Administration Of Triiodothyronine Research Articles

Effect of triiodothyronine on bronchial asthma. II.

Triiodothyronine (T3) administration to patients suffering from chronic bronchial asthma or patients suffering from nasopharyngeal allergy was reported to ameliorate the attacks. Twelve patients aged less than 35 years suffering from chronic bronchial asthma for more than 5 years, who were maintained on usual anti-asthmatic drugs with the exception of steroids and chromoglycate and who were not the subject of repeated attacks of bronchitis were chosen for the study. Each patient was given T3 orally as 40 micron/day divided into two doses, for a period of 60 days. The drug increased the peak flow in all cases. The increase averaged 24.6% +/- 8.48 (P less than 0.001). Three cases reported marked improvement and four were able to reduce the dose of anti-asthmatic drugs. There was no significant change in the pulse rate, ECG, body weight, blood pressure, or appetite. One patient complained of insomnia and another of increased anxiety. It is possible that T3 exerts its beneficial effect through correcting the level of C-AMP, which is known to be low in asthmatics, through improvement of body mechanism for antibody formation, or through other unidentified mechanisms.

Effect of thyroid hormones on microsomal fatty acid chain elongation synthesis in rat liver.

Evidence is presented that rat liver microsomal fatty acid chain elongation synthesis and desaturation, as well as acetyl-CoA carboxylase and fatty acid synthetase, are strongly influenced by thyroid hormone level. Conversely, the fatty acid chain elongation system in mitochondria, unlike the oxidative capacity of palmitate, NADH, succinate and malate, does not seem significantly affected by the thyrotoxic state. In triiodothyronine-induced or thyroxine-induced hyperthyroidism, rat liver acetyl-CoA carboxylase, fatty acid synthetase and microsomal chain elongation and desaturation reactions are not greatly affected after the first 10 days of treatment, while after longer intervals a respective increase in these activities is shown of up to 87, 116 and 65% after 22 days. In propylthiouracil-induced hypothyroidism, all the above synthetic activities are strongly reduced immediately after three days of drug administration and diminished no further following longer periods. Although the pattern of synthesized fatty acids in the thyrotoxic state is similar to that obtained from normal subcellular rat fractions, the esterification process of fatty acids in microsomal lipids appears to be slightly inhibited in hypothyroid rats and increased following triiodothyronine or thyroxine administration. Finally, a reduction in the hepatic cyclic AMP level of about 41% is reported after 19 days of triiodothyronine-administration to rats. On the basis of the observed insensitivity of the mitochondrial fatty acid chain elongation system to the thyrotoxic state, a tentative interpretation of its role in the hepatic cell is postulated.

The influence of thyroidectomy and of triiodothyronine administration on epithelial cell proliferation in the jejunum of rat.

Mitotic rates in epithelial cells lining the bases of the crypts of Lieberkühn in rat jejunum were measured using a stathmokinetic technique. Two weeks after surgical thyroidectomy the mitotic rate in the jejunal crypt cells was significantly lower than that in control animals. During the four hour period immediately after injection of triiodothyronine into thyroidectomized rats the crypt cell mitotic rate was significantly higher than in control animals.

Increased in vitro phosphorylation of rat liver nucleolar proteins following triiodothyronine administration.

It has been shown that triiodothyronine (Ta) administration to thyroidectomized rats induces an increase in the in vitro net 32P uptake into liver nucleolar proteins. Such an increase depends on a stimulation of the nucleolus-associated protein kinase activity and not on a lower dephosphorylation rate.

Modification of nucleic acid levels per mitochondrion induced by thyroidectomy or triiodothyronine administration.

The authors have determined the liver mitochondrial population (number of mitochondria/nucleus) in young rats, which has been thyroidectomized (T) or thyroidectomized and subsequently treated with triiodothyronine (T3). They have observed that thyroidectomy decreased such a population to 72.3% with respect to the normal one, while the T3 administration (at the dose of 10 mug/100 g body weight every second day, from day 50 to day 60 of age) restored the mitochondria number to 81.8% of normal ones. The average levels of proteins per mitochondrion were 8.90 X 10(-13) g in the liver of normal 60-day-old rats. This content was doubled in T rats of the same age while the levels of nucleic acids or the nucleic acid polymerase activities per mitochondrion were enhanced, notwithstanding that the specific values (referred to mg mitochondrial protein) decreased. The T3 administration severely lowered the content of protein per mitochondrion, and this may indicate that thyroid hormones control the normal assemblage of mitochondrial protein.

On the Mechanism of Inhibition by Iodine of the Thyroid Adenylate Cyclase Response to Thyrotropic Hormone

Rats maintained on a low-iodine diet were hypophysectomized, and their diet was than enriched with iodide. Cyclic AMP (cAMP) concentrations achieved in their thyroids following in vitro TSH stimulation were significantly lower than those in the thyroids of control animals that did not receive dietary iodide enrichment. The addition of 0.1% methimazole (MMI) or 1% KC1O4 to the diet abolished this inhibitory effect of iodide. The administration of triiodothyronine in the died did not reproduce the inhibitory effect of iodide. The effect of iodide in vitro on the thyroid cAMP response to TSH was then investigated using paired thyroid lobes obtained from intact rats fed a low-iodine diet. During a 15-min incubation period, concentrations of iodide up to 10(-3)M, together with TSH (125 mU/ml), did not affect the thyroid cAMP response to TSH. In contrast, the preincubation of the lobes in 5 X 10(-5)M Nal for 2 h preceding a final 15-min incubation in medium containing TSH alone resulted in final cAMP concentrations significantly lower than those in paired lobes not exposed to iodide. Basal cAMP concentrations in thyroids not subjected to TSH stimulation were unaffected by preincubation in iodide. The inclusion of TSH during the preincubation period augmented the inhibitory effect of iodide on the final thyroid cAMP concentration achieved. The inclusion of MMI together with iodide during the preincubation period abolished the inhibitory effect of iodide on the final cAMP concentration achieved by TSH stimulation. Direct measurement of newly formed organic iodine in vitro demonstrated it to be inversely proportional to the final cAMP concentration achieved by TSH stimulation. The preincubation of thyroid lobes in iodide was without effect on the subsequent stimulation of cAMP by PGE1, or on the stimulation by F- of adenylate cyclase activity in the thyroid homogenate. The data support the concept of an as yet unknown organic form of iodine that limits thyroid adenylate cyclase responsiveness to TSH stimulation. This may, in part, explain the diverse, and generally inhibitory, actions of iodide on thyroid function.

Variable stabilities and recoveries of rat-liver RNA polymerases A and B according to growth status of the tissue.

1. The effect of growth status on the relative levels and recoveries of DNA-dependent RNA polymerase in rat liver nuclei was determined by two independent procedures: (a) measurement of RNA polymerase A and B activities in fraction IV [Roeder, R. G. and Rutter, W. J. (1970) Proc. Natl Acad. Sci. U.S.A. 65, 675--682] in the presence and absence of low concentrations of alpha-amanitin; (b) DEAE-Sephadex chromatography of fraction IV to resolve RNA polymerases A and B (and possibly other forms of the enzyme). 2. Growth was arrested in young rats (less than 100 g body weight) by hypophysectomy and stimulated by the administration of growth hormone or triiodothyronine. Under these conditions the rate of RNA synthesis in vivo or in isolated nuclei is known to be markedly depressed or stimulated relatively soon after hypophysectomy or hormone administration, respectively. RNA polymerases were obtained from animals under different growth conditions. There were no differences in the activities of nuclear RNA ploymerases per se, when these were separated from their endogenous template and assayed with heterologous denatured DNA. These reports contrast with earlier reports [Smuckler, E. A. and Tata, J. R. (1971) Nat. New Biol. 234, 37--39; Sajdel, E. M. and Jacob, S. T. (1971) Biochem. Biophys. Res. Commun. 45, 707--715]. 3. The discrepancy was resolved when a 'balance sheet' of enzyme recovery was established. Cessation of growth by hypophysectomy led to a marked reduction in the recovery of both forms A and B of the enzyme (less than 20% of the input RNA polymerase activity in fraction iv) following chromatography on DEAE-Sephadex. This effect was reversed within a short time after the administration of growth hormone (3--9 h) or triiodothyronine (18--24 h), leading to a doubling of the enzyme recoveries. These alterations which were more marked for RNA polymerase A, resulted in different elution profiles for RNA polymerases A and B upon chromatography. 4. It is concluded that the use of DEAE-Sephadex chromatography to compare the levels of RNA polymerases A and B isolated from tissues of different growth rate can give rise to over-estimates of apparent changes in their relative activities and that the measurement of enzyme activity in fraction IV is a better index of RNA polymerase levels. The relationship between growth rate of cells, the stability of RNA polymerases, and the importance of determining enzyme recoveries upon chromatography, are discussed.

Neonatal hyperthyroidism: Alterations in behavioural activity and the metabolism of brain norepinephrine and dopamine

Daily administration of triiodothyronine (10 μg/100 g) to newborn rats for 30 days produced signs of hyperthyroidism which included accelerated development of physical and behavioural characteristics accompanying maturation. The hyperthyroid rats displayed progressive increases in spontaneous locomotor activity between 14–35 days, which remained elevated well above control levels even at 105 days. Exposure of developing rats to triiodothyronine increased the endogenous levels of striatal tyrosine and tyrosine hydroxylase as well as the concentration of dopamine in hypothalamus, pons-medulla, mid-brain, striatum and hippocampus. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid was also increased in hyperthyroid rats. In contrast, the steady-state levels of norepinephrine remained unaltered resulting in a significant increase in dopamine to norepinephrine ratio in several regions of the brain examined. The elevated levels of dopamine metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) may be due to an increased turnover of dopamine. Our data suggest that increased thyroid hormone levels may lead to an enhanced synthesis as well as utilization of brain catecholamines which in turn may underlie the observed increases in spontaneous locomotor activity.

Androsterone sulfate concentrations in plasma in hypo- and hyperthyroidism.

Androsterone sulfate concentrations have been measured in the plasma of 16 hypothyroid women and 14 hyperthyroid women by a gas-liquid chromatographic technique and in 23 hypothyroid and 18 hyperthyroid women by radioimmunoassay. In obth studies androsterone sulfate concentrations were significantly higher in the hyperthyroid groups. In one hypothyroid subject, blood was obtained at 20-minute intervals over 24 hours before and after the administration of triiodothyronine; plasma androsterone sulfate, initially 25 mug per dl, increased three-fold as a consequence of treatment.

Evidence for the role of brain biogenic amines in depressed motor activity seen in chemically thyroidectomized rats.

Abstract— The effects of exposure to an antithyroid drug, methimazole, on brain tyrosine hydroxylase and tryptophan hydroxylase activity, as well as the levels of norepinephrine, dopamine, 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid have been investigated in maturing brain. Daily treatment of neonatal rats with methimazole for 30 days induced chemical thyroidectomy as evidenced by significant impairment of body and brain growth. The activities or brain tyrosine hydroxylase and tryptophan hydroxylase and the levels of norepinephrine, dopamine and 5‐hydroxytryptamine were markedly altered in a dose‐ and time‐dependent manner in methimazole‐treated rats. Conversely, the concentration of brain 5‐hydroxyindoleacetic acid was elevated (46%) by methimazole administration. Treatment with the antithyroid drug failed to exert any significant effect on the endogenous levels of brain tryptophan, as well as on the activity of the deaminating enzyme, monoamine oxidase. Administration of triiodothyronine (25 or 100 μg/100 g) to hypothyroid rats for 30 days did not produce any appreciable effect upon the neurochemical parameters related to either norepinephrine or 5‐hydroxytryptamine mctabolism. However, increasing the dose of triiodothyronine to 250 μg/100 g significantly elevated the levels of norepinephrine and 5‐hydroxytryplamine as well as the activities of the two synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Brain 5‐hydroxyindoleacetic acid levels were restored to normal values in thyroid hormone‐deficient rats treated with this higher dose of triiodothyronine. Evidencc also was obtained to show that chemical thyroidectomy suppressed the spontancous locomotor activity in neonatal rats; the changes being apparent at 15 days of age. Our data support the view that thyroid hormone in neonatal life displays an important regulatory effect on the metabolism of norepinephrine, dopamine and 5‐hydroxytryptamine. Since certain amines have been known to be implicated as the neurochemical substrates for behavioural arousal, it is conceivable that the observed hypoactivity in methimazolc‐treated rats may, at least in part, be related to impaired maturation of norepinephrine and dopamine‐synthesizing systems in brains of cretinous rats.

Studies of binding of testosterone-estradiol binding globulin for estradiol-17beta (author's transl)

A fundamental study of testosterone-estradiol binding globulin (TeBG) activity for estradiol-17beta was investigated by equilibrium dialysis. In addition, the interaction of TeBG activity for estradiol and estradiol metabolism during a menstrual cycle and in hyperthyroidism was attempted to elucidate. Estradiol in plasma and 24 hrs urine was measured by radioimmunoassay. TeBG binding capacity (TBC) was measured by ammonium sulfate method and associate constant (Ka) of TeBG for estradiol was estimated by equilibrium dialysis. 1. In several pooled plasmas, the mean Ka of TeBG for estradoil was 1.25 X 10(8) L/M at 4 degrees C and 0.78 X 10(8) L/M at room temperature. The Ka decreased with increasing temperature and could not be determined with a sufficient accuracy at 37 degrees C. The mean TBC was 4.4 X 10(-8) M/L. 2. TBC and Ka of TeBG for estradiol during the normal menstrual cycle of a woman were fairly unchanged. The unconjugated estradiol value in urine showed the same biphasic pattern with a midcycle peak as that of the unconjugated estradiol value in urine. 3. A normal man was induced hyperthyroidism with a administration of triiodothyronine. The treatment of triiodothyronine caused a remarkable increase of TBC, but no changes of Ka of TeBG for estradiol and unconjugated estradiol values in plasma and urine. From these results it was suggested that the rate of metabolism of estradiol increased in hyperthyroidism.

Effect of hypothalamic deafferentation on the secretion of thyrotropin during thyroid blockade and exposure to cold in the rat.

Complete hypothalamic deafferentation, either limited to the median eminence, arcuate nucleus, and basal parts of ventromedial nuclei, or comprising ventromedial nuclei and dorsomedial hypothalamus as well reduced considerably the rise of immunoassayable serum TSH in adult male rats rendered hypothyroid by administration of methimazole. Complete hypothalamic deafferentation extended rostrally to include also the caudal half of the anterior hypothalamus did not affect the TSH response to thyroid blockade. Administration of triiodothyronine (T3) to the goitrogen-treated rats reduced serum TSH rapidly and with equal speed in controls and in deafferented animals, which indicates a direct effect of T3 on the pituitary. Animals which, in addition to the hypothalamic deafferentation, had electrolytic lesions in the median eminence, responded both to thyroid blockade and to T3, but the responses were greatly reduced. The cold-stimulated increase of serum TSH was reduced, but not abolished, in animals deafferented several weeks beforehand, but it was absent in rats deafferented 4 days prior to cold exposure. These results suggest that most, if not all of the thyrotropin-releasing factor (TRF) necessary for normal TSH secretion in resting conditions or during the hypothyroid state, is produced and released in the median eminence-arcuate nucleus area, the adequate activity of which, in turn, depends on intact connections with the anterior hypothalamus. Other hypothalamic and extra-hypothalamic areas containing large amounts of TRF do not seem to be required under these conditions.

Thyroid-Stimulating Hormone Regulation of Ornithine Decarboxylase Activity in the Thyroid

TSH (1.0 U im) caused a 22-fold increase in thyroidal ornithine decarboxylase activity (ODC) 6 hours after administration in intact rats. Hypophysectomized rats treated with 1 U TSH showed a 5-fold increase in thyroid ODC activity. This stimulation appeared to be specific for TSH since hormones known to induce ODC activity in other target tissues, such as ACTH or LH, showed no significant stimulation. DIBUTYRYL CYCLIC AMP and aminopylline caused a 12-fold increase in ODC activity 5 hours after administration. Prostaglandins have also been implicated in the TSH-induced stimulation of cyclic AMP. Indomethacin (1.0 mg/100 g body wt, ip), an inhibitor of prostaglandin synthesis, was administered 3 hours before TSH with a resulting 30% diminution (P less than .001) in ODC activity compared with the administration of TSH alone. To rule out the possibility that the increase in ODC activity with TSH might be due to increased thyroid hormone secretion, ODC activity was evaluated 6 hours after triiodothyronine administration (60 mug/100 g body wt), and no significant increase in thyroid ODC activity was found. Stimulation of ODC activity was 90% inhibited by the intraperitoneal administration of actinomycin D (80 mug/100 g body wt) or cycloheximide (400 mug/100 g body wt) given simultaneously with TSH. These results indicated that TSH specifically stimulated thyroid ODC activity, which may be important for the growth-promoting action of the hormone on the thyroid gland. This action may be mediated by cAMP and prostaglandins and may require new protein synthesis.

The significance of partial suppressibility of serum thyroxine by triidothyronine administration in euthyroid man.

Recent evidence indicates that triiodothyronine (T3) administration may not completely inhibit normal thyroid secretion. To further corroborate this observation, measurement of serum T4-RIA concentrations was performed on 15 normal controls (10 men, 5 women; ages 20-42) who were placed on 100 mug of T3 daily for a 5-week period. Decrements of 53%, 36%, and 28% from the baseline T4-RIA were noted at weeks 1, 2, and 3 respectively. At 3 weeks a nadir T4-RIA of 2.5 mug/100 ml was reached which did not significantly differ from the 4th (2.9 mug/100 ml) and 5th weeks (2.6 mug/100 ml). Further, seven euthyroid patients who had received replacement thyroid hormone for 1-16 were switched to T3 (75-100 mug/day) for 28 days. At the end of this period, their mean T4-RIA was 2.6 mug/100 ml. Similar T3 treatment studies were performed on 20 primary hypothyroid patients. After 4 weeks of T3 all 20 patients displayed a T4-RIA below the limits of assay detectability (less than 0.625 mug/100 ml) while all euthyroid subjects had values greater than 1.2 mug/100 ml. Suppression of T4-RIA with T3 was also noted in 4 patients with pituitary and 2 patients with hypothalamic hypothyroidism. Three days after cessation of T3 treatment in normal subjects, no significant rise in mean T4-RIA was seen (2.3 mug/100 ml). Subsequently, T4-RIA rose to 4.5 mug/100 ml on day 7 and 6.7 mug/100 ml on day 10 (74% of the presuppression value) in normals. A similar rise to 7.9 mug/100 ml 10 days after withdrawal from T3 was noted in the euthyroid subjects who had received long-term thyroid hormone replacement. In contrast, all primary hypothyroid patients had either a minimal or nondetectable elevation in T4-RIA while demonstrating a marked rise in TSH 10 days after T3 withdrawal. An absent or impaired rise in T4-RIA after T3 withdrawal was also noted in patients with pituitary and hypothalamic hypothyroidism. These observations indicated: 1) There is continued thyroidal T4 secretion in euthyroid subjects receiving 100 mug of T3 daily. 2) The hypothesis is advanced that an intact hypothalamic-pituitary-tyhroid axis may be required for continued T4 secretion while on T3. 3) The duration of prior suppression with thyroid hormone medication does not appear to influence this phenomenon.

Red cell changes in heat-acclimated golden hamsters ( Mesocricetus auratus): Endocrine studies

1. 1. Chronic heat exposure of golden hamsters ( Mesocricetus auratus) augments the osmotic fragility and lowers the ATP content of the red blood cells. These changes may be secondary to the well-documented endocrinological adaptations reported in heat acclimation, namely hypothyroidism and hyperaldosteronism. 2. 2. Administration of triiodothyronine (T 3) to heat-acclimated hamsters did not reverse these changes. 3. 3. Prolonged administration of aldosterone to control hamsters did not induce these changes. 4. 4. Potassium levels in the plasma and red blood cells were unaffected by chronic heat exposure. 5. 5. It is concluded that RBC changes in heat-exposed hamsters are a direct result of the thermal stress.

Effect of thyroid hormones on transport of organic substances in the kidneys

Changes in renal transport of organic substances were studied in rabbits during the first 6–8 days of oral administration of thyroid extract and tri-iodothyronine. Renal tubular secretion was found to be activated by thyroid hormones much sooner than glucose reabsorption and glomerular filtration.

N-methyl oxidation in liver mitochondria of triiodothyronine-treated and thyroidectomized rats

The levels of sarcosine dehydrogenase and acid-nonextractable flavin in the inner matrix of mitochondria of rat liver are decreased in animals treated with triiodothyronine and are elevated in the mitochondria obtained from thyroidectomized animals. Administration of triiodothyronine does not affect the electron-transfer flavoprotein associated with the sarcosine dehydrogenase or the relative amounts of soluble and membrane-bound proteins of the mitochondria. In phosphate-washed mitochondria from either the controls or the triiodothyronine-treated rats, the O 2 uptake equals the total of the [ 14C]formaldehyde and [β- 14C]serine isolated as reaction products of the sarcosine-[ 14C]methyl group. In contrast to its restraint of sarcosine or choline oxidation in preparations capable of oxidative phosphorylation, ADP does not inhibit the oxidation of these substrates in mitochondria of rats given triiodothyronine.

Structural changes in rat liver endoplasmic reticulum following triiodothyronine administration

Summary The structure of the hepatic endoplasmic reticulum membrane following triiodothyronine administration to thyroidectomized rats has been probed employing the technique of spin labelling. Hormone-sensitive changes residing in the membrane proteins were observed. No simultaneous change was evidenced in the lipid region of the membrane. It is concluded that one the events associated with the mechanism of action of triiodothyronine in target organs involves either the de novo synthesis or a conformational change of membrane proteins.

Reversal of age-related changes in microsomal enzyme activities following the administration of triamcinolone, triiodothyronine and phenobarbital

1. 1. Microsomes were isolated from the livers of 3- and 24-month-old Fischer rats, and specific activities were determined for glucose-6-phosphatase, NADPH cytochrome c reductase, NADPH diaphorase, NADH cytochrome c reductase, NADH diaphorase and NADH neotetrazolium reductase. 2. 2. In agreement with other reports the specific activities of glucose-6-phosphatase and NADPH cytochrome c reductase decreased in the old animals, and NADH cytochrome c reductase increased. 3. 3. Chronic administration of low doses of triamcinolone almost doubled the specific activity of glucose-6-phosphatase in old animals, but caused essentially no change in young animals. In contrast, treatment with phenobarbital halved this activity in young animals, but was essentially without effect in old animals. Treatment with triiodothyronine and caused a marked stimulation of this activity in both young and old animals. 4. 4. There was very little change in the specific activity of NADPH cytochrome c reductase or NADPH diaphorase following these treatments. 5. 5. NADH cytochrome c reductase, NADH neotetrazolium reductase and NADH diaphorase activities were greatly decreased in both young and old animals by administration of all three compounds. 6. 6. Age-related differences in the activity of these enzymes were either diminished or reversed following each treatment. Old animals were as responsive to these stimuli as young animals, and the highest and lowest specific activities observed for each enzyme during the course of all experiments were very similar for young and old animals of the same sex. These observations suggest that age-related differences in these enzyme activities are probably caused by a different metabolic or endocrine state in young and old animals or their hepatocytes, and not by a deterioration of the integrity or control of the synthesis of these proteins.

Stimulation of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in hypophysectomized rats by L-triiodothyronine.

Diurnally varying activity of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A reductase (EC 1.1.1.34) was decreased to very low levels in hypophysectomized rats with no discernable diurnal rhythm retained. Administration of triiodothyronine (100 mug/100 g of body weight) produced a supranormal level of reductase activity, about 3-4 times the highest activity found in normal rats. Reductase activity began to rise about 30 hr after hormone administration, maintained a constant high level from 48 to 72 hr, and declined to the control level by 96 hr. The supranormal response was elicited equally well either during the day or at night. When normal animals received triiodothyronine, reductase activity was increased only to a level comparable to the highest level found in normal rats. Administration of hydrocortisone markedly inhibited the triiodothyronine-induced increase in reductase activity. This finding suggests that glucocorticoids might act to suppress and thus account for the smaller increase in reductase activity observed in normal rats given triiodothyronine. When actinomycin D was given before the triiodothyronine-induced rise in reductase activity, the increase was effectively blocked, indicating that the hormonal effect requires new RNA synthesis.