Administration Of L-triiodothyronine Research Articles

Involvement of L-triiodothyronine in acetylcholine metabolism in adult rat cerebrocortical synaptosomes.

Despite the recently emerging notion of thyroid-hormone involvement in neurotransmission in the adult mammalian brain, adequate evidence for a cellular basis of the process is still lacking. The present study indicates the involvement of thyroid hormones in cholinergic system of the adult rat cerebral cortex. Administration of L-triiodothyronine (T3, 0.025 to 4 microg/g) in single doses increased the synaptosomal acetylcholinesterase (AchE) and Mg2+-ATPase activity maximally at 24 hours in a dose-dependent way. Propylthiouracil (PTU)-treated hypothyroid rats showed a significant increase in AchE and Mg2+-ATPase activity compared to euthyroid rats. T3-treatment on hypothyroid rats decreased AchE activity in synaptosomes compared to the hypothyroid synaptosomal values. Mg2+-ATPase activity found in (PTU + T3)-treated group and T3-treated group remained high. These results predict that T3 stimulates acetylcholine (Ach) metabolism by increasing AchE activity as well as uptake of the released Ach through an increase in synaptosomal Mg2+-ATPase activity. This indicates a positive impact of T3 on the cholinergic system in the adult mammalian brain.

Acute L-triiodothyronine administration potentiates inotropic responses to beta-adrenergic stimulation in the isolated perfused rat heart.

Acute inotropic effects of triiodothyronine (T3) have been reported, employing both in vivo experimental animal models and in vitro isolated heart perfusions. However, the mechanisms responsible for these acute inotropic effects remain unclear. The aim of this study, therefore, was to delineate the role of the beta-adrenergic receptor system in these acute responses. The hearts from both euthyroid and hypothyroid (treated with 0.05% PTU in drinking water) male Sprague-Dawley rats were used in 5 experimental study protocols. Hearts from euthyroid rats were perfused with buffer containing either T3(10(-7) M) or control while continuously recording left ventricular function for 10 min ('acute effects'). Two-hour perfusions ('subacute effects') and cardiac responses following increasing doses of isoproterenol (10(-10) to 10(-6) M) in the presence or absence of T3-containing buffer (acute interaction) were also determined. In hypothyroid rats, the subacute responses and the acute interactions were investigated. In the presence of T3, an acute, significant potentiation of the inotropic responses following beta-adrenergic stimulation with isoproterenol was observed in both rat cohorts, which was more pronounced in hearts from euthyroid rats. An acute (< 40 s), but transient (79 +/- 8 s), direct inotropic response was observed in hearts from euthyroid rats. No cardiac responses were seen during a 2-h perfusion in hearts from either euthyroid or hypothyroid rats. The acute inotropic effects of T3 in non-ischemic myocardium probably result from an acute interaction between T3 and catecholamines rather than through a direct inotropic effect of T3 alone.

Triiodothyronine does not affect the average incorporation of l-[ 35S]methionine in rat brain structures

The autoradiographic method with l-[ 35S]methionine was used to examine the effect of acute administration of l-triiodothyronine on local rates of brain protein synthesis in free-moving adult rats. Triiodothyronine was given intraperitoneally at doses of 12.5 or 25 μg kg −1. It did not modify the rate of plasma methionine incorporation in the 40 brain regions examined, despite a 4- to 8-fold increase of plasma free triiodothyronine levels. Biochemical analysis confirmed that triiodothyronine (25 μg kg −1) had no apparent effect on the overall rate of protein synthesis in the brain as a whole. These results suggest that changes in the circulating levels of thyroid hormones do not exert a general and direct metabolic effect in brain of intact adult rats.

Fibronectin expression in the normal and hypertrophic rat heart.

We examined changes in the expression of fibronectin during the induction of cardiac hypertrophy by L-triiodothyronine administration and by mineralocorticoid- and salt-induced experimental hypertension. By use of Northern and Western blotting procedures, fibronectin was localized mainly in the atria of normal rat hearts. Atria contained 10- and 5-fold higher relative concentrations of fibronectin mRNA and protein, respectively, compared with ventricles. During the progression of cardiac hypertrophy induced by L-triiodothyronine over a 10-d period, there was a progressive increase in fibronectin mRNA for the first 6 d followed by a return to control levels. The major change could be accounted for by changes in ventricular mRNA, which increased about four- to sixfold. In contrast, protein levels in ventricles increased progressively over the 10-d treatment period. Ribonuclease protection analysis indicated that the relative amounts of fibronectin isoforms containing exons designated EIIIA and EIIIB increased during the progression of hypertrophy. When cardiac hypertrophy was induced by mineralocorticoid and salt treatment, increases in ventricular fibronectin mRNA and protein and the induction of alternatively spliced forms of fibronectin were also observed. However, the extent and temporal pattern of fibronectin expression differed between the two experimental models.

Thyroid hormone increases glyceraldehyde 3-phosphate dehydrogenase gene expression in rat liver

Livers from hypophysectomized rats had low levels of glyceraldehyde 3-phosphate dehydrogenase mRNA. Administration of L-triiodothyronine increased these levels over 20-fold. The peak response was seen 72 h after hormone administration. A half-maximal response was obtained with 5 μg of T3 per 100 g of body weight. Thus the expression of hepatic glyceraldehyde 3-phosphate dehydrogenase appears to be regulated by thyroid hormone.

Acute withdrawal of short-term or prolonged L-triiodothyronine administration to thyroidectomized rats results in similar rapid increases in TSHβ mRNA

In man, following the treatment of hyperthyroidism, or the withdrawal of prolonged suppressive thyroid hormone therapy, recovery from thyrotrope suppression may not occur until thyroid hormone concentrations have been subnormal for several weeks. Short-term studies in rodents have demonstrated a rapid increase in TSH synthesis after the acute withdrawal of thyroid hormones. We treated thyroidectomized rats with supraphysiologic doses of 1-triiodothyronine (T3) for 67 days, then abruptly withdrew treatment and compared the time course of thyrotrope recovery to that in animals given T3 for only 10 days. Increases in TSH beta mRNA after abruptly stopping T3 were qualitatively similar in both groups. After short-term T3 administration, TSH beta mRNA was detectable on the second day after stopping T3 administration and rose an additional 10-fold by day 5. After prolonged T3 administration, TSH beta mRNA was barely detectable on the second day after stopping T3 administration, clearly detectable on the third day, and increased an additional 20-fold by day 7. Compared to animals who received T3 for only 10 days, suppression of the thyrotrope by T3 administration for 67 days resulted in a nonsignificant delay in TSH beta mRNA synthesis of 24 h or less following the abrupt withdrawal of thyroid hormone. It is possible that differences in rat and human thyrotrope responsiveness account for the apparently different biologic behavior.

The response to isoproterenol-stimulated adenylate cyclase activity after administration of L-triiodothyronine is reduced in aged rats.

La modulation liee a l'âge, par l'hormone thyroidienne, de l'activite adenylate cyclase stimulee par isoproterenol a ete etudiee sur des cœurs de rat. Les resultats montrent que cette activite chez des rats âges hyperthyroides, est reduite par rapport aux animaux jeunes hyperthyroides

Thyroid hormone suppression of hepatic levels of phenobarbital-inducible P-450b AND P-450e and other neonatal P-450S in hypophysectomized rats

Mechanism of developmental suppression of cytochrome P-450 (P-450) in rat livers was studied using Western blots. The contents of phenobarbital (PB)-inducible P-450b and P-450e, expressed constitutively in livers, were higher in neonate than in adult rats. The contents were also 10∼50 fold higher in hypophysectomized than in intact adult male rats. Administration of L-triiodothyronine (T 3, 50 μg/kg) or human growth hormone (4U/kg) reversed almost completely the increased amounts of P-450b and P-450e. T 3-induced suppression was also observed on two other neonatal P-450s (P-450 6β-1 and P-448-H), which are expressed in neonatal periods in livers. The postnatal developmental profiles of hepatic P-450b were correlated inversely with that of serum free T 3 level in rats reported ( Walker et al. (1980) Pediat. Res. 14, 249 ). These results suggest, in addition to pituitary growth hormone ( Yamazoe et al. (1987) J. Biol. Chem. 262, 7423 ), the possible involvement of T 3 on the suppressive regulation of PB-inducible and other neonatal P-450s.

Comparison of the toxicity of orally administered l-triiodothyronine (T 3) in rat and cynomolgus monkey

Oral administration of l-triiodothyronine (L-T 3) (0.015–1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1–2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015–0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T 3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T 3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T 3 (7 × 10 −9 to 7 × 10 −7 M) had minimal effects on parameters meters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [ 3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T 3 appeared more toxic to males than females but this was not supported histologically. The histological lesions showed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.

The effects of acute and repeated administration of T 3 to mice on 5-HT 1 and 5-HT 2 function in the brain and its influence on the actions of repeated electroconvulsive shock

The effects of the administration of L-triiodothyronine (T 3) On the function of 5-HT in the CNS and its influence on the actions of electroconvulsive shock have been examined in mice. A single injection of T 3 (100 μg/kg) had no effect 24 hr later on either 5-HT 1A-mediated hypothermia, induced by 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT; 0.5 mg/kg) or the 5-HT 1B-mediated locomotor response to 5-methoxy-3-(l,2,3,6-tetrahydropyridin-4-yl) 1-H-indole (RU 24969; 50 ng i.c.v.). This treatment increased 5-HT 2-induced head-twitches, produced by 5-methoxy- N, N'-dimethyltryptamine (5-MeODMT; 2 mg/kg), but did not alter 5-HT 2 receptors in the frontal cortex, suggesting that this potentiation was mediated indirectly through a modulatory neurotransmitter. One injection of T 3 had no effect on the concentrations of 5-HT in the forebrain or mid/hindbrain, but increased 5-HIAA in the latter region. Daily injections of T 3 for 10 days attenuated the responses to both 8-OH-DPAT and RU 24969. Furthermore, 5-MeODMT-induced head-twitches returned to control values and this was accompanied by a 10% decrease in 5-HT 2 receptors in the cortex. Repeated administration of T 3 increased levels of 5-HT in mid/hindbrain and concentrations of 5-HIAA both here and in forebrain. Hence, treatment with T 3 attenuated the function of 5-HT 1A and 5-HT 1B receptors, but increased 5-HT 2-mediated responses, although the time-courses for these effects were different. Triiodothyronine also enhanced the synthesis and turnover of 5-HT in the brain of the mouse. Repeated electroconvulsive shock (90 V, 1 sec) decreased the hypothermia induced by 8-OH-DPAT. However, 5-MeODMT-induced head-twitches were enhanced by acute and repeated electroconvulsive shock. Administration of T 3 together with electroconvulsive shock did not alter the effects of electroconvulsive shock on 5-HT 1A-mediated hypothermia, but markedly potentiated its actions on 5-HT 2-mediated responses. These findings provide possible pharmacological evidence for the suggested antidepressant effects of T 3 and the potentiation of antidepressant therapy by this thyroid hormone.

Regulation of hepatic lipogenesis in starved and diabetic animals by thyroid hormone.

The effects of intragastric feeding with glucose and of the administration of L-triiodothyronine (T3) on in vivo rates of hepatic lipogenesis were investigated in control (fed ad libitum on normal diet), diabetic (fed ad libitum on normal diet), fat-fed (fed ad libitum on high-fat diet), and starved (food removed for 48 h) rats. Two days of T3 treatment increased hepatic lipogenesis in control and fat-fed animals but not in the diabetic or starved animals, although increases in lipogenesis in diabetic animals were observed after 4 days of T3 treatment. Intragastric glucose feeding increased hepatic lipogenesis in the livers of control animals and T3-treated control animals. Such increases are mediated by an increase in the circulating insulin concentration, as increases are not observed in diabetic rats or T3-treated diabetic rats. Glucose feeding failed to increase hepatic lipogenesis in fat-fed rats or starved rats. Insulin injection together with glucose feeding increased lipogenesis in the fat-fed group but not the starved group; i.e., impaired insulin secretion following an oral glucose load may in part explain the lack of response in the fat-fed but not the starved animals. Marked increases in hepatic lipogenesis after glucose feeding were, however, observed if either the starved or the fat-fed animals were treated with T3. The physiological implications of these observations are discussed.

Familial thyroid hormone resistance

Eight patients with thyroid hormone resistance were found in four generations of a kindred containing 19 members. Results of studies in this family are consistent with an autosomal dominant mode of inheritance for this disorder. The affected family members were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels: thyroxine (T4) = 21.1 ± 2.1 μg/dl; triiodothyronine (T3) = 323 ± 60 ng/dl; free T4 = 5.4 ± 0.9 ng/dl; and free T3 = 1,134 ± 356 pg/dl (mean ± SD). Serum thyrotropin (TSH) levels were normal or slightly elevated in six patients and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. Two patients who had previously undergone subtotal thyroidectomy had elevated baseline serum TSH levels and exaggerated TSH responses to the administration of TRH suggesting subclinical hypothyroidism despite elevated total and free thyroid hormone levels. The absence of thyrotoxicosis and normal serum TSH levels despite elevated serum free T3 and T4 levels in the untreated members of this family are consistent with resistance of pituitary and peripheral tissues to the actions of thyroid hormones. In addition, the absence of hypothyroidism and normal responsiveness of serum TSH to TRH and L-triiodothyronine administration in untreated family members suggest that the thyroid has compensated for the hormone resistance by increased secretory activity under the control of pituitary TSH secretion.

Regulation of hepatic fatty acid-synthesizing enzymes of diabetic animals by thyroid hormone

Subcutaneous administration of l-triiodothyronine (T 3) to diabetic rats restored hepatic acetyl-CoA carboxylase and fatty acid synthetase enzymes to normal levels. T 3 stimulated the fatty acid-synthesizing enzymes of diabetic animals by two different mechanisms. Between 4 and 12 h after T 3 administration, carboxylase and synthetase increased slowly, after which both the enzyme activities increased at faster rate. Carboxylase and synthetase induction could be inhibited by cycloheximide or actinomycin D during the first 12 h. The incorporation of [ 14C]pantothenate into the fatty acid synthetase during 4–12 h followed the same pattern as the development of the enzyme activity. Moreover, liver supernatants from T 3-treated diabetic rats were able to compete with pure fatty acid synthetase for antibody binding sites, the degree of competition increased with increasing period of T 3 treatment. The results suggest that enzymatically inactive precursors of synthetase in the diabetic livers are converted to enzymatically active enzyme as a result of T 3 treatment. The second part of T 3-mediated stimulation (24 to 72 h following T 3 treatment) was inhibited by cycloheximide and actinomycin D. Antibody-antigen titration and measurement of rate of protein synthesis suggest that the increased activity of hepatic synthetase is due to enhanced synthesis of the enzyme for that period. These results indicate that T 3 might play a significant regulatory role in hepatic fatty acid synthesis.

Effect of 3,5,3'L-triiodothyronine administration on serum thyroid hormone levels in hypothyroid patients maintained on constant doses of thyroxine.

In order to investigate the effect of 3,5,3'L-triiodothyronine (T3) administration on thyroid hormone concentrations in serum, thyroxine (T4), T3, 3,3',5'L-triiodothyronine (reverse T3, rT3) and thyroid stimulating hormone (TSH) concentrations in serum were determined before and after T3 administration in 10 hypothyroid patients maintained on constant doses of T4. Ten hypothyroid patients given 100 micrograms of T4 for approximately 3 months had almost normal T4 and T3 concentrations in serum. Seven patients showed almost normal rT3 concentrations in serum and they were slightly diminished in the remaining 3 patients. TSH levels in serum were almost within the normal limit in 7 out of 10 patients. However, despite the elevation of T4 and T3 levels, 3 patients had markedly elevated TSH levels. Values for serum T4 concentrations were decreased 4 weeks after the administration of 50 micrograms T3 in all patients maintained on constant doses of T4, although they were almost within the normal range. T3 concentrations in serum, which was obtained just before the administration of the next daily doses of T3, were markedly elevated in 6 of 10 patients after T3 administration and the remaining 4 patients had also slightly higher T3 concentrations than those before T3 administration. On the other hand, serum rT3 concentrations were diminished in 5 patients during T3 ingestion. They were somewhat diminished or almost unchanged before and after T3 administration in the remai T3 administration and the remaining 4 patients had also slightly higher T3 concentrations than those before T3 administration. On the other hand, serum rT3 concentrations were diminished in 5 patients during T3 ingestion. They were somewhat diminished or almost unchanged before and after T3 administration in the remaining 5 patients. Moreover, 3 patients with elevated TSH levels during T4 administration showed almost normal TSH levels after T4 and T3 ingestion. The results showed the reciprocal relationship between T3 and rT3 levels in serum after T3 administration in hypothyroid patients maintained on constant doses of T4. Furthermore, the present findings suggest that the administration of both T4 and T3 might be a more suitable replacement therapy in the patients with hypothyroidism than T4 alone.

The effect of thyroid hormone on serotonergic neurones: depletion of serotonin in discrete brain areas of developing hypothyroid rats.

A single intraperitoneal injection of 131I in a dose of 200muCi in 1-day-old rats induced hypothyroidism and decreased the activity of tryptophan hydroxylase in mid-brain region. The levels of 5-hydroxytryptamine also were reduced in cerebellum, mid-brain and striatum by 22%, 29% and 31%, respectively. By contrast, the levels of its metabolite, 5-hydroxyindoleacetic acid, were significantly increased in cerebellum, mid-brain and striatal region. To ascertain whether changes induced by neonatal radiothyroidectomy were specific, the effect of replacement thyroid hormone therapy was studied on 5-hydroxytryptamine metabolism. Daily administration of L-triiodothyronine (10 microgram/100g s.c.) for 25 days beginning from five days after radio-iodine treatment enhanced tryptophan hydroxylase activity, tryptophan and 5-hydroxytryptamine levels to values seen in normal rats of the corresponding age group. The concentration of 5-hydroxyindoleacetic acid decreased following L-triiodothyronine treatment. Furthermore, when replacement therapy with L-triiodothyronine was postponed until adulthood, no significant effects could be seen on various parameters related to 5-hydroxytryptamine metabolism. Our data demonstrate that deficiency of thyroid hormone in early life disrupts the normal upsurge of 5-hydroxytryptamine metabolism in brain. A critical period exists in early life of rats during which thyroid hormone must be present for the optimal development of 5-hydroxytryptamine metabolizing systems in maturing brain.

Lithium suppresses elevated behavioural activity and brain catecholamines in developing hyperthyroid rats.

Neonatal hyperthyroidism in rats induced by daily administration of L-triiodothyronine for 30 days since birth resulted in a significant rise in mobility and the metabolism of brain norepinephrine and dopamine. Whereas administration of lithium carbonate (60 mg/kg ip) to normal rats for 6 days produced no effect on spontaneous locomotor activity and increased the synthesis and possibly release of this monoamine in several brain regions, this antimanic drug antagonized the L-triiodothyronine-stimulated increases in mobility as well as norepinephrine and dopamine metabolism of hypothalamus, midbrain, striatum, and cerebral cortex. Furthermore, lithium treatment restored the activity of catechol-O-methyl transferase (EC 2.1.1.6) in young hyperthyroid rats to virtually normal limits. Our data suggest that antiphasic or damping effects of lithium upon mood swings is controlled, at least in part, by catecholaminergic systems in the brain. The interrelationship between brain catecholamines and thyroid hormones seems to be important to our understanding of the action of lithium in affective illness.

Thyrotropin releasing hormone: Antagonism of pentobarbital in rodents

Thyrotropin releasing hormone (TRH) antagonizes the behavioral and temperature reducing effects of pentobarbital in rodents. The hormone is effective whether given before or after the barbiturate. This antagonism by TRH of the effects of pentobarbital probably does not depend upon thyroid hormone release as L-triiodothyronine administration is ineffective.

Studies on the Effect of Thyroid Hormones on Cytochrome-Linked L-α-Glycerophosphate Dehydrogenase of the Mouse

Glycerophosphate, succinate and choline dehydrogenase activities in the mitochondrial preparations from liver, kidney, heart, brain, lung and spleen as well as oxygen consumption by the liver homogenate of the mouse in various thyroid hormone states have been determined. Oxygen consumption by liver homogenate in the absence of any additional substrate or in the presence of glycerophosphate or fructose 1,6-diphosphate is significantly enhanced in 6 hr by the administration of L-triiodothyronine (0.01 μmole/20 g of body weight) and gradually decreased after 131I-treatment. Glycerophosphate dehydrogenase activity in liver and kidney mitochondria is increased 3-fold in 24 hr after a single dose of L-triiodothyronine and decreased after the administration of 131I. The hormone produces a small but significant increase of the activity of heart mitochondria. No changes in the activity are shown in brain, lung and spleen. Succinate dehydrogenase activity of all organs that we examined is not altered significantly ...

Magnesium metabolism in hyperthyroidism and hypothyroidism.

In 1939, Hueber (1) reported clinical improvement in patients with thyrotoxicosis after parenteral administration of magnesium. Wiswell (2) subsequently was unable to demonstrate any change in the peripheral metabolism of thyroid hormone in hyperthyroid patients given magnesium sulfate injections, whereas Neguib (3) reported a decrease in size of both toxic and nontoxic goiters and clinical improvement in three thyrotoxic patients given daily injections of magnesium chloride. Tapley (4) demonstrated that the administration of L-triiodothyronine promptly produced negative magnesium balance in two myxedematous patients and called attention to the similarity between the symptoms of thyrotoxicosis and magnesium deficiency, as well as between myxedema and magnesium excess. That the serum magnesium is elevated in hypothyroidism and decreased in hyperthyroidism has long been known (5-7) but has recently been re-emphasized and as

Failure of L-Triiodothyronine to Alter Significantly Glucose Utilization by Human Erythrocytes.

It was demonstrated that parenteral administration of L-Triiodothyronine (L-T3) initially increased and then decreased utilization of glucose by the RBC of rabbits(1). Because of this fact, we became interested in studying the effects of clinically large doses of this compound on utilization of glucose by the human erythrocytes. Certainly, if a peripheral cellular effect could be demonstrated, then there would be a possibility of establishing a clinically useful tool for reflecting total body metabolism and perhaps evaluating thyroid function. The present investigation was therefore designed to study in humans: 1) normal fluctuations in rate of glucose utilization by RBC, and 2) effect of L-T3 on this rate.Methods and material. Fasting venous blood was obtained from healthy volunteer men and women to insure satisfactory range in age and sex distribution. These individuals were clinically free of any disease and not taking medication. The laboratory procedure followed has been described(1). Blood samples w...