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Diverse bitter stimuli elicit highly similar patterns of Fos-like immunoreactivity in the nucleus of the solitary tract.

Previous studies have demonstrated that oral stimulation with quinine elicits Fos-like immunoreactivity in the first-order gustatory nucleus, the NST, with a different topographic distribution than sucrose or citric acid. However, it is unknown whether the quinine pattern is unique to this alkaloid or common across bitter stimuli with different chemical structures. Indeed, recent physiological experiments suggest that taste receptor cells and primary afferent neurons may exhibit selectivity for various bitter tastants. The present investigation compared the distribution of FLI in NST following stimulation with three bitter chemicals: QHCl, denatonium and propylthiouracil, stimuli that evoked Ca(2+) currents in almost entirely different sets of receptor cells. The results demonstrate that the quinine pattern is not idiosyncratic but instead generalizes to the other two tastants. Although it remains possible that intermingled but different NST neurons are activated by these stimuli, these data suggest that a specialized region in the NST is preferentially involved in processing a common aspect of bitter tastants. In contrast to citric acid, quinine, denatonium and propylthiouracil all elicited vigorous oromotor rejection responses, consistent with our earlier hypothesis that the medial third of the NST may be an afferent trigger zone for oromotor rejection.

Animals↗

Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with anti-thyroid drug treatment.

Two cases of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis following treatment with propylthiouracil and carbimazole are described. Both patients had crescentic glomerulonephritis proven by renal biopsy and responded to immunosuppressive therapy and withdrawal of the anti-thyroid drugs. Though systemic vasculitis associated with propylthiouracil is reported, this is the first report to our knowledge of renal biopsy-proven vasculitis associated with either of these drugs.

Adult↗

Rhabdomyolysis associated with hyperthyroidism.

BACKGROUND: Nontraumatic rhabdomyolysis has been associated with alcohol and drug abuse, seizures, strenuous exercise, muscle hypoperfusion, hyperthermia, electrolyte disturbances, diabetic coma, and hypothyroidism. Hyperthyroidism can be associated with several neuromuscular manifestations, such as thyrotoxic myopathy and thyrotoxic periodic paralysis, both associated with weakness and normal creatine phosphokinase levels. There have been only three reported cases of rhabdomyolysis as a result of thyrotoxicosis. We are reporting the fourth case of such association. CASE REPORT: The patient is a 26-year-old black woman with history of hypertension. She presented to the clinic with blurred vision, headaches, palpitations, weight loss, weakness, and persistent high blood pressure. She was found to have exophthalmus, lid lag, and a symmetric, smooth, and diffuse goiter. Ptosis and diplopia were absent; neurologic examination findings was normal. The patient had positive TPO antibodies, elevated free T4 level, and low thyroid-stimulating hormone (TSH) level. Graves disease was diagnosed and propylthiouracil was prescribed. The patient then returned to the clinic 2 weeks later with weakness and myalgias. Her physical examination findings were unchanged except for mild muscle weakness. Laboratory evaluation showed normal electrolytes, normal renal function, and negative urine drug screening. Creatine phosphokinase was 1276 U/L. Her free T4 and T3 levels were elevated and TSH level was low. The patient was treated with aggressive oral fluid resuscitation. Propylthiouracil was continued and free T4 and T3 normalized along with creatine phosphokinase with resolution of symptoms. CONCLUSIONS: Hyperthyroidism may, theoretically, cause rhabdomyolysis by means of increasing energy consumption associated with depletion of muscle energy stores and substrates. Our patient constitutes the fourth reported case of rhabdomyolysis associated with hyperthyroidism.

Adult↗

The effects of thyroid hormone modulation on rat liver injury associated with ischemia-reperfusion and cold storage.

UNLABELLED: We investigated the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion (I-R) and cold storage in rats. First, euthyroid and thyroxine (T4)-pretreated rats were exposed in vivo to 20-min global liver ischemia, then 30-min reperfusion. Liver injury was assessed by measuring serum alanine aminotransferase (ALT) levels. Liver concentrations of adenine nucleotides, reduced glutathione (GSH), and oxidized glutathione were evaluated. Second, rats were given the antithyroid drug propylthiouracil (PTU). Livers stored at 0-1 degrees C in Euro-Collins' solution for 20 h were reperfused at 37 degrees C for 15 min. Lactate dehydrogenase (LDH) in the effluent perfusate and bile flow were evaluated during reperfusion. Serum ALT levels increased after ischemia and I-R. ALT increased significantly more in T4-pretreated than in euthyroid rats after ischemia and I-R. Preischemic levels of adenosine triphosphate (ATP) were significantly lower in livers from T4-pretreated than in euthyroid rats (6.22 +/- 0.7 and 11 +/- 0.9 nmol/mg protein, respectively; P < 0.05). After ischemia, liver ATP was similarly reduced in T4-pretreated and euthyroid rats. After reperfusion, ATP partially recovered in euthyroid rats but remained low in T4-pretreated rats (6.7 +/- 1.0 and 1.91 +/- 0.7 nmol/mg protein, respectively; P < 0.05). Preischemic levels of liver GSH decreased to 44% in T4-pretreated rats. After ischemia, GSH decreased similarly in euthyroid and T4-pretreated rats. GSH recovered promptly after reperfusion in euthyroid rats but remained low in T4-pretreated rats (13.9 +/- 3.3 and 3.9 +/- 0.9 nmol/mg protein, respectively; P < 0.02). During reperfusion after cold storage, LDH in effluent perfusate was significantly lower and bile flow higher in livers from PTU-pretreated rats than from euthyroid rats. The histopathological changes observed after I-R and cold storage confirmed the biochemical findings. Our results suggest that T4 administration exacerbates pretransplant liver damage by increasing liver susceptibility to I-R, whereas PTU administration reduces the liver injury associated with cold storage. IMPLICATIONS: We studied the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion and cold storage in rats. Thyroxine administration increased susceptibility to ischemia-reperfusion injury, whereas the antithyroid agent propylthiouracil reduced the deleterious effects associated with cold storage.

Adenine Nucleotides↗

Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.

Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.

Antithyroid Agents↗

Thyroxine increases nerve growth factor concentration in adult mouse brain.

The effects of thyroxine and propylthiouracil on nerve growth factor concentrations in cerebral cortex, cerebellum, and brainstem of adult male mice were assessed by using a sensitive radioimmunoassay for the beta-subunit of mouse nerve growth factor. Thyroxine administration significantly increased the concentration of nerve growth factor in all three brain areas compared to control values, whereas propylthiouracil was without effect. These results suggest that thyroid hormones stimulate nerve growth factor synthesis in the mature central nervous system, and raise the possibility that the influence of thyroid hormones on central nervous system development might be mediated or influenced by nerve growth factor.

Animals↗

The development of a febrile response to pyrogen in the thyroid-deficient rabbit.

The development of the febrile response to E. coli lipopolysaccharide (1.5 micrograms/kg, i.v.) in thyroid-deficient rabbits has been studied. Twenty-eight New Zealand White rabbits weighing 2.1-2.3 kg were used. Hypothyroidism was induced by treatment with propylthiouracil (100 or 200 mg/kg body wt./15 days). Thyroid-deficient animals showed a reduction in the febrile response to lipopolysaccharide, but the effect was significantly different (p less than 0.01) from the control only for rabbits treated with 200 mg/kg of propylthiouracil. Propranolol (2 mg/kg, i.p.) given 30 min before lipopolysaccharide also reduced (p less than 0.01) the fever response in control rabbits. The results of this experiment are consistent with the hypothesis that the reduction in the febrile response of thyroid-deficient rabbits is due to the reduced number of beta-adrenergic receptors, or to a change in the availability of neurotransmitter in thermogenically active tissues, such as brown fat.

Animals↗

Thyroid inhibition and developmental increases in fetal rat lung antioxidant enzymes.

After demonstrating that prenatal exogenous thyroid hormone administration to pregnant rats produces decreases in fetal lung antioxidant enzyme (AOE) development despite increases in surfactant development, we examined the role of endogenous thyroid hormones on the development of these two lung systems. We administered the antithyroid drug methimazole (or diluent) to pregnant rats for the final 3 days before premature or term delivery; in a second series of experiments, propylthiouracil was administered for the 10 days before delivery. Both antithyroid drugs, known to cross the placenta, produced significantly decreased thyroid hormone levels in the pregnant dams. Fetal offspring from methimazole-, and propylthiouracil-treated dams demonstrated significant increases in pulmonary superoxide dismutase activity at 20 and 21 days of gestation and in catalase and glutathione peroxidase activities at 21 days compared with control offspring. Surfactant, measured as lung tissue disaturated phosphatidylcholine, was not different between either experimental group and controls. These results suggest that thyroid blockade increases AOE because the influence of thyroid hormone on AOE development may be one of depression. The findings confirm that certain hormonal regulators may influence different developing fetal lung systems in different ways.

Animals↗

Increased heat loss in ovariectomized hypothyroid rats treated with estradiol.

The role of the thyroid in the mediation of an estrogen-associated change in thermal balance was studied in thyroidectomized and in propylthiouracil-treated ovariectomized rats. Prior to propylthiouracil treatment, estrogen-treated ovariectomized rats and intact female rats had higher rates of heat production and dry heat loss at -5 degrees C than ovariectomized rats. Heat production of estrogen-treated and intact female rats was well below their rates of dry heat loss without an alteration in the absolute rate of heat loss in the hypothyroid condition. Heat production exceeded heat loss only in the hypothyroid ovariectomized group not receiving estrogen. Ovariectomized rats without estrogen maintained thermal balance, whereas rectal temperatures fell in both intact and estrogen-treated ovariectomized rats during cold exposure. Increased heat loss unbalanced by heat production was also observed in surgically thyroidectomized estrogen-treated ovariectomized rats tested at -5 degrees C. These results suggest that an estrogen-induced increase in heat loss, which is compensated by an increase in heat production in the euthyroid but not the hypothyroid condition, is one mechanism responsible for estrogen-associated changes in thermal balance during cold exposure.

Animals↗

Effect of inducers on the activity of glutathione S-transferase and other enzymes of the glutathione pathway in cultured human keratinocytes.

Known inducers of the hepatic glutathione (GSH) S-transferases were tested at the limits of their solubility as inducers of the enzyme in cultured human keratinocytes. Neither phenobarbital, trans-stilbene oxide, propylthiouracil, nor butylated hydroxyanisole increased GSH S-transferase activity or led to the appearance of alpha- or mu-forms of the enzyme, as judged by Western blotting. Only the pi-form of the enzyme was found before and after all treatments. Thus, the enzyme is not inducible in keratinocytes. However, 4 mM propylthiouracil did lead to a 50% increase in GSH reductase activity, and phenobarbital at 4 mM completely abolished GSH peroxidase and GSH reductase activity and led to a significant loss of viability.

Butylated Hydroxyanisole↗

Ontogenesis of the kidney in the congenital hypothyroid rat. Biochemical and anatomical parameters of general development.

The effect of congenital thyroid deficiency upon the postnatal development of the rat kidney has been studied by measuring the nucleic acid, protein and lipid contents, and the area and thickness of the different regions in the organ, i.e. cortex, outer and inner medulla. Thyroid deficiency, induced by daily propylthiouracil treatment, strongly affects the development of the renal cortex. The medulla, and still more its inner part which develops early and partly before the onset of thyroid function, is relatively preserved. These effects are completely corrected by daily thyroxine therapy, excluding a possible toxic effect of the antithyroid drug. Moreover, they are partly reversible after cessation of propylthiouracil treatment.

Aging↗

Inhibition of multiplication of Mycobacterium leprae by several antithyroid drugs.

Multiplication of Mycobacterium leprae in the mouse footpad was inhibited when mice were fed, mixed in their diet, 0.05 per cent methimazole, 0.066 per cent USP thyroid powder, methimazole plus thyroid powder, 0.15 per cent 5-n-heptyl-2-thioxo-4-thiazolidinone, 0.1 per cent propylthiouracil, and 0.1 per cent thambutosine for 154 days, beginning on the day of inoculation. All of the treatment regimens, except for the 2 containing thyroid powder, decreased the plasma concentrations of thyroxine and protein-bound iodine. It is suggested that the 2 antithyroid drugs, methiomazole and propylthiouracil, and the 2 antimicrobial agents, heptylthioxothiazolidinone and thiambutosine, all of which possess structural features in common, may exert the antithyroid and antimicrobial effects through a common mechanisms.

Aniline Compounds↗

An in vitro effect of triiodothyronine on rat adipose tissue.

Triiodo-L-thyronine (T(3)) added in vitro to fat pads from normal, or propylthiouracil-treated rats enhanced the rate of release of glycerol and free fatty acids (FFA) in the presence of epinephrine. An effect of T(3) was also demonstrated in the presence of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, or glucagon in studies with tissue from normal rats. The minimal effective concentration of T(3) was approximately 2.5 x 10(-5) mole/liter for intact fat pads and 3 x 10(-6) mole/liter for fat cells. With fat pads from propylthiouracil-treated rats the effect of T(3) was not apparent until the 3rd hr of incubation. Enhancement of epinephrine-stimulated lipolysis by T(3) was evident during the 1st hr of incubation of fat pads from normal rats, and fat cells responded almost immediately to the presence of T(3). When added alone or in the presence of theophylline, 3',5'-adenosine monophosphate or its dibutyryl derivative, T(3) had little or no effect on lipolysis. The effect of T(3) was observed with or without glucose in the medium, and was not inhibited by cycloheximide or actinomycin D. It did not persist when tissues, after incubation in the presence of T(3) were transferred to medium without T(3). No effect of T(3) on glucose uptake in the presence of epinephrine, ACTH, or insulin was demonstrated.

Adipose Tissue↗

Increased sensitivity of the thyroid in iodine-depleted rats to the goitrogenic effects of thyrotropin.

The present studies demonstrate that iodine depletion increases the sensitivity of the thyroid to the goitrogenic effects of thyrotropin. Iodine depletion was induced by feeding rats a low iodine diet containing propylthiouracil for 10-14 days before hypophysectomy. Accumulation of iodine in the thyroid after hypophysectomy was prevented by continuing the antithyroid drugs in the diet. Doses of thyrotropin as low as 3 mU/100 g of body weight per day produced significant thyroid enlargement in 3-7 days in iodine-depleted rats. Adding propylthiouracil or perchlorate to the diet during treatment with thyrotropin did not reduce or augment the goitrogenic response to thyrotropin in iodine-depleted rats. Increasing the level of circulating iodide also did not reduce the goitrogenic response to thyrotropin. The increased sensitivity of the iodine-depleted thyroid gland may provide an explanation for the development of thyroid enlargement without requiring an increased level of circulating thyrotropin.

Animals↗

Modulation of pituitary responsiveness to thyrotropin-releasing hormone by triiodothyronine.

The relative roles of triiodothyronine (T(3)) and thyroxine (T(4)) in modulating pituitary responsiveness to thyrotropin-releasing hormone (TRH) have been assessed. (a) 10 hyperthyroid patients with elevated serum T(2) and T(4) levels showed no pituitary response to TRH. After 2 wk of propylthiouracil therapy T(4) levels had fallen to normal in only five patients while T(2) levels were normal in all. Pituitary responsiveness to TRH returned in all patients with normal or high T(4) concentrations. (b) Patients with isolated elevations of serum T(3) (T(3) toxicosis) failed to respond to TRH. TRH responsiveness was restored when T(3) levels fell to normal after propylthiouracil therapy. (c) When pituitary responsiveness to TRH was tested 60 min after a single oral dose of 50 mug of T(3), which increased serum T(3) levels to slightly above the normal range, no rise in thyrotropin (TSH) was seen in six subjects. These findings indicate that T(3) elevations alone can rapidly inhibit pituitary responsiveness to TRH.

Administration, Oral↗

Monodeiodination of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine to 3,3'-diiodothyronine in vitro.

To study conversion of 3,5,3'-triiodothyroinine (T3) and 3,3',5'-triiodothyronine (rT3) to 3,3'-diiodothyronine (T2) in vitro, T3 or rT3 was incubated at pH 7.35 with homogenates of several rat tissues (liver, kidney, muscle, heart, ling, spleen, intestines, and brain) for 15 min at 37 C. The T2 generated during incubation was measured in an ethanol extract of the incubation mixture by a specific RIA of T2; T4, T3, and rT3 cross-reacted in the T2 RIA only to an extent of 0.006, 0.2, and 0.04%, respectively. T2 was produced regularly when T3 or rT3 was incubated with liver or kidney homogenates; other tissues generated little or no T2 under similar conditions. Studies with liver homogenates revealed that production of T2 from both T3 and rT3 was influenced significantly by tissue and substrate concentractions, temperature, pH and duration of incubation. T3- as well as rT3-monodeiodinating activities were unaffected by large doses (greater than or equal to 3 micrometer) of sodium iodide, diiodotyrosine, and methimazole, but were inhibited in a dose-dependent manner by propylthiouracil, iodiacetic acid, and dinitrophenol. The apparent Km for conversion of T3 to T2 approximated 6.0 micrometer and that for conversion of rT3 to T2' 65 nM. Propylthiouracil and iodoacetic acid inhibited conversion of both T3 and rT3 to T2 in an uncompetititve and a non-competitive manner, respectively. The various data suggest that 1) monodeiodination of T3 and rT3 to T2 is enzymic in nature; 2) liver and kidney may be the major sites of metabolic transformations of T3 and rT3 to T2.

Animals↗

Hypothyroidism-induced changes in triiodothyronine binding to nuclei and cytosol-binding proteins in rat liver.

A tracer dose of [125I]T3 was given iv to normal, thyroidectomized, and propylthiouracil-fed rats and the distribution of radioactivity in serum and liver fractions was studied over 1 h. Total liver homogenate and serum 125I were higher at all times in hypothyroid rats and, in all groups, showed a continuous fall over the period studied. Hepatic nuclear 125I was maximal at 20 min in all and was greater in hypothyroid rats; there was more 125I in the hepatic cytosol of normal rats than in that from either thyroidectomized or propylthiouracil-fed animals. Binding studies with [125I]T3 and purified hepatic neclear preparations in vitro indicated that both the association constant, Ka (1.08-9.0 x 10(9) M-1) and the capacity (500-600 pg/mg DNA) in thyroidectomized and goitrogen-treated rats were similar to those obtained with normal animals. Cytosol, on the other hand, showed a decrease in binding capacity without change in affinity in livers of hypothyroid rats. Analysis of binding data by Hill plots indicated the presence of both positive and negative cooperativity in binding of T3 by rat liver cytosol proteins. In the in vitro experiments, higher serum radioactivity alone could not account for increases in the hepatic nuclear 125I in the hypothyroid rats because cytosol 125I (presumably in dynamic exchange with both blood and nuclei) was less. Consequently, cytosol T3-binding proteins may regulate the free T3 concentration in the cell and, thus influence the distribution of the hormone in other cellular compartments.

Animals↗

The effect of hypothyroidism on growth, serum growth hormone, the growth hormone-dependent somatomedin, insulin-like growth factor, and its carrier protein in rats.

To study the possible mechanisms involved in growth retardation associated with hypothyroidism, serum T4, GH, the GH-dependent somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP) were measured in hypothyroid rats and their age-matched controls. Three groups of rats were studied: infant, immature, and adult. Marked hypothyroidism (serum T4, less than 1 microgram/dl) was produced in experimental animals by providing them with drinking water containing 0.05% propylthiouracil. Infant and immature hypothyroid rats weighed markedly less than normal controls and had significantly reduced serum levels of GH, IGF, and CP. Normal adult rats, treated with propylthiouracil for 60 days, also weighed considerably less than control animals and exhibited a significant drop in serum GH, IGF, and CP during this period. The administration of bovine GH to hypothyroid adult rats for 7 days did not restore either IGF or CP levels to normal, indicating that their decrease in serum was, in part, a direct result of hypothyroidism per se. These results indicate that serum levels of GH, IGF, and CP are at least partly under thyroid hormone control. Furthermore, these studies suggest that the growth retardation associated with hypothyroidism may be mediated through somatomedin activity.

Aging↗