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PubMed1993

Correlation of acid phosphatase but not alkaline phosphatase activity with myelination in the developing mouse brain.

1. Neonatal mice received subcutaneous injections of buffer, thiourea (TU) or propylthiouracil (PTU). 2. The PTU-treated mice were sacrificed on postnatal day 14 (P14) and the TU-treated mice on P28. 3. Brain weights of the TU- and PTU-treated mice were not significantly different from the controls. 4. Acid but not alkaline phosphatase activity in the brainstem decreased after TU and PTU treatment. 5. Myelination as indicated by intensity of luxol fast blue staining was weaker in the drug-treated animals. 6. The level of myelin marker enzyme, 2',3'-cyclic nucleotide 3'-phosphohydrolase, was lower in the brainstem of PTU-treated animals. 7. The results suggest a correlation between acid phosphatase but not alkaline phosphatase activity with myelination in the developing mouse brain.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed1977

Effect of phospholipids on cholesterol-induced modifications in mouse brain.

Mice on an atherogenic diet for 40 days show a decrease in brain content of catecholamines, cyclic AMP and in dopamine degradation, and modification of the glycolytic pathway. The metabolic changes are paralleled by changes in behaviour, i.e. decrease in spontaneous motor activity and in conditioning avoidance response. The decrease in dopamine degradation and in behaviour parameters is partly due to the propylthiouracil present in the diet. Endovenous treatment with sonicated dispersions of bovine brain phospholipids induces a modification in the parameters of behaviour and metabolism. The possibility is discussed that some of the defects arising during the atherogenic diet are related with the establishment of a hypoxic state.

Animals↗

PubMed1989

Inter-species variations in myocardial responsiveness to cardiac glycosides: possible relations to the thyroid status.

Mammalian species differ in their myocardial responsiveness to cardiac glycosides; whereas glycosides induce a marked positive inotropic effect in species such as dog, rabbit and guinea-pig, the rat myocardium is virtually insensitive. We investigated the physiological basis for this phenomenon by testing the hypothesis that the inter-species variations in the response of the myocardium to cardiac glycosides results, at least in part, from species-related differences in the "thyroid status". In the present study we focused on the toxic effects of the glycosides, and studied ouabain-induced delayed afterdepolarizations (DAD): (1) in guinea-pigs, rats and mice, which encompass a wide range of thyroid statuses, as indicated by their O2 consumption and thyroid hormone levels; (2) in guinea-pigs and rats in which the thyroid status was decreased by propylthiouracil treatment or increased by thyroxine administration (in the former species only). DAD were readily induced in guinea-pigs after 40 to 60 min superfusion with 10(-6) M ouabain and 5.4 mM Ca2+. In rats, DAD were induced only when the Ca2+ concentration was raised to 8.1 mM, but were absent in mice even after 2 h of superfusion with ouabain and 8.1 mM Ca2+. In guinea-pigs and rats (at cycle length = 500 ms), DAD amplitude was (means +/- S.E.): 2.8 +/- 0.7 mV and 1.1 +/- 0.4 mV, respectively. The slope of the DAD ascending limb (dV/dt) in guinea-pigs was 47.6 +/- 8.6 mV/s and in rats was 8.1 +/- 3.4 mV/s. In both species DAD characteristics were altered by the thyroid status. In eu-, hyper- and hypothyroid guinea-pigs, DAD amplitude and dV/dt (cycle length = 500 ms) were as follows: 2.8 +/- 0.7 mV and 47.6 +/- 8.6 mV/s; 1.2 +/- 0.4* mV and 12.6 +/- 3.9* mV/s; 7.5 +/- 0.6* mV and 204.0 +/- 18.4* mV/s, respectively (*, P less than 0.005, compared to euthyroid guinea-pigs). The occurrence of triggered beats was also dependent on the thyroid status. They occur more frequently in hypothyroidism and less frequently in hyperthyroidism. Hypothyroidism in rats augmented ouabain toxicity as reflected by an increase in DAD amplitude and dV/dt by 109% and 105%, respectively (P less than 0.05, as compared to euthyroid rats). In conclusion, we suggest that species-related differences in the thyroid status may contribute to the inter-species (as well as for the intra-species) variations in the myocardial responsiveness to cardiac glycosides.

Action Potentials↗

PubMed1990

Influence of hypothyroidism and the reversal of hypothyroidism on hemodynamics and cell size in the adult rat heart.

Hypothyroid-induced atrophy of cardiac myocytes was examined in adult female rats in an effort to correlate hemodynamic and cellular changes associated with this disorder. Additional rats were studied 6 weeks after discontinuing antithyroid treatment to determine if structural and functional changes were completely reversible. To induce hypothyroidism, rats were injected daily with propylthiouracil (PTU) for 4 weeks. Control animals were injected similarly with Tris buffer. At the end of the treatment period, hemodynamic measurements were made prior to obtaining isolated myocytes. Cell volume, length, and cross-sectional area were obtained from the septum, and left and right ventricles of treated and untreated rats. After four weeks treatment with PTU, body weight was unchanged but heart weight was significantly reduced by 24%. Characteristic hemodynamic changes associated with hypothyroidism in the rat were noted (eg. reduced heart rate, cardiac output, dP/dtmax, and ventricular pressure). Cell volume was significantly smaller in hypothyroid rats primarily due to a reduction in myocyte cross-sectional area. The hemodynamic and cellular response to hypothyroidism was similar in the right and left ventricle. Six weeks after discontinuing PTU treatment, cellular and hemodynamics changes had returned to normal. It was concluded that hypothyroidism caused a true cardiac atrophy which was reversible. Reduced myocyte cross-sectional area was responsible for most of the myocyte atrophy.

Animals↗

PubMed1984

Complete recovery of growth deficits after reversal of PTU-induced postnatal hypothyroidism in the female rat: a model for catch-up growth.

Newborn rats of both sexes were treated from birth with the anti-thyroid goitrogen, n-propylthiouracil (PTU) given in the drinking water of the litter (0.1% w/v). One group received the treatment for 25 days, another for 50 days, and a third group for 120 days. The experimental rats showed growth retardation as well as all other classical signs of developmental arrest or delays induced by postnatal hypothyroidism. In order to assess the ability of the hypothyroid animals to recover spontaneously from the retarded state, at days 25, 50 and 120 postnatal the PTU water was replaced with tap water. In each case, within 5-7 days after PTU withdrawal the animals began to show marked compensatory growth accompanied by many signs of behavioral and physiological recovery. In general, the male rats showed higher compensatory growth rates as compared to the females, enabling them to attain significantly higher body weights. However, when growth recovery was followed for up to 6 months it was found that the male rats were unable to attain complete catch-up growth, regardless of the age at which recovery began, while the females of all age groups were able to achieve this goal. In view of the severity of PTU-induced growth retardation, these results suggest significant plasticity of growth processes in the rat, especially in the female. It is suggested that male and female rats recovering from prolonged PTU-induced growth retardation offer a good model system for the study of biochemical, anatomical and physiological aspects of growth recovery and catch-up growth at both the cellular and organismic levels, particularly in relation to the effects of thyroid, growth hormone, and other growth-promoting factors.

Aging↗

PubMed1991

Thyroidal involvement in the expression of avian muscular dystrophy.

We showed previously that propylthiouracil (PTU), a thyroid inhibitor, could alleviate several major signs of hereditary muscular dystrophy in chickens. The goals of the present investigation were to: (1) determine whether a nearly athyroid condition (achieved within two days after hatching by surgical thyroidectomy plus PTU) during an 11-day period beneficially affects the dystrophic condition when followed by triiodothyronine (T3) replacement to 33 days of age; (2) determine the beneficial effects on the expression of avian dystrophy when the thyroidectomized-PTU-treated chickens received a wide range of moderate to low T3 replacement doses beginning by two days after thyroidectomy; and (3) examine the thyroid hormone receptor system in dystrophic muscle for a possible abnormality. Thyroid deprivation increased muscle function (righting ability) and reduced plasma creatine kinase activity in dystrophic chickens. The major thyroid-related abnormality in dystrophic pectoralis muscles was an increased maximum binding capacity of solubilized nuclear T3 receptors.

Animals↗

PubMed1991

Different responses between thyroxine 5'-monodeiodinase and protein disulfide isomerase activities to dietary fat and thyroid status in rat liver.

On the hypothesis that rat hepatic microsomal type I iodothyronine 5'-monodeiodinase (MDI) would be identical to hepatic protein disulfide isomerase (PDI) (Boado et al. Biochem. Biophys. Res. Commun. 155 1297-1304 (1988)), we examined the responses of these enzyme activities to dietary fat and thyroid status in rats. The hepatic MDI activity was higher in rats fed high fat diet than in rats fed low fat diet, but the hepatic PDI activity showed the reverse responses to the diets. Propylthiouracil administration (hypothyroidism) lowered the MDI activity, but elevated the PDI activity. Thyroxine administration (hyperthyroidism) elevated the MDI activity but had no effect on the PDI activity. These results indicate that the two enzyme activities are regulated by different mechanisms in vivo, suggesting that MDI and PDI are not identical enzymes.

Administration, Oral↗

PubMed1991

Effects of thyroid status on the characteristics of alpha 1-, alpha 2-, beta, imipramine and GABA receptors in the rat brain.

The effects of a chronic treatment with L-triiodothyronine (T3; 100 mg/rat/day s.c. for 7 days) or with propylthiouracil (PTU; 50 mg/rat/day for 35 days by stomach tube) on the characteristics of alpha 1, alpha 2, beta, imipramine and GABA binding sites in different brain areas of the adult rat have been studied. T3-treatment caused an increase in the number of [3H]dihydroalprenolol and a decrease in the number of [3H]muscimol binding sites in the cerebral cortex. PTU-treatment caused a decrease in the number of [3H]prazosin, [3H]yohimbine and [3H]dihydroalprenolol binding sites in the cerebral cortex, while the number of [3H]imipramine binding sites was reduced in the cerebral cortex and hypothalamus, and increased in the hippocampus. Affinity constants were never modified. Concurrent experiments showed that the "in vitro" addition of T3 and PTU did not influence the binding of any of the ligands employed to control rat brain membranes. The present data further support the view that neurotransmission in the CNS is influenced by the thyroid status.

Animals↗

PubMed1994

Thyroid hormone stimulates phosphoglycerate mutase activity and isozyme transition in rat muscle tissues.

Triiodothyronine (T3) increases phosphoglycerate mutase (PGAM) specific activity in rat skeletal and cardiac muscles. This increase is concomitant with an increase in the proportion of phosphoglycerate mutase isozymes which contain type-M subunit. Propylthiouracil (PTU), an anti-hormone, not only decreases phosphoglycerate mutase activity with respect to control rats, but also decreases the total M subunit contents. In liver, which only possesses type-B subunit phosphoglycerate mutase, none of the effects were detected.

Animals↗

PubMed1983

Acid protease activity in thyroid gland from patients with Graves' disease.

Although the activity of lysosomal protease in Graves' thyroid is considered to be increased, there has been no quantitative method to estimate the protease activity in the thyroid tissue due to the contamination of thyroglobulin (Tg) which varies in susceptibility to the protease. In the present study, the proteolytic activity (PA) of thyroid lysosomal protease preparation (P25) separated from Tg was assayed using 125I labeled rat Tg. More than 95% of 125I-Tg was hydrolyzed at pH 4.0 without deiodination, and the pattern of liberated iodoamino acids resembled that of pronase digest except for a higher T3/T4 ratio. Thirty-seven Graves' thyroids and 15 paranodular thyroid tissues were assayed. PA, the specific PA (SPA; calculated as PA per mg P25 protein) and PA per DNA content in Graves' thyroids were significantly higher than those in controls. There were good correlations among PA, SPA and PA per DNA content of the thyroid tissue. PA and SPA in the thyroid from 29 patients with Graves' disease treated with propylthiouracil or methimazole did not correlate with serum thyroid hormone level immediately before surgery. In 8 patients treated with KI, PA from 5 patients whose serum thyroid hormone levels had been normalized were significantly lower than those from 3 patients who were still thyrotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Reduction by propranolol of urinary hydroxyproline excretion in human hyperthyroidism: a beta-receptor blockade effect or a membrane stabilizing mechanism?

In order to investigate the mechanism whereby oral propranolol administration reduces the increased rate of urinary hydroxyproline excretion (UHxE) of patients with hyperthyroidism, a comparison was made of the effects of the oral administration of propranolol-timolol, propylthiouracil (PTU), and a placebo to patients with hyperthyroidism and to normal controls. Propranolol decreased the pulse rate (P less than 0.01), serum triiodothyronine (T3) level (P less than 0.05), and UHxE (P less than 0.01) without modifying the serum free thyroxine index (FT4I) or parathormone (PTH) level. Timolol decreased the pulse rate (P less than 0.01) to the same extent as propranolol, had no effect on T3, FT4I, or PTH, and failed to decrease UHxE. Administration of PTU decreased the T3 level (P less than 0.05) to a similar extent as propranolol without modifying the FT4I or PTH level and had no effect on UHxE. Placebo administration had no effect. These results suggest that the reduction of UHxE by propranolol is not due to the beta-receptor-blocking properties of propranolol nor mediated by the propranolol-induced decrease in the level of T3 but is probably due to the membrane-stabilizing properties of propranolol.

Adult↗

PubMed1986

Modulation of myocardial L-triiodothyronine receptors in normal, hypothyroid, and hyperthyroid rats.

To characterize the nuclear receptor believed to mediate the thyroid hormones' actions on the heart, binding of L-[125I]T3 to extracts of myocardial cell nuclei from normal, propylthiouracil, and T4-treated rats has been investigated. Analysis of in vitro iodothyronine binding to this solubilized nuclear preparation revealed multiple saturable, specific binding sites for T3. High affinity binding for T3 (Kd = 4.2 +/- 1.0 X 10(-10) mol/L), and lower affinity (Kd approximately 10(-8) mol/L) binding activity appeared to be independent (Hill plot slope = 1). The mean maximal binding capacity of the high affinity binding site for T3 in euthyroid rats (84 +/- 8 fmol/mg DNA) was increased by approximately 50% in hypothyroidism (120 +/- 6 fmol/mg DNA) and unchanged in hyperthyroidism (88 +/- 25 fmol/mg DNA). The molecular weight of this T3 binding site is estimated to be 50,000-55,000 daltons. The properties of this solubilized binding activity from rat myocardial nuclei are consistent with its putative role as the biologic thyroid hormone receptor. The increase in binding capacity with hypothyroidism suggest regulation by thyroid hormone of its nuclear receptor in myocardium.

Animals↗

PubMed1992

Mitochondrial glutathione in hypermetabolic rats following burn injury and thyroid hormone administration: evidence of a selective effect on brain glutathione by burn injury.

Cerebral cortex, heart, skeletal muscle, and liver mitochondrial glutathione (GSH) levels in severely burned rats are decreased to between approximately 50% to 70% of sham-operated, normally fed controls. In semistarved rats, weight-matched with burned rats, mitochondrial GSH levels in these tissues are decreased to between approximately 70% to 91% of those in sham-operated rats. Total GSH levels in peripheral tissues and brain are decreased to approximately 60% to 65% of control levels in rats with burn injury and food restriction, suggesting a higher mitochondrial GSH turnover in burned rats than in semistarved rats, probably because of higher "stress hormone" levels in burned rats than in semistarved rats. Cerebral cortex mitochondrial GSH levels are unaffected by variations in thyroid hormone status, but liver mitochondrial GSH levels are decreased by triiodothyronine and increased by propylthiouracil. The present results suggest that mitochondrial GSH is not only regulated by the rate of GSH synthesis in the cytosol, but seems to be under hormonal influence as well; stress hormones and triiodothyronine may decrease mitochondrial GSH by increasing mitochondrial oxygen consumption with increased reactive oxygen species formation or by increasing GSH exchange between mitochondria and the cytosol. These findings may be of importance therapeutically in increasing antioxidative defenses to limit oxidative stress injury in hypermetabolic patients.

Animals↗

PubMed1993

Stimulation of brain natriuretic peptide release from the heart by thyroid hormone.

This study was designed to examine the involvement of thyroid hormone in the release of brain natriuretic peptide (BNP) from the heart. We measured plasma immunoreactive BNP (ir-BNP) concentrations in patients with untreated hyperthyroidism. We also measured BNP values in experimental rats with hyperthyroidism induced by thyroxine (T4) and in rats with hypothyroidism induced by propylthiouracil (PTU). The in vitro effects of triiodothyronine (T3) and T4 on the release of BNP were examined in newborn rat atrial and ventricular myocytes in primary culture. Plasma BNP levels were increased in hyperthyroid patients compared with normal control subjects. Plasma BNP levels were increased in hyperthyroid rats and decreased in hypothyroid rats compared with euthyroid rats. Plasma BNP level was correlated with serum T4 level in hyperthyroid patients and hyperthyroid rats. A major component of ir-BNP in plasma from hyperthyroid patients was human BNP-32 and that in plasma from hyperthyroid rats was rat BNP-45. T4 and T3 stimulated release of ir-BNP from both cultured atrial and ventricular myocytes in a dose-dependent manner. Plasma BNP concentration is frequently increased in hyperthyroidism, and thyroid hormone may regulate BNP release from both atrial and ventricular myocytes.

Adult↗

PubMed1982

Effects of induced thyroid deficiency on the development of suckling behavior in rats.

The effects of propylthiouracil (PTU) on the ontogeny of suckling behavior in rats were examined. The drug was given at two dosage levels of 0.3% and 0.5% respectively mixed with rat diet throughout gestation and suckling. The thyroid glands of treated fetuses and pups and of untreated control animals of the same age groups were monitored by histologic examination. At the behavioral level, the frequency of individual movements of head, forelimbs and mouth was significantly reduced in treated fetuses. The combination movements of head, mouth and forelimbs showed severe deficits both quantitatively and qualitatively for all ages in the experimental group from day 18 of gestation. Hypothyroid pups of dams raised on 0.5% PTU were unable to attach to the nipple of the mother and died within a few days. Pups of dams raised on 0.3% PTU showed longer latencies for nipple attachment, and their gross motor movements of rooting and suckling were greatly impaired. These results have been discussed in relation to the development of suckling behavior to indicate that, during ontogeny, some decisive step in the integration of individual movements takes place in utero from day 18 of gestation. This coincides with the establishment of pituitary thyroid relationship, which is continued through postnatal stages.

Animals↗

PubMed1992

A possible genetic association between PROP-tasting and alcoholism.

Fifty-five young adult subjects and their parents were classified as alcoholic or nonalcoholic based on a standardized questionnaire (the MAST) filled out by the subjects. Subjects' thresholds for detection of 6-n-propylthiouracil (PROP; a PTC-like compound) were determined with the experimenter blind to MAST responses. There was a significantly higher proportion of nontasters of PROP among children of alcoholics than among children of nonalcoholics. There was no relationship between the child's alcoholism status and ability to taste PROP. These results are inconsistent with the view that excessive use of alcohol causes the association between nontasting and alcoholism and are consistent with the view that there is a genetic association between PROP/PTC-tasting and alcoholism.

Adolescent↗

PubMed1994

Naloxone stimulates oxygen consumption but not ventilation in hypothyroid hamsters.

Male golden Syrian hamsters made hypothyroid by 5 wk of propylthiouracil (PTU) treatment and control hamsters given tap water were studied. Both groups of nine animals demonstrated increased oxygen consumption after SC naloxone administration relative to saline treatment. Naloxone stimulated ventilation and ventilation in response to hypoxic (10% O2) and hyperoxic, hypercapnic (7% CO2 in oxygen) challenges in control hamsters. Relative to their responses to saline, PTU-treated hamsters exhibited no stimulation of ventilation nor of ventilation in response to the gas challenges after naloxone treatment. These results suggest that (a) the stimulation of oxygen consumption by naloxone does not directly increase ventilation; and (b) thyroid hormone status in the hamster affects opioid modulation of ventilation.

Animals↗

PubMed1994

PTC/PROP tasting: anatomy, psychophysics, and sex effects.

Taste worlds of humans vary because of taste blindness to phenylthiocarbamide (PTC) and its chemical relative, 6-n-propylthiouracil (PROP). We review early PTC studies and apply modern statistical analyses to show that a higher frequency of women tasted PTC crystals, and were tasters (threshold classification). In our laboratory, scaling of PROP bitterness led to the identification of a subset of tasters (supertasters) who rate PROP as intensely bitter. Supertasters also perceive stronger tastes from a variety of bitter and sweet substances, and perceive more burn from oral irritants (alcohol and capsaicin). The density of taste receptors on the anterior tongue (fungiform papillae, taste buds) correlate significantly with perceived bitterness of PROP and support the supertaster concept. Psychophysical data from studies in our laboratory also show a sex effect; women are supertasters more frequently. The anatomical data also support the sex difference; women have more fungiform papillae and more taste buds. Future investigations of PTC/PROP tasting and food behaviors should include scaling to identify supertasters and separate sex effects.

Female↗