Effect of amiodarone on serum lipids, lipoprotein lipase, and hepatic triglyceride lipase

We have determined the effects of chronic amiodarone treatment on lipid metabolism and compared them with those of hypothyroidism in the rat. Serum triglyceride was lower in both amiodarone-treated and hypothyroid rats; total cholesterol was higher in hypothyroid rats, and serum high density lipoprotein cholesterol remained unchanged. Amiodarone increased adipose tissue lipoprotein lipase activity. Hepatic triglyceride lipase activity was decreased in both hypothyroid and amiodarone-treated groups. The effects of amiodarone on serum triglyceride and adipose tissue lipoprotein lipase were reversed by concomitant administration of T3. The activity of hepatic triglyceride lipase, however, was not increased. Our findings indicate that amiodarone causes marked changes in lipid metabolism which are similar to those found in hypothyroidism.     

Effects of amiodarone and desethylamiodarone on pituitary deiodinase activity and thyrotropin secretion in the rat

The effect of acute administration of amiodarone, its major metabolite desethylamiodarone and iodine in an amount equal to that contained in amiodarone on serum thyroid hormone and thyrotropin (TSH) concentrations and hepatic and pituitary 5' deiodination of thyroxine (T4) in the euthyroid and hypothyroid rat was evaluated. Amiodarone, desethylamiodarone and iodine all caused a decrease in serum T4 and triiodothyronine (T3) concentrations in euthyroid rats, while serum TSH concentrations and pituitary and hepatic 5' deiodinase activities were decreased only in the amiodarone and desethylamiodarone-treated animals. Serum TSH was increased in the iodine treated rats. Amiodarone, but not iodine, decreased serum T3 and TSH concentrations and pituitary and hepatic 5' deiodinase activities in hypothyroid rats. Inhibition of hepatic 5' deiodinase activity was also observed by the addition of amiodarone in vitro in the absence of dithiothreitol (DTT) but not in the presence of DTT. The decrease in the serum T4 concentration observed with amiodarone and desethylamiodarone administration is probably secondary to the inhibitory effect of iodine released from the drugs on thyroidal T4 synthesis and secretion. Iodine inhibition of thyroidal T3 synthesis and secretion, decreased T4 substrate for a peripheral generation of T3 and inhibition of T4 to T3 conversion all contribute to the decrease in serum T3 observed. The decrease in the serum TSH concentration, despite low serum T4 and T3 concentrations and inhibition of pituitary 5' deiodinase, suggest that amiodarone may function as a thyroid hormone agonist in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of amiodarone on serum thyroid hormones and hepatic thyroxine 5'-monodeiodination in rats

Amiodarone (2-n-butyl-3,4'-diethylaminoethoxy-3', 5'-diiodobenzoyl-benzofurane) is an antiarrhythmic drug which increases serum T4 and rT3 levels in patients and lowers serum T3 levels. To investigate its effects on T4 metabolism and its cardiac action, we fed amiodarone to male Fisher rats at doses of 5, 15, and 45 mg/kg BW X day; controls received potassium iodide for 4-7 weeks, and another group received sodium ipodate. At 4 weeks, amiodarone caused a dose-dependent increase in the serum T4 concentration and a slight reduction of serum TSH without a change in the serum T3 concentration. These changes were not present at 7 weeks. Sodium ipodate raised serum T4 concentrations at both times. Rats treated with T4 (150 micrograms/kg BW X day) to suppress thyroidal secretion of hormone and with amiodarone (15 mg/kg) had marked reduction of serum T3 concentrations compared with controls receiving T4 without amiodarone. Liver homogenates from rats treated with amiodarone showed marked reduction on T4 5'-monodeiodinase activity in a dose-related manner. Amiodarone added to liver homogenates in vitro at concentrations of 0.001-1 mM did not inhibit T3 production from T4, whereas ipodate added in vitro (0.01-1 mM) did inhibit T3 production. Rats treated with amiodarone showed a lowering of the resting heart rate and a reduction of the increment in heart rate after iv isoproterenol administration. The cardiac Ca++ myosin ATPase activity was reduced in rats receiving amiodarone (45 mg/kg) compared with that in controls. The data indicate that rats treated with amiodarone have reduced peripheral conversion of T4 to T3 owing to impaired hepatic T4 5'-monodeiodinase activity. In addition, these rats have slowing of heart rate and reduction of cardiac Ca++ myosin ATPase activity. These findings are consistent with the hypothesis that amiodarone blocks some effects of thyroid hormone on the heart, but additional studies are needed to test this hypothesis.     

Myosin isoenzyme distribution and Ca+2-activated myosin ATPase activity in the rat heart is influenced by fructose feeding and triiodothyronine

Studies were conducted to determine if the level of cardiac Ca+2-activated myosin ATPase activity and ventricular myosin isoenzyme distribution are influenced by both T3 administration and fructose feeding. Previous studies have shown that in the cardiac ventricle of hypothyroid rats, only myosin V3 is present, and the Ca+2-activated myosin ATPase activity is markedly decreased. Hypothyroid [thyroidectomized (Tx)] rats were fed a diet containing 60% fructose or a regular diet (47% complex carbohydrates) for 4 weeks. Fructose feeding of hypothyroid rats led to a significant increase in Ca+2-activated myosin ATPase activity (Tx regular diet, 0.33 +/- 0.02 mumol Pi/mg protein X min; Tx fructose diet, 0.54 +/- 0.04 mumol Pi/mg protein X min). In addition, myosin V1 was detectable in the heart of fructose-fed Tx rats, but was absent in Tx rats on the regular diet. To determine if fructose had an effect of similar magnitude in animals of different thyroid states, Tx rats were injected with 0.075, 0.150, 0.225, and 0.300 micrograms T3/100 g BW daily and placed on fructose or regular diets. The fructose-induced increase in Ca+2-myosin ATPase activity was between 24-27% in Tx rats receiving 0-0.15 micrograms T3/100 g BW daily. In animals receiving 0.225 and 0.300 micrograms T3/100 g BW daily, fructose feeding did not induce a significant increase in myosin ATPase activity. This is due to the fact that the Ca+2-activated myosin ATPase activities of euthyroid and hyperthyroid animals are not significantly different from each other. In hypothyroid rats receiving a 60% glucose diet, Ca+2-myosin ATPase activity showed a significant 20% increase above the value in regular diet-fed Tx rats. Fructose- and glucose-induced changes in Ca+2-myosin ATPase activity occurred in the absence of changes in thyroid hormone or insulin levels. Our findings may indicate that cardiac carbohydrate consumption influences the predominance of ventricular myosin isoenzymes in the rat heart.     

甲状腺功能低下对大鼠肝细胞核T3受体的影响

目的探讨甲低大鼠肝核Ｔ３受体特性的变化,为阐明甲状腺激素对肝细胞核Ｔ３受体的作用提供实验资料。方法用０．５％ＮａＣｌＯ４诱导大鼠甲状腺功能低下,采用该室建立起来的Ｔ３和离体肝细胞核结合实验的方法,观察甲状腺功能低下对大鼠肝核Ｔ３受体的影响。结果甲状腺功能低下大鼠肝核Ｔ３受体的亲合常数（Ｋａ）增加,最大结合容量（ＭＢＣ）明显下降,Ｔ３受体占位率与对照组无显著差别,且ＭＢＣ与血清Ｔ３、Ｔ４呈正相关。结论肝核Ｔ３受体的数目受甲状腺激素的调节与控制,甲状腺激素对肝脏的作用主要通过调节核Ｔ３受体的结合容量,而非通过改变受体占位率来实现的     

AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH beta and alpha subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH beta and alpha mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.     

Diagnosis of amiodarone-iodine-induced thyrotoxicosis(AIIT) associated with severe nonthyroidal illness

A rare case of amiodarone-iodine-induced thyrotoxicosis (AIIT) associated with nonthyroidal illness is reported. Serum total thyroxine (TT4) and free T4 (FT4) concentrations were elevated and serum TSH was undetectable as frequently observed also in euthyroid amiodarone-treated patients. At variance with common forms of AIIT, serum total triiodothyronine (TT3) was reduced due to low-T3 syndrome. The laboratory diagnosis was made on the basis of elevated free T3 (FT3) levels. Thus, in patients with severe nonthyroidal illness submitted to chronic amiodarone treatment, thyroid status can only be determined by free hormone measurement, particularly FT3 in the case of thyrotoxicosis.     

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg.kg-1.day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylamiodarone levels under the above experimental conditions were 0.20 +/- 0.067 and 0.17 +/- 0.058 mg/l, respectively, which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]-tetraiodothyroacetic acid (10 muCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 +/- 0.008 in controls to 0.074 +/- 0.009 l/day in amiodarone-treated rabbits (p less than 0.05). However, when expressed per unit body weight (1.day-1.kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 +/- 6.7 h in controls vs 49.2 +/- 12.4 h in amiodarone-treated).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin-like growth factor binding protein expression in the hypothyroid rat is age dependent.

Thyroid hormone is essential for normal growth and development. For certain T4 effects, there is a critical period during ontogeny when normal T4 levels are required, and thyroid replacement after that period cannot correct the changes in hypothyroid animals. We have previously described a prolonged high expression of serum insulin-like growth factor binding protein (IGFBP)-2 during the perinatal period in congenitally hypothyroid rats. To see if this effect was confined only to a certain period during rat ontogeny, we made rats hypothyroid with methimazole treatment either prenatally, or at different postnatal ages from 1 to 14 days of life, and at adult age. Serum IGF-I levels were reduced by approximately 30% in all the 18-day-old hypothyroid animals, and did not correlate with the duration of the hypothyroid state. Serum IGF-I levels in the adult animals were 50% of control levels. At the age of 18 days, control animals had only very low levels of IGFBP-2 demonstrable by western ligand blotting, whereas the congenitally hypothyroid animals had elevated levels. Pups placed on methimazole treatment since the first day of life showed higher IGFBP-2 levels at the age of 18 days, although the change was not as prominent as in the congenitally hypothyroid animals (200% vs. 500% of control levels, respectively). Binding protein changes were approximately 2-fold at the mRNA level. Rats started on methimazole after the first 5 days of life showed normal low levels of IGFBP-2 at the age of 18 days. Abnormal IGBFP-2 expression in congenitally or neonatally hypothyroid animals could be corrected by thyroid hormone replacement, if started during the first week of the life, but not later. In adult hypothyroid animals, there was no induction of IGFBP-2 expression, but the levels of IGFBP-3 and -4 were decreased to 80% and to 30% of control levels, respectively. IGFBP-3 messenger RNA (mRNA) levels were decreased to 50% of control levels but IGFBP-4 mRNA levels were paradoxically increased in the hypothyroid animals. All these changes could be corrected by T4 replacement. In conclusion, there exists a critical period during the perinatal development of the rat, when thyroid hormone is essential for a subsequent normal IGFBP-2 ontogenic pattern. Adult animals show a completely different IGFBP response to hypothyroidism, with a decrease of IGFBP-3 and -4 levels. Thus, the effects of thyroid hormone on IGF-IGFBP axis regulation depend on the developmental stage of the animal.     

Hypothyroid-like effect of amiodarone in the ventricular myocardium of the rat

Summary Due to the similar electrophysiological effects of amiodarone and hypothyroidism in the myocardium, the induction of a local hypothyroid state has been proposed as the mechanism of action of amiodarone. To examine this hypothesis we have studied the influence of amiodarone on the distribution of ventricular isomyosins — a sensitive parameter of the thyroid state in the rat heart — and the effects of amiodarone on 3,5,3-triiodothyronine (T₃) myocardial nuclear receptor binding in vivo.Amiodarone induced a dosage-dependent redistribution of isomyosins similar to hypothyroidism, while simultaneously inducing a low T₃ syndrome at the higher dose level. In hypothyroid rats, which were pretreated with amiodarone, substitution of T₃ (2 g/100 g) led to a complete reversal of the myosin pattern not differing from control hypothyroid rats which were only given T₃; the effect of T₃ (0.5 g/100 g) was however partially inhibited by amiodarone. Nuclear receptor binding of T₃ determined in hypothyroid rats in vivo was unaffected by amiodarone.We conclude that amiodarone induces a hypothyroid-like state in the ventricular myocardium of rats by inhibiting the action of T₃ — an effect which cannot be attributed to an antagonism at the T₃ nuclear receptor level.     

Impacts of the coexistence of diabetes and hypothyroidism on body weight gain,leptin and various metabolic aspects in albino rats

The present study was conducted to assess the interrelationship and the influence of the coexistence of diabetes and hypothyroidism on thyroid hormone levels, insulin levels and biochemical variables related to carbohydrate, lipid and protein metabolism in addition to thyroid gland and Islets of Langerhans histological changes and antioxidant defense system. Diabetes mellitus was induced by intraperitoneal injection of streptozotocin to fasting albino rats at dose level of 45 mg/kg b. w. Hypothyroidism in diabetic and normal rats was induced by adding methimazole in drinking water (0.02% w/v) for 4 weeks. The obtained results revealed that hypothyroidism interacts with diabetes in a way that prevents the progress of the hyperglycemic state. This may be due to the increase in the insulin secretory response in diabetic hypothyroid than diabetic rats. Serum T3 level decreased in order in diabetic (? 26.63%), hypothyroid (? 61.89%) and diabetic hypothyroid (? 65.69%) rats while T4 level was increased in diabetic rats and decreased in hypothyroid ones. The decrease in T3 level in diabetic animals in spite of T4 increase may be attributed to the decrease in conversion of T4 to T3 as a result of hepatic 5^′-DI decreased activity. Liver glycogen content was three-fold decreased in diabetic rats and was not significantly altered in both hypothyroid and diabetic hypothyroid rats. The serum leptin level and body weight gain were decreased in diabetic and diabetic hypothyroid rats; the leptin level was more deteriorated in diabetic hypothyroid rats while body weight gain was more affected in diabetic rats. Serum triglycerides level was more increased in diabetic rats than in diabetic hypothyroid ones on one hand, while total lipids, total cholesterol, LDL-cholesterol levels as well as cardiovascular indices were more deteriorated in diabetic hypothyroid rats than diabetic ones on the other hand. Serum total protein and globulin levels were decreased in diabetic rats and were increased in hypothyroid and diabetic hypothyroid rats. Hepatic total thiols and glutathione contents and catalase and peroxidase activity were profoundly decreased in diabetic rats while they (except glutathione) were increased in hypothyroid and diabetic hypothyroid rats. In conclusion, the hypothyroidism may have a counteracting effect on the hyperglycemic state and the elevated serum T4 level as well as the deteriorated antioxidant defense system found in diabetes mellitus, but both experimentally-induced diseases may synergize in inducing more elevation of serum total lipids, total cholesterol and LDL-cholesterol and more decrease in leptin levels.     

Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias

Amiodarone, a drug that has electrophysiologic actions resembling those of hypothyroidism, increases serum levels of T4 and reverse T3 (rT3) and decreases T3. The drug's long-term effects on thyroid function are poorly defined. Serial thyroid hormone indexes in 76 patients given amiodarone for 6 to 32 months (mean +/- standard deviation 16 +/- 7) for arrhythmias were determined serially. Over this period, 68 patients (89%) remained euthyroid; hypothyroidism developed in 6 (8%) and hyperthyroidism developed in 2 (3%). In patients who remained euthyroid, thyroid hormone alterations attained steady-state values at 3 months: T4 increased 42% (p less than 0.01), rT3 increased 172% (p less than 0.01) and T3 decreased 16% (p less than 0.05), without significant effect on thyroid stimulating hormone. For the euthyroid patients, the 90% tolerance limits (95% confidence) over the follow-up period for T4 was 5 to 19 micrograms/dl (normal 4 to 12), for T3 36 to 163 ng/dl (normal 60 to 160), for rT3 22 to 131 ng/dl (normal 15 to 50) and for thyroid stimulating hormone 0 to 14 microU/ml (normal 1 to 6). The changes in hormone indexes in hyperthyroid or hypothyroid patients were unrelated to the cumulative dose or duration of drug therapy. The most reliable diagnostic indexes for amiodarone-induced altered thyroid state were: thyroid stimulating hormone level over 20 microU for hypothyroidism and T4 over 20 ng/dl or high T3 over 200 ng/dl for hyperthyroidism. All levels were within the 90% tolerance limits derived for these hormones from patients remaining euthyroid on amiodarone long-term.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of rat cardiac Kv1.5 gene expression by thyroid hormone is rapid and chamber specific.

Thyroid hormone affects the contractile and electrophysiological properties of the cardiac myocyte that result in part from changes in the expression of thyroid hormone-responsive cardiac genes, including those that regulate membrane ion currents. To determine the molecular mechanisms underlying this effect, expression of a voltage-gated K+ channel, Kv1.5, was measured in response to thyroid hormone. Using quantitative RT-PCR methodology, the content of Kv1.5 messenger RNA (mRNA) in left ventricles of euthyroid rats was 4.25+/-0.6x10(-20) mol/microg total RNA and was decreased by 70% in the hypothyroid rat ventricle to 1.27+/-0.80x10(-20) mol/microg RNA (P<0.01). Administration of T3 to hypothyroid animals restored ventricular Kv1.5 mRNA to control levels within 1 h of treatment, making this the most rapid T3-responsive cardiac gene reported to date. The half-life of Kv1.5 mRNA was 1.9 h and 2.0 h in euthyroid and hypothyroid ventricles, respectively, and T3 treatment of the rats did not alter its half-life. In atrial myocardium, expression of Kv1.5 mRNA (6.10+/-0.37x10(-20) mol/microg RNA) was unaltered by thyroid hormone status. The myocyte-specific and chamber-selective expression of Kv1.5 mRNA was confirmed in primary cultures of rat atrial and ventricular myocytes.     

The effect of thyroid hormone on size of fat depots accounts for most of the changes in leptin mRNA and serum levels in the rat.

The physiological consequences and mechanism(s) for thyroid hormone-induced alterations in serum leptin are not known. To address this, leptin expression in rats was evaluated in relationship to food intake, fat mass, and body temperature in rats with pharmacologically altered thyroid status. Total body weight, food intake, and temperature were decreased in hypothyroid rats. Fat weight was decreased in both chronically hypothyroid and hyperthyroid rats (n = 6/group). Serum leptin was linearly correlated with fat weight, epididymal and retroperitoneal fat leptin mRNA concentration, but not total body weight. Serum leptin was decreased in the chronically hyperthyroid rats. When fat weight was used as a covariant, serum leptin was not different between the three groups. Epididymal fat leptin mRNA was higher in euthyroid (n = 7) than in hypothyroid and hyperthyroid rats. Retroperitoneal fat leptin mRNA was not affected by thyroid status. A positive linear relationship between food intake and free triiodothyronine (FT3) index was observed, but not between food intake and serum leptin alone. In a time course study, serum leptin, epididymal fat leptin mRNA content, and fat weight did not change within 24 hours of high-dose triiodothyronine (T3) (n = 6/group), but both temperature and epididymal fat S14 mRNA content rapidly increased. These findings demonstrate that thyroid state influences circulating leptin levels, but primarily does so indirectly through the regulation of fat mass. Leptin does not influence core body temperature across thyroidal state. Finally, thyroid state is more important to regulate food intake, through an as yet undefined mechanism, than are thyroid state-associated changes in serum leptin.     

Thyroid dysfunction during chronic amiodarone therapy

Clinical and laboratory features of 99 patients receiving long-term amiodarone therapy were analyzed to determine which individuals may be at a high risk for developing amiodarone-induced thyroid dysfunction. The group of 68 men and 31 women was followed up for an average of 27 months (range 3 to 60). There were no differences in age, sex, dose of amiodarone, type or severity of underlying heart disease or baseline serum thyroxine levels in patients who developed hypothyroidism (n = 32) or hyperthyroidism (n = 5) or remained euthyroid (n = 62). Baseline serum thyrotropin levels were statistically higher in patients who became hypothyroid, but there was considerable overlap with the other patient groups. Serum reverse triiodothyronine (reverse T3), which has been suggested to be a marker of amiodarone efficacy, correlated directly with serum thyroxine levels, and was not an independent variable. There was no pattern to the time course for development of thyroid dysfunction, which occurred in 49% of those followed up and developed as early as 1 month or, in one individual, as late as after 3 years of amiodarone therapy. There are few guidelines for replacement therapy in patients with amiodarone-induced hypothyroidism. L-thyroxine dosage was adjusted cautiously in these high risk individuals to achieve serum thyroxine levels within the reference range of euthyroid individuals taking amiodarone: the mean dosage required was 136 micrograms/day. Normalization of serum thyrotropin (TSH) would have required doses of L-thyroxine that were judged to be excessively high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid effects of the flavonoid EMD 21388 on serum thyroid hormone binding and thyrotropin regulation in the rat

Naturally occurring and synthetic flavonoids are potent inhibitors of thyroid hormone 5'-deiodination and binding to human serum transthyretin (TTR) in vitro. We now describe the inhibitory effect of the most potent flavonoid, 3-methyl-4',6-dihydroxy-3',5'-dibromo-flavone (EMD 21388), on the serum protein binding of T4 and T3 and subsequent alterations of pituitary-thyroid function in the rat. Eight to 10 mumol/liter EMD 21388 added to pooled rat serum completely displaced [125I]T4 or [125I]T3 binding from TTR, the major thyroid hormone-binding protein in the rat, and markedly increased the percentages of free T4 and T3, measured by equilibrium dialysis. One to 4 h after the ip administration of 2 mumol EMD 21388/100 g BW to euthyroid rats, [125I]T4 and [125I]T3 binding to TTR decreased, serum T4 and T3 concentrations decreased, and the percentages of free T4 and free T3 increased. No changes were observed in the free T4 and free T3 concentrations. Serum TSH concentrations decreased at 1 h and were very low thereafter. EMD 21388 administration did not affect the elevated serum TSH concentrations in hypothyroid rats, strongly suggesting that the flavonoid does not directly affect TSH secretion. No changes were observed in hepatic type I 5'-deiodinase in euthyroid rats and pituitary type I and type II 5'-deiodinase in euthyroid and hypothyroid rats after EMD 21388 administration. We conclude that the ip administration of EMD 21388 to euthyroid rats inhibits T4 and T3 binding to TTR, with subsequent increases in the percentages of free T4 and free T3 and decreased serum T4 and T3 concentrations. The decrease in the serum TSH concentration was possibly due to transcient increases in the serum free T4 and/or free T3 concentrations, resulting in increased pituitary thyroid hormone content.     

Hormonal influences on cardiac myosin ATPase activity and myosin isoenzyme distribution

It has been recognized for a long time that changes in hormone secretion can influence cardiac function; however, the biochemical basis for these changes has only recently been clarified. In this review the influences of hormonal status on the contractile protein myosin is discussed. Myosin has a rod-like portion and a globular head and consists of two myosin heavy chains (MHC) and four light chains (LC), two of which are identical. The globular head is the site of an ATP-splitting enzyme, the myosin ATPase, and increases in myosin ATPase activity are closely related to an increased velocity of contraction of the heart. Myosin ATPase activity shows marked response to alterations in thyroid hormone, insulin, glucocorticoid, testosterone and catecholamine levels, but marked animal species differences in this response occur. Thyroid hormone administration to normal rabbits, for example, increases myosin ATPase activity markedly, but the myosin ATPase activity of hyperthyroid rats remains unchanged. In contrast, in hypothyroid rats myosin ATPase activity is markedly decreased but the hypothyroid rabbit shows no such response. These species-related differences in the hormonal response of myosin ATPase activity result from the predominance pattern of specific myosin isoenzymes. In the normal rat heart three myosin isoenzymes, v₁, V₂ and V₃, can be separated electrophoretically. Myosin V₁ predominates (70% of total myosin), and has the highest myosin ATPase activity, whereas in rabbits myosin v₃, which has a lower myosin ATPase activity, is the predominant isomyosin. Thyroid hormone administration to rabbits induces myosin V₁ predominance and therefore increases myosin ATPase activity, whereas in hyperthyroid rats only a small further increase in V₁ predominance can occur. The alterations in myosin isoenzyme predominance and myosin ATPase activity are closely correlated to changes in cardiac contractility. Hormone-induced alterations in myosin isoenzyme predominance are mediated through changes in the formation of two isoforms of myosin heavy chain. Changes in the expression of different myosin heavy chain genes are most likely responsible for the thyroid hormone and insulin-induced alterations in myosin isoenzyme predominance. Investigation of the control of myosin heavy chain formation can provide further insights into the hormonal control of a multigene family as well as broaden our understanding of the molecular events which result in altered cardiac contractility. It is currently unclear if androgens, glucocorticoids and catecholamines influence myosin ATPase activity through changes in myosin isoenzyme predominance resulting from alterations in myosin heavy chain gene expression. Post-translational modifications of myosin heavy chain and light chain polypeptides have also to be considered.     

Caloric restriction does not alter thyrotropin secretion in hypothyroidism

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.