Administration Of Triiodothyronine Research Articles

β-adrenergic and muscarinic cholinergic receptors in rat submaxillary glands. Effects of thyroidectomy

Administration of triiodothyronine to thyroidectomized rats increased the density of β-adrenergic receptors in rat submaxillary gland without significantly changing the density of muscarinic cholinergic receptors. Thus, thyroid hormone appears to regulate β-adrenergic sensitivity in the rat salivary gland.

Sequential Changes in the Nuclear Triiodothyronine Receptors and Mitochondrial α-Glycerophosphate Dehydrogenase Activity after the Administration of Triiodothyronine

The dynamics of the induction of nuclear triiodothyronine (T3)-receptors and mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) were studied in rat liver after a single injection of a large amount of T3. The maximal binding capacity (Cmax) and association constant (Ka) of the nuclear receptors were determined by Scatchard analyses with and without correction for endogenous T3 measured by radioimmunoassay. It was demonstrated that the administration of T3 induced sequential increases in the number of nuclear T3-receptors and alpha-GPD activity in the liver. The nuclear receptors were rapidly increased to 2.5 times the hypothyroid level and thereafter decreased with a half-life of about 2 days. A parallel change in alpha-GPD activity was noted after a lag period. The total amount of extracted nuclear proteins in the liver was increased 3 days after the administration of T3. It seems likely, therefore, that the T3-induced increase in nuclear receptors is responsible, at least in part, for the induction of this enzyme. The possibility is also suggested that the nuclear receptors may be a nonhistone protein selectively synthesized in an early stage of the hormonal stimulation. Following the injection of T3, marked changes in apparent Ka were seen when no correction was made for the amount of endogenous T3 bound to the extracted nuclear proteins. With the correction, however, Ka remained the same despite the changes in the nuclear receptors and enzyme activity. The results obtained provide further evidence for the hormonal modulation of the nuclear receptors which is closely linked with the hormonal effect.

Myocardial colchicine-binding proteins: Possible relation to DNA synthesis initiation

Administration of tri-iodothyronine (T 3 ) to 2-week-old rats resulted in enhanced [ 3 H]thymidine incorporation into myocardial cells (126±1.7 dpm/μg DNA vs 69±1.2 dpm/μg DNA in untreated controls, P 3 injection. This suggested that microtubular proteins may be involved in the initiation of DNA synthesis. This possibility was further evaluated by studying the extent of [ 3 H] colchicine binding to myocardial extracts as an index of tubulin content and polymerization. [ 3 H] colchicine-binding decreased progressively with age (49±1.9 pmol/mg/h at 5 days vs 21±0.7 pmol/mg/h at 180 days) with no change in the decay rate of the reaction. The extent of tubulin polymerization also decreased from 39±1.2% at age 5 days to 19±1.4% at age 180 days. In contrast, T 3 administration to neonatal rats resulted in enhanced [ 3 H]colchicine-binding (36±1.7 pmol/mg vs 27±1.5 pmol/mg in controls, P 3 prior to the peak in thymidine incorporation. These results indicate that microtubular assembly may be involved in the early steps of myocardial DNA synthesis activation.

Effect of triiodothyronine administration on the plasma TSH and prolactin responses to TRH in patients with hypothalamic-pituitary insufficiency.

A study was carried out in 10 patients with multiple pituitary hormone deficiencies to determine the response of thyroid-stimulating hormone (TSH) and prolactin (PRL) to thyrotropin-releasing hormone (TRH) and their suppressibility by treatment with triiodothyronine (T3) given at a dose of 60 microgram/day for 1 week. In 3 patients the basal tsh values were normal and in 7 patients, 2 of whom had not received regular thyroid replacement therapy, they were elevated. The response of TSH to TRH was normal in 6 patients and exaggerated in 4 (of these, 1 patient had not received previous substitution therapy and 2 had received only irregular treatment). The basal and stimulated levels of TSH were markedly suppressed by the treatment with T3. The basal PRL levels were normal in 7 and slightly elevated in 3 patients. The response of PRL to TRH stimulation was exaggerated in 2, normal in 6 and absent in 2 patients. The basal PRL levels were not suppressible by T3 treatment but in 4 patients this treatment reduced the PRL response to TRH stimulation. From these findings the following conclusions are drawn: (1) T3 suppresses TSH at the pituitary level, and (2) the hyperreactivity of TSH to TRH and the low set point of suppressibility are probably due to a lack of TRH in the type of patients studied.

Effect of thyroidectomy on intracellular amount and distribution of exchangeable Ca 2+ in isolated rat liver cells

The effect of thyroidectomy and replacement therapy on intracellular calcium was studied in isolated rat liver cells. The cells were first loaded with 45Ca and the efflux of isotope followed for 4 h. The cells maintained their viability during this period as judged from staining with trypan blue and rate of respiration. Two different time constants could be resolved by the peeling method. The experiments showed that thyroidectomy markedly reduced the pool of calcium with the slowest turnover while the other pool remained unchanged. Administration of triiodothyronine (T 3) to the thyroidectomized animals 48 h before the experiment normalized the rate of respiration but did not restore the slow turnover pool of calcium.

T_3 Euthyroidism in Thyroid Carcinoma

Letters and Corrections1 October 1978T3 Euthyroidism in Thyroid CarcinomaROBERT L. PEAKE, M.D.ROBERT L. PEAKE, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-89-4-578_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In the article "T3Euthyroidism in Follicular Thyroid Carcinoma" by Kabadi and Albin (Ann Intern Med88:359-360, 1978) there is mention in the case history that "the patient was maintained on 75 µg of Cytomel®/day". No dates are given for the administration of triiodothyronine, but it must be clarified that the patient was not receiving this drug when the normal T3levels were obtained later in the course of her disease.... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: The University of Galveston Medical Branch Galveston, TX 77550 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1978Volume 89, Issue 4Page: 578-578KeywordsDrug administrationDrugsThyroid carcinomaTriiodothyronine Issue Published: 1 October 1978 PDF DownloadLoading ...

Alpha-adrenergic receptor in rat heart. Effects of thyroidectomy

The effects of thyroid status on alpha-adrenergic receptors in the rat myocardium were investigated. The potent antagonist [3H]dihydroergokryptine was used to identify alpha-adrenergic receptors in rat heart particulate and sarcolemmal fractions. Administration of triiodothyronine to thyroidectomized rats decreased specific binding to alpha-adrenergic receptors in heart particulate and sarcolemmal fractions by 41% and 45%, respectively. Scatchard analysis revealed that the cardiac sarcolemmal fraction from thyroidectomized rats contained 29.3 fmol/mg of protein, as compared with 17.0 fmol/mg of protein found in the heart preparation of thyroidectomized rats treated with triiodothyronine. The equilibrium dissociation constants for the interaction of receptors with dihydroergokryptine were similar (about 1.5 nM) in the heart sarcolemmal fractions derived from these two groups of rats. The results of this study demonstrate that thyroid hormone can regulate the number of cardiac alpha-adrenergic receptors. In addition, there appears to be a reciprocal relationship between alpha-adrenergic and beta-adrenergic receptors in the rat myocardium.

Effect of acute administration of triiodothyronine in chicken. Liver glycogen depletion and amino acid incorporation to proteins.

Single injections of thyroid hormone (T3) produce liver glycogen depletion in chickens. This effect cannot be suppressed by protein synthesis inhibitors and is previous to the hormone-induced increase in protein synthesis.

Effect of passive immunization with an antiserum to thyrotropin (TSH)-releasing hormone on plasma TSH levels in thyroidectomized rats.

The role of TRH in mediating the rapid rise of plasma TSH which occurs upon interruption of short term negative feedback inhibition by exogenous thyroid hormone in thyroidectomized (TX) rats was investigated by passive immunization with rabbit antiserum to TRH (TRH-AS). Administration of triiodothyronine (T3), 10 μg/kg ip to TX adult male rats with indwelling right atrial catheters, led within 24 h to a suppression of plasma TSH from hypothyroid to near euthryoid levels. Upon discontinuation of T3 after one or two daily injections, plasma TSH remained maximally suppressed for 24 h, but began to rise by 32 h after the last dose of T3 and returned to hypothyroid levels within 36–48 h. Intravenous administration of 1 ml TRH-AS, 24 h after the last dose of Ta, failed to abolish the subsequent TSH rise. TRH antibody titers in rat plasma 12–48 h after passive immunization were equal to or greater than those which had previously been found adequate to inhibit the acute rise of TSH after cold exposure. To explore the possibility that an early effect of TRH-AS had disappeared by 12 h, antiserum was administered to untreated TX and age-matched normal control rats. Plasma TSH was suppressed within 15–30 min in both groups; the duration of this suppression was between 2 and 4 h in TX and between 8 and 24 h in normal rats. The rate of fall of plasma TSH was consistent with a complete cessation of pituitary TSH secretion in normal rats, but suggested only a partial suppression in TX rats. TRH antibody titers were higher in TX than in normal rats at all times during the 24 h period after antiserum administration and, therefore, could not account for the less prolonged and incomplete suppression of plasma TSH. The similar disappearance rates of TRH antibody from plasma of TX and control rats also argue against the hypersecretion of TRH after thyroidectomy. These results suggest that although TRH exerts a role in maintaining basal levels of TSH secretion, the hypersecretion of TSH in TX rats is to a large extent independent of TRH control. (Endocrinology102: 799, 1978)

Selective alterations in hepatic enzyme response after reduction of nuclear triiodothyronine receptor sites by partial hepatectomy and starvation

Partial hepatectomy results in a decrease in the nuclear triiodothyronine binding capacity of rat liver. Although we confirmed reports that starvation causes a reduction in binding capacity, starvation alone did not fully account for the decrease after hepatectomy. Reduction in nuclear binding sites both by hepatectomy and starvation failed to impair the response to triiodothyronine administration as measured by an increase in the enzyme activity of mitochondrial α-glycerophosphate dehydrogenase, but significantly blocked the triiodothyronine response as measured by cytosolic malic enzyme. These findings indicate that triiodothyronine response is influenced by currently undefined metabolic factors and raises the possibility that such factors cause a selective decrease in receptors associated with the gene for malic enzyme.

Increased activity of rat liver nucleolar protein kinase following triiodothyronine administration

Triiodothyronine (T 3) administration to thyroidectomized rats induces a significant increase in the nucleolus-associated protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) activity. The general, properties of the protein kinase solubilized from liver nucleoli have been investigated. Mg 2+ (20 mM) is essential for the reaction and an appropriate concentration of NaCl (100 mM) is required to achieve maximal phosphorylation rates. The optimal pH for casein phosphorylation is 7.6. The kinase phosphorylates casein more efficiently than phosvitin and displays an almost undetectable activity towards histones and protamine. No significant stimulation of the kinase activity by cyclic AMP has been detected. The apparent K m values for casein and ATP are 1.5 mg/ml and 1.5 · 10 −5 M, respectively, and are not affected by the hormone administration.

Glucocorticoid-stimulated utilization of substrates in hepatic mitochondria

Glucocorticoids administered to rats have been found to stimulate the rates of utilization of substrates by subsequently isolated hepatic mitochondria. This stimulation was observed in the carboxylation and decarboxylation of pyruvate and in the oxidation of β-hydroxybutyrate and succinate during state 3 and uncoupled conditions. These effects were produced by cortisol, triamcinolone, and dexamethasone, but not by deoxycorticosterone. Responses to the steroids were similar to those observed after glucagon or triiodothyronine administration. The stimulation of the rate of pyruvate decarboxylation was shown to occur independently of the rate of pyruvate carboxylation. Steroids varied with respect to the time required after in vivo administration for stimulation of metabolism to occur, as well as for achievement of maximally stimulated levels. Significant stimulation was obtained within 60 min after treatment with cortisol-succinate and 90 min after dexamethasone or cortisol. Maximal stimulation was observed after 2 to 4 h of treatment. The dose dependency of the mitochondrial responses was observable in the increase in the rates of pyruvate carboxylation after dexamethasone or cortisol treatment. Of the two steroids tested, dexamethasone was approximately 2000-fold more potent than cortisol in increasing mitochondrial activity. The effects of 30 min of treatment with glucagon or 20 h with triiodothyronine were additive with the stimulation produced by glucocorticoids. Complete additivity was found in the increased rates of pyruvate carboxylation, while oxidation of substrates was approximately 75% additive.

Effects of Triiodothyronine Administration in Patients with Chronic Renal Failure

Clinically euthyroid patients with severe, chronic, non-thyroidal illnesses usually have decreased serum total and absolute free T3 concentrations. Since T3 is the metabolically more active of the two thyroid hormones, it has been suggested that these patients may be hypothyroid and thus may benefit from T3 therapy. To test this hypothesis, five patients with chronic renal failure requiring maintenance haemodialysis were treated with 5 microgram T3 eight hourly, increasing at three weekly intervals to 10 microgram eight hourly, 20 microgram eight hourly and finally 30 microgram eight hourly. The mean +/- SD serum T3 level did not change over the 12 week period (1.42 +/- 0.17 vs. 1.41 +/- 0.26 nmoll-1 whilst the mean serum T4 and TSH levels fell from 87.0 +/- 15.2 to 47.5 +/- 18.8 nmoll-1 and 1.9 +/- 0.9 to 1.3 +/- 1.6 mUl-1 respectively. Only the change in T4 levels was significant (P less than 0.005). A significant decrease in mean serum T4 levels was apparent even after the treatment period with 5 microgram T3 eight hourly (87.0 +/- 15.2 vs. 51.2 +/- 15.7; P less than 0.005). The mean fasting serum triglyceride level fell from 1.16 +/- 0.74 to 0.94 +/- 0.74 mmoll-1 (P less than 0.05) and the mean fasting serum cholesterol level fell from 6.06 +/- 1.13 to 4.69 +/- 1.10 mmoll-1 (P less than 0.05). There were no subjective improvements in any of the patients. From the marked changes in serum T4 levels during the administration of T3, it is concluded that, prior to treatment, the patients were biochemically euthyroid and not hypothyroid and thus did not require T3 therapy.

Muscarinic cholinergic receptors in rat heart. Effects of thyroidectomy.

The effects of thyroid status on muscarinic cholinergic receptors in the rat myocardium were investigated. The potent muscarinic antagonist [3H]quinuclidinyl benzilate was used to identify muscarinic cholinergic receptors in rat heart particulate fractions from control, hypothyroid, and hyperthyroid rats. Thyroidectomy increased specific [3H]quinuclidinyl benzilate binding to heart particulate fractions by about 60% as compared to euthyroid rat cardiac preparations. Administration of triiodothyronine to euthyroid rats decreased specific binding to muscarinic cholinergic receptors by about 20%. Scatchard analysis revealed that the cardiac particulate fraction from thyroidectomized rats contained 134 fmol of [3H]quinuclidinyl benzilate binding sites per mg of protein, as compared with 85 fmol/mg of protein found in the heart preparation of thyroidectomized rats chrinically treated with triiodothyronine. The equilibrium dissociation constant for the interaction of receptors with quinuclidinyl benzilate was the same (1 nM) in the heart particulate fractions derived from these two groups of rats. The results of this study demonstrate that thyroid hormone can regulate the number of cardiac muscarinic cholinergic receptors. Thus, the parasympathetic nervous system may participate in the cardiovascular abnormalities in different thyroid states.

SECONDARY PITUITARY HYPERPLASIA IN ADDISON'S DISEASE

In patients with Addison's disease, whether treated or untreated for the previous 24 hours, hydrocortisone produced only a partial suppression of their elevated adrenocorticotrophic-hormone (A.C.T.H.) levels. This is comparable to untreated myxœdema, in which administration of triiodothyronine fails to inhibit secretion of thyrotrophin (T.S.H.). In myxœdema, however, continued treatment produces normal T.S.H. levels. Inadequate A.C.T.H. suppressibility in patients with Addison's disease while on treatment may be due to the maintenance of a secondary pituitary hyperplasia by inadequate replacement therapy. This may be clinically important, especially in the genesis of Nelson's syndrome.

Failure of triiodothyronine to inhibit TSH-mediated thyroid hormone release in man.

We studied the effect of short-term triiodothyronine administration on thyroid gland responsivity to exogenous thyrotropin in four euthyroid human subjects. Thyroidal iodine release and serum thyroxine during daily im injections of bovine TSH were not significantly inhibited, despite a four-fold elevation in serum T3 concentrations. This negative finding contrasts with earlier positive reports of a regulatory "short-loop" effect of elevated circulating T3 on the thyroid gland. This difference may be due either to the use in previous murine or in vitro studies of non-physiologic, high doses of exogenous T3, or failure to control the withdrawal of the trophic effect of endogenous TSH in man on the subsequent glandular response.

Relation of triiodothyronine and reverse triiodothyronine administration in rats to hepatic L-triiodothyronine aminotransferase activity.

The effects of administration of 3,5,3'-triiodothyronine (T3) to normal and to hypothyroid male rats upon the hepatic activity of L-triiodothyronine aminotransferase were determined using 3,5-dinitro-L-tyrosine as substrate in the assay. Initial studies in normal rats demonstrated that basal enzyme activity was highest in liver and kidney of the organs tested, and that virtually no activity was detectable in skeletal muscle, serum, thyroid or pituitary gland. Hepatic enzyme activity increased from birth to a peak at 80-120 days and declined thereafter. Daily administration of T3 to normal rats in doses of 5 mug/100g BW for 8 days significantly elevated hepatic enzyme activity above normal. In daily doses of 2.5mug/100g BW, T3 restored the depressed enzyme activities in hypothyroid rats to normal. Daily administration of 3,3',5'-triiodothyronine (reverse T3) to normal rats in doses of 17.5 mug/100g BW and greater for 3 days increased L-T3 aminotransferase activity more than 30% above normal levels. Reverse T3 appeared to be approximately as active as T3 in increasing the hepatic activity of L-T3 aminotransferase.

Cortisol secretion and metabolism in anorexia nervosa.

We studied cortisol secretion and metabolism in 10 women with anorexia nervosa. The 24-hour mean plasma cortisol concentration was 8.9 mug per deciliter (controls, 4.9) (P less than 0.01). Secretory patterns showed normal circadian rhythms. Cortisol half-life was prolonged from 60 to 78 minutes (P less than 0.01), and metabolic clearance rate was decreased from 359 to 177 liters per day (P less than 0.001). Cortisol production was normal (19.4 mg per day). Urinary cortisol was slightly elevated in two of five patients. These findings, as well as the increased tetrahydrocortisol/tetrahydrocortisone ratio (1.2 vs 0.65, P less than 0.01), also appear in hypothyroid patients. Thyroid-function studies showed normal total and free thyroxine and thyrotropin, but low plasma tri-iodothyronine levels (52.7+/-13.2 vs. 137.8+/-24.1 ng per deciliter in the controls, P less than 0.001). In five additional patients with anorexia nervosa studied before and after short-term tri-iodothyronine administration, metabolic abnormalities decreased as plasma tri-iodothyronine levels rose to or above normal.

Effect of Triiodothyronine Treatment on Prolactin Secretion in Patients with Amenorrhea-Galactorrhea

In order to determine the role of thyroid hormone in prolactin (PRL) secretion in patients with amenorrhea-galactorrhae, PRL response to 500 mug of iv thyrotropin-releasing hormone (TRH) was studied before and after the administration of triiodothyronine (T3) in 10 patients with amenorrhea-galactorrhea. Seven of these patients were euthyroid and the other 3 had hypothyroidism. The patients in the euthyroid group received 50 mug of T3 daily for 7 days and 75 mug q.d. for the ensuing 14 days. The hypothyroid patients received T3 at progressively increasing doses from 10 mug q.d. to 75 mug q.d. during 34 to 68 days. In the initial test, the elevated basal levels of PRL, 61.9 +/- 9.8 ng/ml (Mean +/- SE) exhibited a slight but insignificant net increase (7.7 +/- 2.1 ng/ml) after TRH injection in the euthyroid group. However, a marked response to TRH with a net increase of 147.2 +/- 26.3 ng/ml from the basal level of 47.3 +/- 11.2 ng/ml was observed in the hypothyroid patients. After treatment with T3, both the basal level (56.9 +/- 8.3 ng/ml) and the net increase (9.9 +/- 3.6 ng/ml) of PRL following TRH stimulation remained virtually unchanged in the euthyroid group. The hypothyroid group, in contrast, displayed a significant depression of both the basal level (26.1 +/- 13.0 ng/ml) and the net increase (33.8 +/- 6.5 ng/ml) of PRL to TRH stimulation. The diminution of the basal levels and responses of thyroid-stimulating hormone (TSH) to TRH stimulation was observed in all cases of both groups. These results suggest that the level of thyroid hormone has little pathogenic role in PRL secretion in euthyroid patients with amenorrhea-galactorrhea, in contrast to its marked effect in hypothyroid patients with amenorrhea-galactorrhea.

Stimulation of the synthesis of hepatic fatty acid synthesizing enzymes of hypophysectomized rats by 3,5,3′- l-triiodothyronine

The levels of hepatic fatty acid synthesizing enzymes, acetyl-CoA carboxylase and fatty acid synthetase, are lowered to about one-tenth of the controls in hypophysectomized animals, whereas the lung enzymes decrease by only 25–30%. Administration of 3,5,3′- l-triiodothyronine to the hypophysectomized animals returns the hepatic and lung enzyme activities to the control values. Optimum levels are achieved at a dose of about 150 μg/100 g body wt and 3–4 days after triiodothyronine administration. The triiodothyronine response can be reduced by 80% with actinomycin-D or cycloheximide but not with hydrocortisone hemisuccinate. Antibody-antigen titrations and measurements of the rate of synthesis of fatty acid synthetase are indicative of increased synthesis of fatty acid synthetase and not of activation of the preexisting inactive species. These measurements provide evidence for the involvement of hormones other than insulin in the control of synthesis of fatty acid synthesizing enzymes.