970). Similarly, in patients who undergo 131 1 treatment at a time when they are still toxic, the concomitant administration of propranolol may be helpful in reducing the symptoms associated with thyroid hormone release from radiation thyroiditis, should the latter occur. This is particularly important in older patients with cardiac disease since this group is more likely to respond adversely to any sudden release of thyroid hormones.

In two other situations a role for propranolol has been suggested but is, as yet, not firmly established. Routine preoperative preparation of thyrotoxic patients for subtotal thyroidectomy. Several reports suggest that propranolol may be safely used as the sole agent in the routine preoperative preparation of thyrotoxic patients for subtotal thyroidectomy (Pimstone and Joffe, 1970; Lee et aI, 1973; Michie et

712

LEWIS LANDSBERG

al. 1974; Toft et aI, 1976). The usual dose is 40 mg p.o. every six hours for about two weeks. This may be done with or without iodide but. interestingly enough, thyroid vascularity appears to be decreased even when iodides are not given (Toft et aI, 1976). Preoperative preparation with propranolol alone is apt to be much quicker than conventional preparation with a thionamine. and. after the attainment of euthyroid state, inorganic iodide (Michie et al. 1974). The propranolol regimen is also considerably easier to manage and less complex than the conventional one. It remains to be confirmed. however, that pre- and intraoperative management can be safely carried out with propranolol alone before this regimen replaces the more complex. but fully tested and time-honoured, conventional regimen of thionamide plus inorganic iodide. The fact that thyroid storm can apparently develop in patients receiving large doses of propranolol is particularly worrisome in this regard (Eriksson et aI, 1977). Thyrotoxicosis in pregnancy. This is the other situation in which propranolol has been suggested as a possible sole therapeutic agent (Langer et al. 1974; Bullock, Harris and Young, 1975). Since thionamides. especially in high dose, have the real risk of producing neonatal hypothyroidism the possibilities of beta blockade are certainly attractive. Many more studies are needed, however. to establish the safety of propranolol with regard to both the fetus and the course of labour before this regimen can be recommended.

Summarization and Hypothesis: Adrenergic Blockade In Hyperthyroidism It is abundantly clear that adrenergic blocking agents have an influence on the physiological effects of thyroid hormone and the clinical manifestations of thyrotoxicosis. They have had extensive use in the clinical management of hyperthyroidism in selected circumstances. and the indications for their use appear to be increasing, especially in the realm of surgical preparation of the thyrotoxic patient. Since endogenous sympatho-adrenal activity is not increased in hyperthyroidism. and since it is by no means certain that thyroid hormones enhance the peripheral effects of catecholamines (particularly on the cardiovascular system), it is not at all clear why adrenergic blockade suppresses some of the manifestations of excessive thyroid hormone. One possible explanation of the effectiveness of adrenergic blockade involves a change in the suppressibility of central sympathetic outflow. Perhaps the normal (or only slightly suppressed) activity of the sympatho-adrenal system in hyperthyroid patients is inappropriately high, given the functional state of the circulatory and metabolic systems. In other words. in the hyperthyroid patient the direct effects of thyroid hormones may summate with the effects of catecholamines and the heightened functional state reflect both thyroid hormone (which is increased) and catecholamines (which are 'normal' but inappropriate). Adrenergic blockers would be effective by removing the catecholamine-induced component of the heightened functional state. This hypothesis suggests that unidentified factors related to the hyperthyroid state prevent normal suppression of central sympathetic outflow. There is no

CATECHOLAMINES AND HYPERTHYROIDISM

713

direct evidence for this, although it is known that administration of thyroid hormone to animals increases the turnover of norepinephrine in the brain (Parker, 1972; Engstrom, Svensson and Waldeck, 1974; Rastogi and Singhal, 1976). This could reflect a direct stimulatory effect of thyroid hormone on central sympathetic centres that govern adrenergic outflow, Alternatively, an increase in central sympathetic outflow could be secondary to increased afferent impulses from the periphery. It has recently been shown that experimentally induced hypermetabolism increases cardiac output by a neurally mediated route that depends upon afferent impulses from the hypermetabolic tissues (Liang and Hood, 1976). Reflex sympathetic stimulation might also result from the fall in total peripheral resistance induced by thyroid hormone. Either of these mechanisms could explain the seemingly inappropriate level of sympathetic outflow in hyperthyroidism. The suppressibility of the sympathetic nervous system in hyperthyroidism warrants further study in an attempt to better define the relationship between hyperthyroidism and the sympatho-adrenal system.

REFERENCES Ahn. C. S. (1971) Glycogen metabolism of the thyroid. Endocrinology, 88, 1341·1348. Ahn. C. S., Athans, J. C. & Rosenberg, I. N. (1969) Effects of epinephrine and of alteration in glandular blood flow upon thyroid function: studies using thyroid vein cannulation in dogs. Endocrinology. 84,501·507. Allen. 1. A.• Lowe. D. C.• Roddie. I. C. & Wallace. W. F. M. (1973) Studies on sweating in clinical and experimental thyrotoxicosis. Clinical Science and Molecular Medicine. 45, 765·773. Anton. A. H. & Gravenstein. J. S. (1970) Studies on thyroid-catecholamine interactions in the isolated rabbit heart. European Journal of Pharmacology, 10,311·318. Aoki. V. S.• Wilson. W. R. & Theilen. E. O. (1972) Studies of the reputed augmentation of the cardiovascular effects of catecholamines in patients with spontaneous hyperthyroidism. Journal of Pharmacology and Experimental Therapeutics, 181, 362-368. Aoki. V. S.. Wilson, W. R., Theilen. E. 0 .. Lukensmeyer. W. W. & Leaverton. P. E. (1967) The effects of triiodothyronine on hemodynamic responses to epinephrine and norepine· phrine in man. Journal of Pharmacology and Experimental Therapeutics, 157,62·68. Bayliss. R. I. S. & Edwards. O. M. (1971) Urinary excretion of free catecholamines in Graves' disease. Endocrinology, 49, 167·173. Beaven, M. A.• Costa. E. & Brodie. B. B. (1963) The turnover of norepinephrine in thyrotoxic and nonthyrotoxic mice. Life Sciences, 4, 241·246. Beley, A., Rochette, L. & Bralet. 1. (1973) Influence de traitement par la thyroxine et Ie propylthiouracile sur Ie taux de renouveUement de la noradrenaline dans huit organes peripheriques du rat. Archives Internationales de Physiologie et de Biochimie. 81,287·298. Brewster. W. R. Jr, Isaacs. J. P., Osgood. P. F. & King, T. L. (1956) The hemodynamic and metabolic interrelationships in the activity of epinephrine, norepinephrine and the thyroid hormones. Circulation, 13, 1·20. Brodie. B. B., Davies, J. I.. Hynie. S.• Krishna. G. & Weiss, B. (1966) Interrelationships of catecholamines with other endocrine systems. Pharmacological Reviews. 18, 273-289. Brodows, R. G.• Ensinck. J. W. & Campbell, R. G. (1976) Mechanism of plasma cyclic AMP response to hypoglycemia in man. Metabolism. 25, 659·663. Brus. R.• Hess. M. E. & Jacobowitz. D. (1970) Effect of 6·hydroxydopamine and thyroxine on chronotropic response to norepinephrine. European Jou".al of Pharmacology. 10, 323·327.

714

LEWIS LANDSBERG

Buccino, R. A., Spann, J. F. Jr, Pool, P. E., Sonnenblick, E. H. & Braunwald, E. (1967) Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium. Journal of Clinical Investigation. 46, 1669-1682. Bullock, J. I., Harris, R. E. & Young, R. (1975) Treatment of thyrotoxicosis during pregnancy with propranolol. American Journal of Obstetrics and Gynecology, 121, 242·245. Cairoli, V. J. & Crout, J. R. (1967) Role of the autonomic nervous system in the resting tachycardia of experimental hyperthyroidism. Journal of Pharmacology and Experimental Therapeutics, 158, 55-65. Canary, J. J., Schaff, M., Duffy, B. J. Jr & Kyle, L. H. (1957) Effects of oral and intramuscular administration of reserpine in thyrotoxicosis. New England Journal of Medicine, 257, 435-442. Christensen, N. J. (1972) Increased levels of plasma noradrenaline in hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 35, 359-363. Christensen, N. J. (1973) Plasma noradrenaline and adrenaline in patients with thyrotoxicosis and myxoedema. Clinical Science and Molecular Medicine, 45, 163-171. Coleoni, A. H. (1972) Effects of the administration of catecholamine·depleting drugs on the thyroid function of the rat. Pharmacology, 8, 300-310. Cook, D. R. & Chodoff, P. (1970) Anesthetic management of an incompletely controlled hyperthyroid patient for thyroidectomy. Anesthesiology, 33,562·564. Coulombe, P., Dussault, 1. H., Letarte, J. & Simard, S. J. (1976) Catecholamines metabolism in thyroid diseases. I. Epinephrine secretion rate in hyperthyroidism and hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 42, 125-131. Coville, P. F. & Telford, J. M. (1970) Influence of thyroid hormones on the sensitivity of cardiac and smooth muscle to biogenic amines and other drugs. British Journal of Pharmacology, 39,49-68. . Cravey, G. M. & Gravenstein, J. S. (1965) The effect of thyroxin, corticosteroids, and epinephrine on atrial rate. Journal of Pharmacology and Experimental Therapeutics, 148, 75-79. Das, G. & Krieger, M. (1969) Treatment of thyrotoxic storm with intravenous administration of propranolol. Annals of Internal Medicine, 70, 985-988. deGroot, L. J. & Leonard, J. J. (1970) Hyperthyroidism as a high cardiac output state. American Heart Journal, 79, 265-275. Engstrom, G., Svensson, T. H. & Waldeck, B. (1974) Thyroxine and brain catecholamines: increased transmitter synthesis and increased receptor sensitivity. Brain Research, 77, 471-483. Ericson, L. E., Melander, A., Owman, C. & Sundler, F. (1970) Endocytosis of thyroglobulin and release of thyroid hormone in mice by catecholamines and 5-hydroxytryptamine. Endocrinology, 87,915-923. Eriksson, M., Rubenfeld, S., Garber, A. J. & Kohler, P. O. (1977) Propranolol does not prevent thyroid storm. New England Journal of Medicine, 296, 263·264. Field, F. P., Janis, R. A. & Tribble, D. J. (1973) Relationship between aortic reactivity and blood pressure of renal hypertensive, hyperthyroid, and hypothyroid rats. Canadian Journal of Physiology and Pharmacology, 51, 344-353. Frazer, A., Hess, M. F. & Shanfeld, J. (1969) The effects of thyroxine on rat heart adenosine 3' ,5'-monophosphate, phosphorylase "b" kinase and phosphorylase "a" activity. Journal of Pharmacology and Experimental Therapeutics. 170,10-16. Fregly, M. J., Nelson, E. L. Jr, Resch, G. E., Field, E. P. & Luthuer, L. O. (1975) Reduced beta-adrenergic responsiveness in hypothyroid rats. American Journal of Physiology. 229 916-924. ' Gaffney, T. E., Braunwald, E. & Kahler, R. L. (1961) Effect of guanethidine on trio iodothyronine-induced hyperthyroidism in man. New England Journal of Medicine, 265 16·20. ' Galton, V. A. (1965) Thyroid hormone-catecholamine interrelationships. Endocrinology. 77

~~.

'

Georges, L. P., Santangels, R. P., Mackin, J. F. & Canary, J. J. (1975) Metabolic effects of propranolol in thyrotoxicosis. I. Nitrogen, calcium, and hydroxyproline. Metabolism, 24, \l-21. Goetsch, E. (1918) Newer methods in the diagnosis of thyroid disorders: pathological and clinical. New York State Journal of Medicine. 18, 259-267.

CATECHOLAMINES AND HYPERTHYROIDISM

715

Grossman. W.. Robin. N. I.. Johnson. L. W., Brooks, H. L., Selenkow. H. A. & Dexter, L. (197Ia) Effects of beta blockade on the peripheral manifestations of thyrotoxicosis. Annals of Internal Medicine. 74, 875-879. Grossman, W.. Robin. N. I., Johnson, L. W., Brooks. H. L.. Selenkow, H. A. & Dexter, L. (1971b) The enhanced myocardial contractility of thyrotoxicosis: role of the beta adrenergic receptor. Annals of Internal Medicine. 74, 869-874. Guttier. R. B.. Shaw, J. W., Otis, C. L. & Nicoloff, J. T. (1975a) Epinephrine-induced alterations in urinary' cyclic AMP in hyper- and hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 41,633-637. Guttier, R. B.. Otis, C. L.. Shaw, J. W.. Warren, D. W. & Nicoloff, J. T. (1975b) The effect of thyroid hormone on adenyl cyclase (AC) - a potential site for thyroid hormone action. Proceedings of the International Conference on Thyroid Hormone Metabolism. Glasgow. Scotland, August 7-9. Excerpta Medica International Congress Series. Haber, E. & Wrenn, S. (1976) Problems in identification of the beta-adrenergic receptor. Physiological Reviews. 56,317-338. Hadden. D. R., Montgomery, D. A. D .• Shanks. R. G. & Weaver, J. A. (1968) Propranolol and iodine-131 in the management of thyrotoxicosis. Lancet. 11,852-854. Harrison. T. S. (1964) Adrenal medullary and thyroid relationships. Physiological Reviews, 44, 161-185. Hays, M. T. & Solomon. D. H. (1969) Effect of epinephrine on the peripheral metabolism of thyroxine. Journal of Clinical Investigation, 48, 1114-1123. Hess. M. E. & Shanfeld. J. (1965) Cardiovascular and metabolic interrelationships between thyroxine and the sympathetic nervous system. Journal of Pharmacology and Experimental Therapeutics, 148, 290-297. Howitt. G., Rowlands, D. J.• Leung. D. Y. T. & Logan, W. F. W. E. (1968) Myocardial contractility. and the effects of beta-adrenergic blockade in hypothyroidism and hyperthyroidism. Clinical Science. 34, 485-495. Ichikawa, A., Matsumoto. H.• Sakato. N. & Tomita. K. (1971) Effect of thyroid hormones on epinephrine-induced lipolysis in adipose tissue of rats. Journal of Biochemistry. 69, 1055-1064. Kaciuba-Uschilko, H. (1971) The effect of previous thyroxine administration on the metabolic response to adrenaline in new-born pigs. Biology of the Neonate. 19, 220-226. Krishna, G .• Hynie. S. & Brodie, B. B. (1968) Effects of thyroid hormones on adenyl cyclase in adipose tissue and on free fatty acid mobilization. Proceedings of the National Academy of Sciences of the United States of America. 59, 884-889. Kunos. G., Vermes-Kunos, I. & Nickerson. M. (1974) Effects of thyroid state on adrenoreceptor properties. Nature. 250,779-781. Kuschke, H. J., Wernze, H. & Becker, G. (1960)'Sympatho-adrenal activity in thyrotoxicosis. British Medical Journal, II, 1656. Landsberg. L. & Axelrod. J. (1968) Influence of pituitary, thyroid, and adrenal hormones on norepinephrine turnover and metabolism in the rat heart. Circulation Research. 22, 5S9-57l. Langer, A., Hung, C. T., McA'nulty, J. A.• Harrigan. J. T. & Washington, E. (1974) Adrenergic blockade: a new approach to hyperthyroidism during pregnancy. Obstetrics and Gynecology, 44, 181-186. Leblanc, J. & Villemarie, A. (1970) Thyroxine and noradrenaline on noradrenaline sensitivity, cold resistance, and brown fat. American Journal of Physiology. 218, 1742-1745. Lee, T. C.• Coffey. R. J.. Mackin. J.. Cobb, M., Routon, M. & Canary, J. J. (1973) The use of propranolol in the surgical treatment of thyrotoxic patients. Annals of Surgery. 177, 643-647. Lee, W. Y., Bronsky, D. & Waldstein, S. S. (1962) Studies of thyroid and sympathetic nervous system interrelationships. II. Effects of guanethidine on manifestations of hyperthyroidism. Journal of Clinical Endocrinology and Metabolism. 22, 879-885. Levey, G. S. & Epstein. S. E. (1969) Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems. Journal o/Clinical Investigation. 48, 1663-1669. Levey, G. S., Skelton, C. L. & Epstein, S. E. (1969) Influence of hyperthyroidism on the effects or norepinephrine on myocardial adenyl cyclase activity and contractile state. Endocrinology, 85, 1004-1009.

716

LEWIS LANDSBERG

Liang. C. & Hood. W. B. Jr (1976) Afferent neural pathway in the regulation of cardiopulmonary Tesponses to tissue hypermetabolism. Circulation Research. 38, 209·214. Maayan, M.> L. & Ingbar. S. H. (1970) Effects of epinephrine on iodine and intermediary metabolism in isolated thyroid cells. Endocrinology, 87, 588·595. Mackin, J. F.. Canary. J. 1. & Pittman, C. S. (1974) Thyroid storm and its management. New England Journal of Medicine, 291, 1396·1398. Margolius. H. S. & Gaffney. T. E. (1965) The effects of injected norepinephrine and sympathetic nerve stimulation in hypothyroid and hyperthyroid dogs. Journal of Pharmacology and Experimental Therapeutics. 149, 329·335. Markowitz. C. & Yater. W. M. (1932) Response of explanted cardiac muscle to thyroxine. American Journal of Physiology. 100, 162-166. Mazzaferri. E. L. & Skillman. T. G. (1969) Thyroid storm: a review of 22 episodes with special emphasis on the use of guanethidine. Archives of Internal Medicine. 124, 684·690. Mazzaferri. E. L.. Reynolds. J. C., Young. R. L., Lt. Col.. Thomas. C. N.• Lt. Col. & Parisi. A. F. (1976) Propranolol as primary therapy for thyrotoxicosis. Archives of Internal Medicine, 136, SO-56. McDonald. C. H.• Shepeard. W. L.. Green. M. F. & deGroat, A. F. (1935) Response of the hyperthyroid heart to epinephrine. American Journal of Physiology, 112, 227·230. McLarty. D. G., Brownlie. B. E. W.• Alexander, W. D., Papapetrou. P. D. & Horton, P. (1973) Remission of thyrotoxicosis during treatment with propranolol. British Medical Journal. II, 332·334. McNeill, J. H. & Brody, T. M. (1968) The effect of triiodothyronine pretreatment on amine. induced rat cardiac phosphorylase activation. Journal of Pharmacology and Experimental Therapeutics. 161,40-46. McNeill, J. H., Muschek, L. D. & Brody. T. M. (1969) The effect of triiodothyronine on cyclic AMP, phosphorylase, and adenyl cyclase in rat heart. Canadian Journal of Physiology and Pharmacology. 47, 913·916. Melander, A. & Sundler. F. (1972) Interactions between catecholamines. 5.hydroxytryptamine and TSH on the secretion of thyroid hormone. Endocrinology. 90, 188-193. Melander. A., Nilsson. E. & Sundler. F. (1972) Sympathetic activation of thyroid hormone secretion in mice. Endocrinology. 90, 194·199. Melander, A., Sundler, F. & Westgren, U. (1973) Intrathyroidal amines and the synthesis of thyroid hormone. Endocrinology. 93, 193·200. Melander, A., Ericson. L. E .• Ljunggren, J.·G .• Norberg, K.·A., Persson, B., Sundler, F., Tibblin, S. & Westgren. U. (1974a) Sympatheticinnervation of the normal human thyroid. Journal of Clinical Endocrinology and Metabolism. 39, 713-718. Melander. A.. Ericson. L. E., Sundler, F. & Ingbar, S. H. (1974b) Sympathetic innervation of the mouse thyroid and its significance in thyroid hormone secretion. Endocrinology. 94, 959-966. Melander, A., Ranklev. E., Sundler, F. & Westgren, U. (1975) Seta,-adrenergic stimulation of thyroid hormone secretion. Endocrinology, 97,332·336. Michie, W., Hamer-Hodges, D. W.• Pegg. C. A. S., Orr. F. G. G. & Bewsher, P. D. (1974) Beta·blockade and partial thyroidectomy for thyrotoxicosis. Lancet. I, 1009-1011. Murray, 1. F. & Kelley. 1. J. Jr (1959) The relation of thyroidal hormone level to epinephrine response: a diagnostic test for hyperthyroidism. Annals of Internal Medicine. 51, 309.321. Nakashima, M., Maeda, K., Sekiya, A. & Hagino, Y. (1971) Effect of hypothyroid status on myocardial responses to sympathomimetic drugs. Japanese Journal of Pharmacology. 21, 819-825. Nemecek, G. M. & Hess. M. E. (1974) Cardiovascular and metabolic responses to thyroid hormones in animals after sympathectomy or treatment with nerve growth factor. Neuropharmacology. 13, 317·332. Nicoloff, 1. T. (1970) A new method for the measurement of acute alterations in thyroxine deiodination rate in man. Journal of Clinical Investigation. 49, 267·273. Nishizawa, Y., Hamada, N., Fujii, S., Morii, H., Okuda, K. & Wada, M. (1974) Serum dopamine·beta·hydroxylase activity in thyroid disorders. Journal of Clinical Endocrinology and Metabolism. 39, 599·602. Noth. R. H. & Saulding, S. W. (1974) Decreased serum dopamine·beta·hydroxylase in hyper. thyroidism. Journal of Clinical Endocrinology and Metabolism. 39, 614-617.

CATECHOLAMINES AND HYPERTHYROIDISM

717

Parker. L. N. (1972) The turnover of norepinephrine in the brain stems of dysthyroid rats. Journal of Neurochemistry. 19, 1611-1613. Pietras. R. J., Real, M. D., Poticha, G. Soo Bronsky, D. & Waldstein. S. S. (1972) Cardiovascular response in hyperthyroidism. Archives of Internal Medicine. 129, 426-429. Pimstone. B. & Joffe. B. (1970) The use and abuse of beta-adrenergic blockade in the surgery of hyperthyroidism. South African Medical Journal. 44, 1059-1061. Raab. W. (1944) Epinephrine tolerance of the heart altered by thyroxine and thiouracil. Journal of Pharmacology and Experimental Therapeutics. 82, 330-338. Rastogi. R. B. & Singhal, R. L. (1976) Influence of neonatal and adult hyperthyroidism on behavior and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain. Journal of Pharmacology and Experimental Therapeutics, 198,609-618. Rosenblum. H., Hahn, R. G. & Levine, S. A. (1933) Epinephrine: its effect on the cardiac mechanism in experimental hyperthyroidism and hypothyroidism. Archives of Internal Medicine, 51,279-289. Rosenqvist, U. (1972a) Adrenergic receptor response in hypothyroidism: an in vitro study on human adipose tissue and rabbit aorta. Acta Medica Scandinavica (Supplement). 532, 1·28. Rosenqvist, U. (l972b) Inhibition of noradrenaline-induced lipolysis in hypothyroid subjects by increased alpha-adrenergic responsiveness. Acta Medica Scandinavica. 192,353·359. Rosenqvist, U. (l972c) Noradrenaline·induced lipolysis in subcutaneous adipose tissue from hypothyroid subjects. Acta Medica Scandinavica. 192, 361·369. Rosenqvist. U. & Boreus, L. O. (1972) Enhancement of the alpha adrenergic response in aorta from hypothyroid rabbits. Life Sciences. 11,595-604. Rude, R. K., Oldham, S. B., Singer, F. R. & Nicoloff, J. T. (1976) Treatment of thyrotoxic hypercalcemia with propranolol. New England Journal of Medicine, 294, 431-433. Sawyer, M. E. M. & Brown, M. G. (1935) The effect of thyroidectomy and thyroxine on the response of the denervated heart to injected and secreted adrenine. American Journal of Physiology, 110,620·635. Schneckloth, R. E., Kurland, G. S. & Freedberg, A. S. (1953) Effect of variation in thyroid function on the pressor response to norepinephrine in man. Metabolism, 2, 546-555. Shanks, R. Goo Hadden. D. R.• Lowe, D. C., McDevitt, D. G. & Montgomery. D. A. D. (1969) Controlled trial of propranolol in thyrotoxicosis. Lancet. I, 993-994. Sobel, B. E.• Dempsey. P. J. & Cooper. T. (1969) Normal myocardial adenyl cyclase activity in hyperthyroid cats. Proceedings of the Society for Experimental Biology and Medicine. 132, 6-9. Steele, R. E. & Wekstein, D. R. (1973) Effects of thyroxine on calorigenic response of the newborn rat to norepinephrine. American Journal of Physiology. 224, 979·984. Sterling, K. & Hoffenberg. R. (1971) Beta blocking agents and antithyroid drugs as adjuncts to radioiodine therapy. Seminars in Nuclear Medicine. 1,422·431. Stoffer, S. S., Jiang, M.-S., Gorman, C. A. & Pikler, G. M. (1973) Plasma catecholamines in hypothyroidism and hyperthyroidism. Journal of Clinical Endocrinology and Metabolism. 36,587-589. Stout. B. D .• Wiener. L. & Cox. J. W. (1969) Combined alpha and beta sympathetic blockade in hyperthyroidism. Annals of Internal Medicine. 70, 963-970. Taylor. R. Roo Covell, J. W. & Ross, J. Jr (1969) Influence of the thyroid state on left ventricular tension-velocity relations in the intact. sedated dog. Journal of Clinical Investigation. 48, 775·784. Thier, M. D .• Gravenstein. J. S. & Hoffman, R. G. (1962) Thyroxin, reserpine, epinephrine and temperature on atrial rate. Journal of Pharmacology and Experimental Therapeutics. 136, 133-141. Tice. L. W. & Creveling, C. R. (1975) Electron microscopic identification of adrenergic nerve endings on thyroid epithelial cells. Endocrinology. 97, 1123-1129. Toft, A. D.• Irvine, W. J., McIntosh, D., Macleod, D. A. D., Seth, J., Cameron, E. H. D. & Lidgard, G. P. (1976) Propranolol in the treatment of thyrotoxicosis by subtotal thyroid· ectomy. Journal of Clinical Endocrinology and Metabolism, 43, 1312-1316. Tucci, J. R. & Kopp, L. (1976) Urinary cyclic nucleotide levels in patients with hyper· and hypothyroidism. Journal of Clinical Endocrinology and Metabolism. 43, 1323·1329. van derSchoot, J. V. & Moran, N. C. (1965) An experimental evaluation ofthe reputed influence of thyroxine on the cardiovascular effects of catecholamines. Journal of Pharmacology and Expen'mental Therapeutics. 149, 336·345.

718

LEWIS LANDSBERG

Waldstein, S. S. (1966) Thyroid-catecholamine interrelations. Annual Review of Medicine, 17, 123-132. Wartofsky, L., Dimond, R. C., Noel, G. L., Frantz, A. G. & Earll, J. M. (1975) Failure of propranolol to alter thyroid iodine release, thyroxine turnover, or the TSH and PRL responses to thyrotropin-releasing hormone in patients with thyrotoxicosis. Journal of Clinical Endocrinology and Metabolism. 41, 485-490. Wiener, L., Stout, B. D. & Cox, J. W. (1969) Influence of beta sympathetic blockade (propranolol) on the hemodynamics of hyperthyroidism. AmericanJournal ofMedicine, 46, 227-233. Wildenthal, K. (1971) Responses to cardioactive drugs of fetal mouse hearts maintained in organ culture. American Journal of Physiology, 221, 238-241. Wildenthal, K. (1972) Studies of isolated fetal mouse hearts in organ culture: evidence for a direct effect of triiodothyronine in enhancing cardiac responsiveness to norepinephrine. Journal of Clinical Investigation. 51, 2702-2709. Williams, L. T., Leikowitz, R. J., Watanabe, A. M., Hathaway, D. R. & Besch, H. R. Jr (1977) Thyroid hormone regulation of beta-adrenergic receptor number. Journal of Biological Chemistry, 252, 2787-2789. Will-Shahab, L. & Wollenberger, A. (1974) Influence of thyroid state on the binding of noradrenaline to a cardiac subcellular fraction containing the beta-adrenoreceptor. Acta Bio/ogica et Medica Germanica, 32, KI-K8. Wilson, W. R., Theilen, E. O. & Fletcher, F. W. (1964) Pharmacodynamic effects of betaadrenergic receptor blockade in patients with hyperthyroidism. Journal of Clinical Investigation. 43, 1697-1703. Wilson, W. R., Theilen, E. 0., Hege, J. H. & Valenca, M. R. (1966) Effects of beta-adrenergic receptor blockade in normal subjects before, during, and after triiodothyronine-induced hypermetabolism. Journal 01 Clinical Investigation, 45, 1159-1169. Wiswell, J. G., Hurwitz, G. E., Corohno, V., Bing, O. H. L. & Child, D. L. (1963) Urinary catecholamines and their metabolites in hyperthyroidism and hypothyroidism. Journal of Clinical Endocrinology and Metabolism, 23, 1102-1106.