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PubMedDate not supplied

Thyrotropin-induced increase in phosphoprotamine phosphatase activity in rat thyroid.

Phosphoprotamine phosphatase activity in the rat thyroid was examined by studying the release of inorganic phosphate from [32P]-phosphorylated protamine. Rats were given a normal diet supplemented or not with thyroxine (T4) (3 mg/l in 0.05% bovine serum albumin solution) or propylthiouracil (1 g/l in 1% sucrose solution) in drinking water for various periods. TSH was injected ip, 100 mU per animal. A significant increase of phosphatase specific activity-units per mg protein (3-fold) as well as units per gland- was observed following goitrogen treatment, whereas a decrease (50%) was seen in response to T4. Both the soluble and particle activities were similarly affected. As total activity decreased after T4 treatment, it appeared that only the Mn2+-stimulating enzyme was concerned, the Mn2+-unstimulated part remaining unaltered. In vitro cyclic AMP or cyclic GMP at concentrations from 10 micro M to 200 micro M had no effect on these phosphatase activities. TSH injected in chronically T4-treated rats (32 days treatment) failed to produce any significant enhancement in phosphatase activity whatever the time of injection before sacrifice (from 2 to 6 h). On the contrary a single injection of TSH in animals subjected to short treatment with T4 (2 days) induced an elevation of the enzyme activity, restoring partially the initial level. These findings suggest that TSH controls protein dephosphorylation activities in the thyroid. Furthermore, they offer additional evidence that prolonged T4 administration leads to decreased responsiveness to TSH.

Animals↗

PubMedDate not supplied

Effect of barbital on the pituitary-thyroid axis.

Barbital (diethylbarbituric acid), administered via the drinking water (0.1% solution), elicited mild goitrogenic responses in rats (p less than 0.05), accompanied by a slight depression in serum T4 titers (p less than 0.02). The goitrogenic responses appeared to be the result of slight elevations in the serum TSH levels and in the case of neonate rats, whose mothers were fed barbital during pregnancy and lactation, the elevations of TSH in the circulation were pronounced (p less than 0.01). However, continuation of barbital treatment beyond puberty resulted in mean serum TSH titers declining to twice the mean control values so that only the variances between the data were different(p less than 0.05). This group of young adults showed endocrine profiles which resembled those of more mature rats. The latter group included the mothers of these young adults and of the neonates. In contrast to the action of barbital, feeding rats 0.05% propylthiouracil (PTU) in the drinking water caused substantial increases in mean serum levels of TSH (p less than 0.001) and goiter size (p less than 0.001). Moreover, the precipitous declines in serum T4 elicited by PTU were of far greater magnitude than that caused by barbital (p less than 0.001).

Animals↗

PubMed1998

The effects of thyroid status on plasma leptin levels in women.

Leptin, the product of the adipose specific ob gene, regulates food intake and energy expenditure. However, little is known about the effects of thyroid status on plasma leptin levels in women. We determined fasting plasma leptin levels before and 1 month after restoration of euthyroidism in 20 female patients with hypothyroidism, 20 female patients with hyperthyroidism and 20 age and BMI-matched female controls. To restore the normal thyroid function patients with hypothyroidism were treated with levothyroxine, whereas patients with hyperthyroidism were treated with propylthiouracil. Plasma leptin levels were measured by a RIA method with a sensitivity of 0.5 microgram/l. Leptin levels were significantly lower in patients with hypothyroidism before treatment (4.17 +/- 2.58 micrograms/l) than in patients with hyperthyroidism (6.80 +/- 4.3 micrograms/l; z = -2.06, p = 0.037). Leptin levels were significantly higher in hyperthyroid patients than in the control group (3.71 +/- 1.69 micrograms/l, z = -2.44, p = 0.014) whereas leptin levels in the hypothyroid patients were not significantly different from those in control subjects (z = -0.16, p = 0.87). Restoration of euthyroid state was not associated with a significant change in leptin levels either in the hypothyroid (from 4.17 +/- 2.58 to 5.22 +/- 3.4 micrograms/l; z = -1.74, p = 0.08) or in the hyperthyroid group (from 6.80 +/- 4.37 micrograms/l to 7.93 +/- 6.25 micrograms/l z = -0.89, p = 0.37), although a tendency for leptin to increase was observed in both groups. There was no correlation between plasma leptin and FT3, FT4, TSH, or BMI either before or after therapy in both groups. Leptin levels were significantly correlated with BMI in the control group (r = -0.53, p = 0.018). We conclude that plasma leptin levels are increased in hyperthyroidism and unchanged in hypothyroidism. Furthermore, our study demonstrates that mean plasma leptin levels are not influenced by short term restoration of euthyroidism in both hypothyroidism and hyperthyroidism, although an effect of long-term treatment may not be excluded.

Adult↗

PubMed2005

Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion.

AIMS/HYPOTHESIS: The aims of this work were to determine the effect of hypothyroidism on insulin-stimulated glucose turnover and to unravel the potential mechanisms involved in such an effect. METHODS: Hypothyroidism was induced by administration of propylthiouracil, with partial T4 substitution. Euglycaemic-hyperinsulinaemic clamps, associated with the labelled 2-deoxy-D-glucose technique for measuring tissue-specific glucose utilisation, were used. To assess a possible involvement of leptin in the modulation of glucose metabolism by hypothyroidism, leptin was infused intracerebroventricularly for 6 days. A group of leptin-infused rats was treated with rT3 to determine a potential role of T3 in mediating the leptin effects. RESULTS: Compared with euthyroid rats, hypothyroid animals exhibited decreased overall glucose turnover and decreased glucose utilisation indices in skeletal muscle and adipose tissue. Leptinaemia in hypothyroid rats was lower while resistin mRNA expression in adipose tissue was higher than in euthyroid animals. Intracerebroventricular leptin infusion in hypothyroid rats partially restored overall, muscle and adipose tissue insulin-stimulated glucose utilisation and improved the reduced glycaemic response observed during insulin tolerance tests. The leptin effects were due neither to the observed increase in plasma T3 levels nor to changes in the high adipose tissue resistin expression of hypothyroid rats. The administration of leptin to hypothyroid animals was accompanied by increased expression of muscle and adipose tissue carnitine palmitoyl transferases, decreased plasma NEFA levels and reduced muscle triglyceride content. CONCLUSIONS/INTERPRETATION: Hypothyroidism is characterised by decreased insulin responsiveness, partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by intracerebroventricular leptin administration.

Adipose Tissue↗

PubMed2004

A rare case of Graves' disease during regular hemodialysis.

We report a case of Graves' disease in a patient on regular hemodialysis. The patient also suffered from Wolff-Parkinson-White (WPW) syndrome and paroxysmal atrial fibrillation, which may both have been manifestations of the Graves' disease because of the increased oxygen demand. To our knowledge, this is the first case to illustrate the usefulness of the antithyroid agent propylthiouracil for Graves' disease complicated by endstage renal disease (ESRD) and WPW syndrome.

Antithyroid Agents↗

PubMedDate not supplied

Radiation retinopathy caused by low dose irradiation and antithyroid drug-induced systemic vasculitis.

BACKGROUND: We report on a patient with Graves' disease with radiation retinopathy caused by low-dose irradiation and antithyroid drug-induced antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. CASE: A 38-year-old woman with Graves' disease presented with bilateral blurred vision, microaneurysms, telangiectasia, and macular edema. The patient was examined by ophthalmoscopy and fluorescein angiography, and radiation retinopathy was diagnosed. OBSERVATIONS: The patient had been treated with low-dose irradiation for her Graves' ophthalmopathy a few years earlier. She also had ANCA-positive vasculitis induced by the antithyroid drug (propylthiouracil, PTU) that had been prescribed for her at that time. Because of multiple avascular areas on both retinas, she was treated by intensive retinal photocoagulation to control progressive retinopathy. CONCLUSIONS: The radiation doses used to treat Graves' disease ophthalmopathy are low. Nevertheless, there is still a risk of radiation retinopathy developing in patients with PTU-induced ANCA-positive vasculitis.

Adult↗

PubMed2005

Changes in antioxidant status, protein concentration, acetylcholinesterase, (Na+,K+)-, and Mg2+ -ATPase activities in the brain of hyper- and hypothyroid adult rats.

It is a common knowledge that metabolic reactions increase in hyperthyroidism and decrease in hypothyroidism. The aim of this work was to investigate how the metabolic reactions could affect the total antioxidant status (TAS), protein concentration (PC) and the activities of acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+ -ATPase in the brain of hyper- and hypothyroid adult male rats. Hyperthyroidism was induced in rats by subcutaneous administration of thyroxine (25 microg/l00 g body weight) once daily for 14 days, while hypothyroidism was induced by oral administration of propylthiouracil (0.05%) for 21 days. TAS, PC, and enzyme activities were evaluated spectrophotometrically in the homogenated brain of each animal. TAS, PC, and Mg2+ -ATPase activity were found unaffected in hyperthyroidism, while AChE and Na+,K+ -ATPase activities were reduced by 25% (p < 0.01). In contrast, TAS, (Na+,K+)-ATPase and Mg2+-ATPase activities were found to be increased (approx. 23-30%, p < 0.001) in the hypothyroid brain, while AChE activity and PC were shown to be inhibited (approx. 23-30%, p < 0.001). These changes on brain enzyme activities may reflect the different metabolic effects of hyper- and hypothyroidism. Such changes of the enzyme activities may differentially modulate the brain intracellular Mg2+, neural excitability, as well as the uptake and release of biogenic amines.

Acetylcholine↗

PubMed2005

Effects of experimental increases and decreases in thyroxine levels on the extent of cataleptic freezing reactions in rats.

Numerous clinical observations have provided evidence for a tight connection between impairments in the functions of the hypothalamo-hypophyseal-thyroid system and nervous and mental disorders. The aim of the present work was to compare the effects of experimental decreases and increases in blood thyroxine levels on the extents of two types of pathological freezing reaction in male Wistar rats--spontaneous catalepsy and catalepsy evoked by pinches at the nape of the neck (pinch-induced catalepsy). Chronic administration of the thyroxine synthesis inhibitor propylthiouracil (5 mg/kg/day for 28 days) significantly decreased the blood hormone level and sharply increased the proportion of animals showing spontaneous catalepsy and the immobility time, but had no effect on the extent of pinch-induced catalepsy. At the same time, chronic administration of thyroxine (0.1 mg/kg/day for 28 days), which produced significant increases in blood hormone levels, had no effect on the extent of spontaneous catalepsy but significantly increased the proportion of animals showing pinch-induced catalepsy and the duration of this type of catalepsy. It is concluded that both insufficiency and excess of thyroid hormones have cataleptogenic actions, but enhance different types of catalepsy.

Animals↗

PubMed1989

Thyrotoxicosis complicating pregnancy.

During the 12-year period from 1974 through 1985, nearly 120,000 women were delivered of infants at Parkland Hospital, and pregnancy was complicated by overt thyrotoxicosis in 60 of them (1:2000). Initial treatment was based on clinical assessment, and propylthiouracil was usually given in doses of 300 to 800 mg daily. In compliant women seen by midpregnancy, euthyroidism was achieved by a mean of 8 weeks; however, the daily dose was decreased to less than or equal to 150 mg by delivery in only 10%. Metabolic status at delivery correlated directly with pregnancy outcome, and women treated earlier in pregnancy were more likely to be euthyroid at delivery and to have good outcomes. Diagnosis of thyrotoxicosis antecedent to pregnancy was associated with earlier treatment, and 80% of 28 such women were euthyroid by delivery. Conversely, 32 women with a first diagnosis during pregnancy had the preponderance of morbidity, including five of six stillbirths and six of seven cases of heart failure. This group was characterized by a relative delay in gestational age at diagnosis. Preterm delivery, perinatal mortality, and maternal heart failure were more common in women who remained thyrotoxic despite treatment and in those who were never treated. Although we infrequently achieved maintenance doses recommended by most, because there were minimal adverse effects from therapy described here and because uncontrolled thyrotoxicosis caused significant maternal and perinatal morbidity, aggressive medical therapy seems appropriate, especially when pregnancy is advanced.

Adult↗

PubMed1992

Myeloperoxidase-catalyzed iodination and coupling.

Myeloperoxidase (MPO), which displays considerable amino acid sequence homology with thyroid peroxidase (TPO) and lactoperoxidase (LPO), was tested for its ability to catalyze iodination of thyroglobulin and coupling of two diiodotyrosyl residues within thyroglobulin to form thyroxine. After 1 min of incubation in a system containing goiter thyroglobulin, I-, and H2O2, the pH optimum of MPO-catalyzed iodination was markedly acidic (approximately 4.0), compared to LPO (approximately 5.4) and TPO (approximately 6.6). The presence of 0.1 N Cl- or Br- shifted the pH optimum for MPO to about 5.4 but had little or no effect on TPO- or LPO-catalyzed iodination. At pH 5.4, 0.1 N Cl- and 0.1 N Br- had a marked stimulatory effect on MPO-catalyzed iodination. At pH 4.0, however, iodinating activity of MPO was almost completely inhibited by 0.1 N Cl- or Br-. Inhibition of chlorinating activity of MPO by Cl- at pH 4.0 has been previously described. When iodination of goiter thyroglobulin was performed with MPO plus the H2O2 generating system, glucose-glucose oxidase, at pH 7.0, the iodinating activity was markedly increased by 0.1 N Cl-. Under these conditions iodination and thyroxine formation were comparable to values observed with TPO. MPO and TPO were also compared for coupling activity in a system that measures coupling of diiodotyrosyl residues in thyroglobulin in the absence of iodination. MPO displayed very significant coupling activity, and, like TPO, this activity was stimulated by a low concentration of free diiodotyrosine (1 microM). The thioureylene drugs, propylthiouracil and methimazole, inhibited MPO-catalyzed iodination both reversibly and irreversibly, in a manner similar to that previously described for TPO-catalyzed iodination.

Animals↗

PubMed1988

Effect of hypothyroidism on the lipid composition and fluidity of rat colonic apical plasma membranes.

Prior studies have suggested that the lipid composition and lipid fluidity of cellular membranes of various organs are altered in the hypothyroid rat. To date, the effects of hypothyroidism on these parameters have not been examined in rat colonic apical plasma membranes. In the present experiments, male Sprague-Dawley rats were fed a pelleted diet (control group) or the same diet containing 0.1% propylthiouracil (hypothyroid group) for 3 weeks. The lipid composition and lipid fluidity of apical plasma membranes prepared from colonocytes of these two groups of animals were then examined and compared. Membranes prepared from the hypothyroid animals were found to possess a higher level of linoleic acid (18:2) and a lower level of arachidonic acid (20:4) than membranes from control animals. The molar ratio of cholesterol/phospholipid was also lower in hypothyroid membranes secondary to a decreased cholesterol content compared to their control counterparts. Moreover, the lipid fluidity of colonic apical plasma membranes, as assessed by (1) the ratio of excimer to monomer fluorescence intensities of the lipid-soluble fluorophore pyrenedecanoic acid and (2) the anisotropy values of the fluorophore DL-12-(9-anthroyloxy)stearic acid using steady-state fluorescence polarization techniques, was greater in hypothyroid animals. These data, therefore, indicate that alterations in the lipid composition and fluidity of colonic apical plasma membranes can be detected in hypothyroid rats.

Animals↗

PubMed1979

Properties of cyclic AMP-dependent protein kinase in normal and goitrous rat thyroid gland.

Most of the cyclic AMP-dependent protein kinase activity in propylthiouracil-induced goiters and control rat thyroid glands was found in the soluble fraction. The activity in the particulate fractions was cyclic AMP-independent. Protein kinase activity was 2--3-fold higher in all the subcellular fractions of goitrous tissue than of control tissue. In the presence of Triton X-100, both groups showed a significant increase in kinase activity in all subcellular fractions, and the kinase activity in the particulate fractions could now be slightly stimulated by cyclic AMP. Again, enzyme activity in fractions from goiters was significantly higher than in control tissue. Two major peaks, Types I and II, of soluble cyclic AMP-dependent protein kinase activity could be separated by DEAE-cellulose chromatography. Chronic in vivo stimulation by TSH was associated with a selective increase in Type II isoenzyme activity. Elution and pH profiles, dissociation of subunits with 0.5 M NaCl, and activity ratios (-cyclic AMP/+cyclic AMP) for various substrates for Type II isoenzyme in goitrous and control tissue were similar. The elevated activity in goitrous tissue was manifested by an increase in V for histone, ATP, Mg2+ and cyclic AMP, with no change in the apparent Km.

Animals↗

PubMed1975

Electron microscopy of low iodinated thyroglobulin molecules.

Thyroglobulin molecules were studied in the electron microscope with negative staining technique. In a first series of experiments samples of thyroglobulin varying in iodine content from 0.5 to 0.03% were prepared from the thyroids of mice and rats kept on iodine-poor diets. All samples contained thyroglobulin molecules of the normal ovoid shape, not deviating in size or shape from molecules obtained from normal thyroids. However, in addition, another type of molecule having a cylindrical shape was observed in all samples. The proportion of these cylindrical molecules increased from a few per cent in the moderately iodine-poor thyroglobulin samples to more than 80% in the highly iodine-deficient thyroglobulin (0.03%). In a second series of experiments extremely iodine-poor thyroglobulin (smaller than 0.005%) was obtained from propylthiouracil-treated rats. In these preparations practically all molecules had a cylindrical shape. These samples also contained smaller particles interpreted to be dissociation products. The cylindrical molecules were of two types, one appearing compact and measuring 250 times 135 A (length times diameter) and the other appearing porous and having a length of 145 and a diameter of 205 A. It is concluded that the cylindrical molecules represent non- or low-iodinated thyroglobulin and it is suggested that the porous cylindrical molecule is an unfolded form of the compact cylinder.

Animals↗

PubMed1983

Neurotensin regulation of TSH secretion in the rat.

Tri-iodothyronine stimulates neurotensin secretion from rat hypothalami in vitro. Propylthiouracil treatment of rats is associated with a decrease in anterior pituitary neurotensin content, an increase in hypothalamic content and an impaired release of peptide from hypothalami in vitro. In addition neurotensin has a direct inhibitory effect on TRH-stimulated TSH release from anterior pituitary in vitro. These observations suggest a physiological role for neurotensin in the control of TSH secretion in the rat.

Animals↗

PubMed1985

Pituitary 1,25-dihydroxyvitamin D3 receptors in hyperthyroid- and hypothyroid-rats.

The binding of 1 alpha,25-dihydroxy (26,27-methyl-[3H]) cholecalciferol ([3H]1,25-(OH)2D3) to its receptor in cytosol of the anterior pituitary cells was examined in hyperthyroid- and hypothyroid rats, as well as in normal rats. The binding capacity increased by 41% in L-Thyroxine-treated hyperthyroid rats and decreased by 49% in propylthiouracil-ingested hypothyroid rats as compared with normal control rats, whereas the affinity of the receptor for [3H]-1,25(OH)2D3 showed no difference among these 3 animal groups. These findings indicate that the number of 1,25(OH)2D3 receptors in the pituitary may be regulated by thyroid hormone, and further suggest that 1,25-(OH)2D3 may play some role in regulating functions of the anterior pituitary.

Animals↗

PubMed1991

Stimulation of phagocytosis in rat polymorphonuclear leukocytes by A23187 is accompanied by activation of myeloperoxidase.

The incubation of polymorphonuclear leukocytes from rats with A23187 resulted in stimulation of phagocytosis with a concomitant increase in the activity of myeloperoxidase. Activation of the enzyme by A23187 reached the maximum at 2.5 min of incubation and preceded the maximum stimulation of phagocytosis. Propylthiouracil, an inhibitor of myeloperoxidase, and Ca2+ chelators prevented activation of myeloperoxidase and phagocytosis by A23187. These results indicate that A23187 increases intracellular Ca2+ level, followed by activation of myeloperoxidase involved in stimulation of phagocytosis.

Affinity Labels↗

PubMed1982

Mechanism of inactivation of thyroid peroxidase by thioureylene drugs.

We have investigated the mechanism by which the thioureylene drugs, 1-methyl-2-mercaptoimidazole (MMI) and 6-n-propylthiouracil (PTU), inactivate thyroid peroxidase (TPO). Our results indicate that inactivation of TPO by MMI and PTU involves a reaction between the drugs and the oxidized heme group produced by interaction between TPO and H2O2. This conclusion is supported by the following observations. First, addition of a low concentration of H2O2 to a solution of TPO shifted lambda max of the Soret band from 411 to 420 nm, reflecting the formation of an oxidized form of TPO (TPOox). Addition of MMI or PTU to TPOox produced a Soret spectrum that was significantly different from the spectrum of native TPO or TPOox, whereas addition of MMI or PTU to native TPO produced no significant change in the heme spectrum. Second, studies with radiolabeled MMI and PTU combined with simultaneous assays of enzyme activity (guaiacol assay) showed that firm binding of the drugs to TPO and inactivation of the enzyme occurred on addition of the drugs to TPOox. However, neither binding nor inactivation occurred on addition of the drugs to native TPO. Third, the presence of a low concentration of iodide prevented the shift in the Soret spectrum, the binding of labeled drug, and the loss of enzyme activity associated with the addition of thioureylene drugs to TPO + H2O2. Under these conditions we assume that the enzyme was present as TPO X Iox, a form in which the heme is present in the same reduced state as in native TPO. This would explain the protective action of iodide on the inactivation of TPOox by MMI and PTU.

Antithyroid Agents↗

PubMed1993

Tissue- and subunit-specific regulation of G-protein expression by hypo- and hyperthyroidism.

Thyroid hormone status has profound effects on signal transduction in various tissues throughout the body. Therefore, we quantified the signal transducing G-proteins in the rat heart, cerebral cortex, vas deferens and liver by immunoblotting and pertussis toxin labeling in response to chemically induced hypothyroidism (treatment with propylthiouracil) and hyperthyroidism (treatment with triiodothyronine). Levels of the pertussis toxin (PTX) substrates Gi alpha and Go alpha in the heart and vas deferens were inversely correlated with thyroid hormone levels, i.e. Gi alpha and Go alpha were decreased or unchanged in hyperthyroid rats and increased in hypothyroid rats compared to control animals. The cerebral cortex and liver expression of PTX substrates Gi alpha and Go alpha was not affected by changes in thyroid hormone. Regulation of Gs alpha protein was more complex in that Gs alpha was unaffected in the other tissues tested. Expression of G-protein beta-subunits was not affected by thyroid status in the heart, liver, or cerebral cortex. Our results suggest that tissue- and G-protein-specific factors are involved in the regulation of G-protein subunits by thyroid hormone. Moreover, cardiac expression of Gs alpha is upregulated by increases or decreases in the normal level of thyroid hormone.

Animals↗