T3-treated Animals Research Articles

Synaptosomal Action of Thyroid Hormone: Changes in Na+-K+-ATPase Activity in Adult Rat Cerebral Cortex

In view of the lack of knowledge on the thyroid hormone (T3) action in adult mammalian brain the present investigation was undertaken to assess the role of this hormone on synaptosomal function of adult rat cerebral cortex. Single injection of various doses of T3 showed dose-dependent inhibition of the synaptosomal Na(+)-K(+)-ATPase activity with its maximum effect at 24 hr in comparison to the untreated control values. The magnitude of the inhibitory response of T3 gradually diminished with the advancement of time (48 and 72 hr). Propylthiouracil (PTU) treatment caused stimulation of the synaptosomal Na(+)-K(+)-ATPase activity in comparison to the untreated control animals. T3 treatment to the PTU-treated animals showed inhibition of the Na(+)-K(+)-ATPase activity at a level very similar to that found in only T3-treated animals. The study indicates involvement of T3 in synaptosomal function of adult rat.

Effect of thyroid hormone treatment on redox and phosphate potentials in rat liver.

In the present study rat liver cytosolic/mitochondrial redox and phosphate potentials were evaluated as a function of thyroid hormone status. T3 treatment resulted in a dose-dependent 2-fold decrease in the cytosolic redox potential, as reflected by the liver lactate/pyruvate ratio, with a concomitant increase in the liver capacity of handling an ethanol load. The effect of T3 on liver cytosolic redox potential was correlated with a T3-induced increase in mitochondrial glycerol-3-phosphate dehydrogenase activity. The apparent liver cytosolic phosphate potential was calculated from the glycerol-3-phosphate/3-phosphoglyceric acid ratio, using 31P-nmr under conditions of rapid equilibrium within the glycerol-3-phosphate/3- phosphoglyceric acid metabolic section and was found to be essentially unaffected by T3 treatment. The apparent total cellular phosphate potential measured by 31P-nmr, however, was decreased in T3-treated animals, reflecting a decrease in the apparent liver mitochondrial phosphate potential induced by T3 treatment. Also, while the apparent cellular phosphate potential of euthyroid rats was independent of ethanol administration, the reduced cellular phosphate potential of T3-treated rats was normalized by ethanol treatment. In conclusion, thyroid hormone treatment induces in vivo a dramatic decrease in the liver cytosolic redox potential, with a concomitant increase in the liver oxidizing capacity. The decrease in cytosolic redox potential induced by thyroid hormone treatment is accompanied by a decrease in mitochondrial phosphate potential. Liver mitochondrial ATP production in thyroid hormone-treated animals appears to be rate limited by the availability of cytosolic reducing equivalents.

Determination of femur structural properties by geometric and material variables as a function of body weight in rats

Since thyroid hormone accelerates energy-requiring processes, a negative caloride balance often exists in the hyperthyroid state. To assess the role of this induced calorie deficit in the production of thyrotoxic myopathy, we have examined the effect of calorie deprivation on creatine excretion in experimental hyperthyroidism. Since food restriction decreases fecal excretion of thyroid hormone, a low-residue glucose-supplemented diet has been used to produce calorie-replete hyperthyroid animals having circulating thyroid hormone levels comparable to half-starved hyperthyroid animals. Calorie-deprived hyperthyroid animals have a 2–4-fold increase in creatine excretion when compared to fully fed hyperthyroid animals having comparable thyroid hormone levels. Although a negative calorie balance greatly enhances creatinuria in experimental hyperthyroidism, it is not a necessary condition for thyroid hormone-induced creatinuria. Calorie-replete hyperthyroid animals consistently gained weight, indicating a positive calorie balance. Nevertheless, these animals manifested increased creatinuria when compared to euthyroid controls. Therefore, excess thyroid hormone appears to cause muscle damage as reflected in creatinuria by a mechanism other than mobilization of muscle protein to provide endogenous calories. A study of the effect of triiodothyronine (T3) on creatine and urea excretion in fasting rats led to the same conclusion. T3 plus fasting produced a much more marked creatinuria than fasting alone. During the first 48 hr of fasting, the rate of weight loss and urea excretion were comparable in T3-treated and control animals. Nevertheless, the rate of creatine excretion during this interval was 10–12-fold increased in the T3-treated group. In these experiments, there was clearly a dissociation between T3 stimulation of urea excretion and the magnitude of creatinuria induced. Although a negative calorie balance appears to hasten the development of thyrotoxic myopathy, accelerated muscle proteolysis to supply an induced calorie deficit is not an adequate model to account for muscle involvement in hyperthyroidism.

Neonatal hyperthyroidism disrupts hippocampal LTP and spatial learning

Excess thyroid hormone at an early stage of development produces marked neurochemical and morphological alterations in the rat hippocampal formation. In order to better understand the functional significance of these changes, we tested adult rats treated neonatally with triiodothyronine (T3), and their control litter mates, in a spatial learning task and for the induction of long-term potentiation (LTP) in the dentate gyrus (DG) of the hippocampal formation. The T3-treated rats were significantly impaired in their performance on the spatial task in comparison to their matched controls. Similarly, the efficacy of LTP induction was significantly attenuated in the T3-treated animals. Further, a significant correlation was obtained between LTP induction and performance on the spatial learning task. Thus, a brief neonatal excess of thyroid hormone produces impairments in spatial learning along with decreases in LTP, long held as a model of learning and memory. This relationship provides a unique opportunity to study associations between behavioral, physiological, pharmacological and morphological processes intimately associated with the hippocampal formation.

Thyroid Hormone Increases Muscle/Fat Glucose Transporter Gene Expression in Rat Skeletal Muscle*

The enhancement of metabolic rate by thyroid hormone in target tissues is accompanied by increased glucose utilization, which in skeletal muscle and many other tissues is regulated at the level of membrane transport. To elucidate the role of thyroid hormone as a regulator of glucose transport in skeletal muscle, we have examined its effects on the expression of the muscle/fat (insulin-regulatable) glucose transporter, a distinct glucose transporter isotype whose expression is limited to insulin-sensitive tissues and which appears to be the major glucose transport protein in skeletal muscle. Treatment of hypothyroid rats with L-T3 (T3; 100 micrograms/100 g BW.day for 6 days) increased the abundance of the muscle/fat glucose transporter protein in crude membranes from hindlimb muscle, assessed by immunoblotting, to 145 +/- 8% of the control value in animals fasted for 17-20 h before death and to 159 +/- 16% of the control value in animals fed ad libitum (mean +/- SE). In purified plasma membranes, this effect of thyroid hormone was greater (208 +/- 23% and 219 +/- 13% of control in fasted and fed animals, respectively). Similar increases were found in an intracellular membrane fraction. Levels of muscle/fat glucose transporter mRNA were also increased in hindlimb muscle from the T3-treated rats, to 261 +/- 17% and 316 +/- 23% of control values in fasted and fed animals, respectively. In contrast, the erythroid glucose transporter protein and its mRNA, which are only weakly expressed in skeletal muscle but strongly expressed in brain, were not substantially increased by T3 treatment in either tissue. In experiments comparing hypothyroid, euthyroid, and chronically T4-treated animals, muscle/fat glucose transporter protein and mRNA abundance in skeletal muscle were also found to be dependent on thyroid status. Thyroid hormone may, thus, be an important regulator of the muscle/fat glucose transporter in skeletal muscle.

T3 Preserves Respiratory Function in Sepsis

Sepsis produces profound hypothyroidism. This hypothyroid state is associated with altered lung metabolism and structural integrity. We studied the respiratory function of rats during sepsis-induced hypothyroidism with or without T3 treatment. Forty-four male Holtzman rats underwent cecal ligation and puncture (CLP). Treatment was administered at six hours after surgery consisting of intraperitoneal injection of T3 (15 micrograms/kg, n = 19) or saline (n = 25). At 20 hours (Group A) or 30 hours (Group B) following CLP, respiratory drive was assessed by serial occlusion pressure technique (P0.1). The rats were killed and static elastance determined by serial air inflation to 10 cc. The lungs were excised for weight determination. The P0.1 values were significantly greater in T3-treated animals over controls in Group A (9.3 +/- 0.7 vs. 6.6 +/- 2.2, p less than 0.05 by t test); elastance was significantly improved by T3 treatment in Group B (p less than 0.05 by two-way ANOVA). Lung weight, pH, pO2, pCO2, respiratory rate (RR), and mortality were not significantly different between groups. Control animals were hypothyroid by 20 hours after CLP (T3 less than 12.5 ng/dL) whereas T3-treated animals were euthyroid (T3 = 145 +/- 43 ng/dL). Pulmonary dysfunction frequently accompanies sepsis; the euthyroid state appears protective. We found a significantly improved respiratory drive in septic animals with T3 treatment. Lung elastance was similarly improved in late sepsis with T3 treatment. The data suggest that T3 treatment preserves respiratory function in septic rats as evidenced by respiratory drive and compliance.

Effect of thyroidectomy and subsequent treatment with triiodothyronine on kidney mitochondrial oxidative phosphorylation in the rat

The effect of thyroidectomy (Tx) and subsequent treatment with triiodothy-ronine (T3) on rat kidney mitochondrial oxidative phosphorylation was examined. Thyroidectomy resulted in lowering of state 3 respiration rates and cytochrome contents. Thyroidectomized animals administered with T3 (20 Μg/100 g body wt) resulted in the nonsynchronous stimulation of state 3 respiration rates in kidney mitochondria with glutamate, Β-hydroxybutyrate, succinate and ascorbate+TMPD as substrates. Cytoch-rome contents were also elevated differentially. Increase in the state 4 respiration rates was transient and reversible. However, primary dehydrogenases were not generally altered in the Tx and T3-treated Tx animals. The results thus indicate that the T3treatment to-Tx animals brings about differential and nonsynchronous increase in the respiratory parameters and respiratory chain components of kidney mitochondria.

Isoprenaline-induced increase in mRNA levels of inhibitory G-protein ?-subunits in rat heart

Long-term beta-adrenergic stimulation has been shown to desensitize the beta-adrenoceptor/adenylyl cyclase signalling pathway at both the receptor and the G-protein level. To further elucidate the cellular mechanism of G-protein regulation we investigated the influence of prolonged infusion of isoprenaline (2.4 mg/kg.d) on myocardial mRNA levels of different G-protein alpha-subunits in rats. For comparison rats were treated with triiodothyronine (T3; 0.5 mg/kg.d) which induces cardiac hypertrophy like isoprenaline but has different effects on the adenylyl cyclase system. Isoprenaline- and T3-treated animals developed an increase in heart/body weight ratio of 41 +/- 3% and 27 +/- 4%, respectively (P less than 0.05). Isoprenaline increased myocardial total RNA concentration by 39 +/- 6% (P less than 0.05). Hybridization with 32P-labeled rat cDNAs demonstrated an expression rank order of Gs alpha-mRNA greater than Gi alpha-2-mRNA greater than Gi alpha-3-mRNA and no detectable expression of Gi alpha-1-mRNA in rat myocardium. mRNA levels of Gs alpha, Gi alpha-2 and Gi alpha-3 were 36.9 +/- 1.28, 10.7 +/- 1.07 and 3.7 +/- 0.19 pg/micrograms total RNA, respectively. Isoprenaline increased Gi alpha-2- and Gi alpha-3-mRNA concentrations per microgram total RNA by 49 +/- 18% and 27 +/- 7%, respectively (P less than 0.05). This effect was abolished by simultaneously administered propranolol (9.9 mg/kg.d), indicating a beta-adrenoceptor-mediated mechanism. In contrast, T3-induced cardiac hypertrophy was not accompanied by changes in Gi alpha-mRNA expression. Gs alpha-mRNA levels were unaffected by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid Hormone Regulation of Peptidylglycine α-Amidating Monooxygenase Expression in Anterior Pituitary Gland

Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) is a copper-, molecular oxygen-, and ascorbate-dependent enzyme which catalyzes the COOH-terminal amidation of bioactive peptides. Expression of PAM in the adult male rat anterior pituitary was evaluated after experimental manipulation of thyroid status. Levels of PAM mRNA increased 4- to 7-fold in animals made hypothyroid by treatment with 6-n-propyl-2-thiouracil or thyroidectomy and were not diminished below control levels in animals made hyperthyroid by treatment with T4. Treatment of thyroidectomized animals with T4 prevented the increase in PAM mRNA levels; similar doses of T4 returned serum TSH and anterior pituitary PAM mRNA to euthyroid values. Based on Northern blot analysis and amplification of fragments derived from rat PAM-1 by reverse transcription and the polymerase chain reaction, thyroid status did not affect the distribution of PAM mRNA among its various alternatively spliced forms. The specific activity of PAM in the anterior pituitary was increased slightly in both the soluble and particulate fractions from chemically hypothyroid rats; the majority of the PAM activity in the rat anterior pituitary was soluble, and increased secretion of enzyme may account for the lesser effect of chemical thyroidectomy on specific activity compared to mRNA levels. Western blot analysis demonstrated a 104-kDa PAM protein in particulate fractions prepared from control, PTU-treated, and T4-treated animals. The soluble fraction contained major PAM proteins of 95 and 75 kDa, and PTU treatment brought about an increase in the prevalence of the 75-kDa form of PAM protein.(ABSTRACT TRUNCATED AT 250 WORDS)

The Influence of Thyroid Hormone Status on the Hypothalamo-Hypophyseal Growth Hormone Axis*

Growth hormone (GH) synthesis is known to be impaired by either abnormally high or low levels of thyroid hormone. To determine the effects of these conditions on the central regulation of GH secretion, we have examined their effects on the hypothalamic regulatory peptides GH-releasing hormone (GH-RH) and somatostatin (SRIF). In thyroidectomized rat hypothalamus, a dramatic increase in GH-RH mRNA occurred in parallel with a decrease in peptide content. The significance of this phenomenon is uncertain and might possibly reflect some posttranscriptional derangement of GH-RH synthesis or an increased rate of GH-RH synthesis and release. In the hyperthyroid group, GH-RH showed significant decreases in both peptide and mRNA levels that might possibly reflect a decrease in GH-RH synthesis and secretion. No change was observed in SRIF peptide or mRNA levels in either thyroidectomized or T4-treated animals. As expected, GH mRNA levels in the anterior pituitary were dramatically decreased by thyroidectomy and unaffected by T4 treatment. In addition, in thyroidectomized pituitaries, the mature GH mRNA was observed to alter its structure, increasing in size by approximately 100 nucleotides. This increase in size was found to result from an increase in poly(A) tail length, the significance of which is as yet unclear.

Effect of experimentally induced thyrotoxicosis on oxidative energy metabolism in rat heart mitochondria

Treatment of rats with T3 resulted in a significant decrease in body weight, while the heart weight increased. T4 treatment had less marked effect on body weights but resulted in decreased heart weights. Serum T4 levels decreased significantly with simultaneous increase of T3 level following T3 treatment, whereas with T4 treatment, levels of both T4 and T3 increased in the serum. Low doses of T3 (0.5 µg ) caused decrease in mitochondrial protein content while high dose of T4 (1 µg), caused significant increase in mitochondrial mass. The state 3 respiration rates were significantly depressed following T3 and T4 treatments, in a substrate specific manner with the effects being more pronounced with T3; these responses with T4 were dose-dependent for succinate and ascorbate + N,N,N′,N′-tetramethyl-p-phenylenediamme. State 4 respiration rates also exhibited similar corresponding changes. ADP/O ratios were not changed but ADP-phosphorylation rates were decreased significantly particularly so with the T3-treated animals. Treatment with T3 also resulted in lowering of intramitochondrial cytochrome contents. Similar effects were seen also with higher doses of T4. The results thus indicate that T3- and T4- thyrotoxicosis results in impaired energy metabolism in heart mitochondria.

Energy expenditure associated with sodium/potassium transport and protein synthesis in skeletal muscle and isolated hepatocytes from hyperthyroid sheep

The object of the present study was to determine the effect of thyroxine (T4) treatment of sheep on protein synthesis and associated energy costs in skeletal muscle and hepatocytes. Protein synthesis, and ouabain-sensitive and cycloheximide-sensitive respiration in isolated intercostal muscle and hepatocytes were determined in sheep after 5 weeks of daily injections of either saline or T4. Plasma T4 and total triiodothyronine (T3) concentrations were doubled and free T3 concentrations were quadrupled by T4 injections. The fractional rates of protein synthesis increased in isolated external intercostal muscle and hepatocytes from hyperthyroid sheep. Fractional rates of protein synthesis in isolated external intercostal muscle and hepatocytes were linearly correlated with plasma free T3 concentrations. Total oxygen consumption of muscle and hepatocytes was unaffected by T4 injections. Ouabain-sensitive respiration increased in hepatocytes and muscle of T4-treated animals. Cycloheximide-sensitive respiration was elevated in hepatocytes from hyperthyroid sheep. Cycloheximide-sensitive respiration in muscle was unaffected by T4 treatment. The present experiment demonstrates that T4 increases protein synthesis in ruminants. The energy expenditure in support of Na+, K(+)-ATPase and protein synthesis in skeletal muscle and hepatocytes may account for 34-60% of total cellular energy expenditure.

Tissue-specific isoform regulation of Na+-K+-ATPase by thyroid hormone in ferrets

We have shown previously that in the ferret heart there are two isoforms of Na+-K+-ATPase, alpha(+) and alpha, and that these isoforms undergo developmental changes. In the present study, we examine regulation of the isoenzymes by thyroid hormone, which is well known to increase activity of Na+-K+-ATPase in different tissue preparations. Ferrets were injected with L-thyroxine (T4) (0.5 mg/kg, sc) for 3 wk. The T4-treated ferrets gained 58 +/- 32 g body wt compared with 366 +/- 24 g for the control ferrets. Plasma 3,5,3'-triiodothyronine concentrations of the T4-treated animals increased about eightfold 16-18 h after the last injection. The number of alpha(+)- and alpha-subunits in heart homogenates estimated by [3H]ouabain binding was 3.5 +/- 0.1 and 2.5 +/- 0.1 pmol/mg protein, respectively [alpha(+)/alpha = 1.40]. In the T4-treated ferrets, there was no significant increase of the alpha(+)-isoform (3.2 +/- 0.2 pmol/mg protein), whereas the number of alpha-isoform increased significantly to 4.1 +/- 0.3 pmol/mg protein [alpha(+)/alpha = 0.78]. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of partially purified cardiac plasma membrane preparations reveals similar pattern of changes of the isoenzymes. In the kidney, however, there was no significant change in the number of alpha-isoform, which is the predominant isoform in the kidney, and T4 does not appear to induce synthesis of alpha(+)-isoform in the kidney. It is concluded that thyroid hormone induces both isoform- and tissue-specific regulation of the Na+-K+-ATPase alpha-subunits in the ferret. These specific regulations of the isoforms seem to suggest important physiological roles of the isoenzymes.

Thyroid hormones and muscle metabolism in dogs.

Muscle contents of ATP, ADP, AMP, creatine phosphate and creatine as well as glycogen, some glycolytic intermediates, pyruvate and lactate were compared in the intact, thyroidectomized and triiodothyronine (T3) treated dogs under resting conditions. After thyroidectomy muscle glycogen, glucose 1-phosphate and glucose 6-phosphate contents were significantly elevated while in T3-treated animals these variables were decreased in comparison with control dogs. Muscle free glucose was not altered by thyroidectomy but T3 treatment significantly increased its content. Muscle lactate content was elevated both in hypo- and hyperthyroid animals. Muscle ATP and total adenine nucleotide contents were significantly increased in hyperthyroid dogs while no differences were found between the three groups in the muscle creatine phosphate content. It is assumed that in T3-treated animals carbohydrate catabolism is enhanced in the resting skeletal muscle in spite of high tissue ATP content. Muscle metabolite alterations in hypothyroid dogs seem to reflect the hypometabolism accompanied by a diminished rate of glycogenolysis with inhibited rate of pyruvate oxidation or decreased rate of lactate removal from the cells.

Effect of thyroxine replacement therapy on the growth patterns of body, brain, and cerebellum in the neonatal hypothyroid rat

The reversibility of the effects of propylthiouracil induced neonatal hypothyroidism by daily subcutaneous injections of l-thyroxine (T4) was investigated in the rat. Four groups of rat pups were used in this experiment: Group I (control) received equivalent amounts of saline sucutaneously; Group II (hypothyroid) received propylthiouracil injections daily; Group III (T4-14) are hypothyroid rats who received daily T4 replacement therapy (2.5 μg/day) subcutaneously starting on Day 14; Group IV (T4-21) are also hypothyroid rats whose T4 replacement therapy (2.5 μg/day) was started on Day 21. The four parameters studied were body length, body weight, brain weight, and cerebellar weight in these four groups of animals at 4, 7, 10, 14, 21, 28, 35, and 42 postnatal days. A minimum of eight animals were studied for each time sequence. The present study clearly indicated the beneficial effect of T4 therapy on the length and body weight of the hypothyroid animals, whether therapy was started at Postnatal Day 14 or 21. In addition, a more important finding of this study was the significant increase in brain and cerebellar weights of T4-treated animals compared to the hypothyroid animals, this beneficial effect being more striking in the T4-14 group when compared to that in the T4-14 animals.

Propranolol and thyroxine-induced hypertrophic rabbit hearts: Effect on heart size and regional O2 supply/consumption variables

The purpose of this study was to determine the effect of acute and chronic propranolol on heart size and regional O2 supply/consumption variables in thyroxine (T4)-treated rabbit hearts. New Zealand white rabbits were given 0.5 mg/kg T4 for 3 or 16 days with and without concomitant 2 mg/kg propranolol. Another group was given 16 days of propranolol alone and another 3-day T4 group was given 2 mg/kg propranolol 1 h before the experiment began. Another group served as control. Myocardial blood flows were determined using radioactive microspheres and small arteriolar and venous O2 saturations were determined using microspectrophotometry. Treatment with T4 for 3 or 16 days increased the heart weight/body weight ratio, myocardial blood flow, and regional O2 consumption. 16-day T4 treatment resulted in myocardial flow 195% and O2 consumption 300% above control group values. When propranolol was given chronically along with T4, heart weight/body weight ratios did not increase to the degree seen with 3 or 16 days of T4, alone. Propranolol given acutely in 3-day T4-treated animals, resulted in a reduced O2 consumption and O2 extraction, though not to the extent seen with chronic propranolol treatment of T4-treated animals. Acute propranolol treatment slightly reduced myocardial blood flow in 3-day T4-treated animals, while chronic treatment significantly reduced it. Chronic propranolol treatment in 16-day T4-treated animals resulted in a significant reduction in flow and O2 consumption. Thus, T4 treatment increased O2 consumption, flow, and heart size and these effects could be attenuated using acute and chronic propranolol.

Thyroid hormone regulation of heme synthesis in rat liver.

Thyroid hormone alters the rate of heme degradation and the levels of cytochrome P450 in rat liver. These studies report the effects of thyroid status on the activity of hepatic delta-aminolevulinate synthase (ALAS), the initial and rate-limiting enzyme in heme synthesis. Thyroidectomized male Sprague-Dawley rats received sc injections of diluent or hormones. T3 was found to stimulate ALAS activity in the liver in doses which rendered the animals euthyroid (0.3 microgram/100 g BW.day). Higher doses failed to enhance enzyme activity further. T4 had similar effects but was less potent; rT3 had no effect on ALAS activity. The administration of a large single dose of T3 (50 micrograms/100 g BW) produced a significant (P less than 0.001) increase in ALAS activity 72 h later. Allylisopropylacetamide administration induced ALAS activity to identical levels in both hypothyroid and T3-replaced animals when administered at a dose of 200 mg/kg body wt. A dose of 400 mg/kg body wt allylisopropylacetamide, one associated with maximal induction of ALAS, resulted in an 80% higher enzyme activity in T3-treated animals compared with controls. Exogenous T3 had no effect on ALAS activity in sham-operated animals. These findings indicate that thyroid status can influence the activity of ALAS, the rate-limiting enzyme in the synthesis of heme in rat liver, as well as heme degradation and the content of cytochrome P450 in this organ.

Protein Degradation in Skeletal Muscle during Experimental Hyperthyroidism in Rats and the Effect of β-Blocking Agents*

beta-Blocking agents are increasingly used in the management of hyperthyroid patients. The effect of this treatment on increased muscle protein breakdown in the hyperthyroid state is not known. In the present study, experimental hyperthyroidism was induced in rats by daily ip injections of T3 (100 micrograms/100 g BW) during a 10-day period. Control animals received corresponding volumes of solvent. In groups of rats the selective beta-1-blocking agent metoprolol or the nonselective beta-blocker propranolol was infused by miniosmotic pumps implanted sc on the backs of the animals. Protein degradation was measured in incubated intact soleus and extensor digitorum longus muscles by determining tyrosine release into the incubation medium. The protein degradation rate in incubated extensor digitorum longus and soleus muscles was increased by 50-60% during T3 treatment. Metoprolol or propranolol did not influence muscle protein breakdown in either T3-treated or control animals. The results suggest that T3-induced increased muscle proteolysis is not mediated by beta-receptors, and muscle weakness and wasting in hyperthyroidism might not be affected by beta-blockers.

Transplacental stimulation of fetal lung maturation: effect of triiodothyronine in the female and male rabbit fetus.

We have recently demonstrated that intramuscular administration of triiodothyronine (T3) or thyroxine (T4) to the rabbit doe results in its transfer across the placenta. In this study we investigated the effect of maternally administered T3 upon the functional and morphologic fetal lung maturation. T3 (175 micrograms/kg) or the vehicle was injected intramuscularly into the New Zealand White rabbit does on days 25 and 26 of gestation. On day 27 of pregnancy, the does were killed and the fetuses were delivered. Maternal and fetal plasma T3, glucose and insulin and fetal plasma corticosteroid concentrations were determined. The functional pulmonary maturity was assessed by performing the pressure-volume hysteresis while morphologic maturity was established by histologic techniques. Enhanced functional as well as morphologic fetal lung maturation was observed in female as well as male fetuses in T3-treated animals. However, there was a significant increase in the fetal mortality after T3 treatment, and the duration of survival in the extrauterine environment on premature delivery was not prolonged.

Thyroxine increases submandibular gland nerve growth factor and epidermal growth factor concentrations precociously in neonatal mice: evidence for thyroid hormone-mediated growth factor synthesis.

Thyroxine (T4) administration to adult female mice significantly increases submandibular gland (SMG) nerve growth factor (NGF) and epidermal growth factor (EGF) concentrations and does so in a time- and dose-dependent manner. Postnatal maturation of the SMG can be markedly accelerated by T4 treatment. We, therefore, performed a series of experiments to examine the effect of T4 on SMG NGF and EGF content and concentration as a function of postnatal age in neonatal mice. In experiment 1, male and female neonatal Swiss-Webster mice received daily subcutaneous injections of T4 (0.4 micrograms/g body weight) for 6, 13, or 20 days and were sacrificed 24 h after the last injection. Vehicle injected mice served as controls. SMG NGF and EGF content and concentration were measured by specific double antibody radioimmunoassay systems. Pools were made using either female or male SMGs. Since no significant differences were noted for NGF or EGF content using sex of the animal as the determining variable, the values were combined. At 7 days of age, mean SMG NGF and EGF content and concentration of control mice significantly exceeded those of T4-treated animals (p less than 0.05). At 14 days of age, mean SMG NGF and EGF content in T4-treated mice significantly exceeded those in control mice by 39- and 22-fold, respectively (p less than 0.001). At 21 days of age, these increases were 4100- and 2400-fold, respectively. In order to determine more precisely the time of onset of responsivity of the SMG to thyroid hormones, a second series of experiments was performed.(ABSTRACT TRUNCATED AT 250 WORDS)