Modulation of rat liver mitochondrial antioxidant defence system by thyroid hormone

In the present study the effect of thyroid hormone (T(3)) on oxidative stress parameters of mitochondria of rat liver is reported. Hypothyroidism is induced in male adult rats by giving 0.05% propylthiouracil (PTU) in drinking water for 30 days and in order to know the effect of thyroid hormone, PTU-treated rats were injected with 20 microg T(3)/100 g body weight/day for 3 days. The results of the present study indicate that administration of T(3) to hypothyroid (PTU-treated) rats resulted in significant augmentation of oxidative stress parameters such as thiobarbituric acid reactive substances and protein carbonyl content of mitochondria in comparison to its control and euthyroid rats. The hydrogen peroxide content of the mitochondria of liver increased in hypothyroid rats and was brought to a normal level by T(3) treatment. Induction of hypothyroidism by PTU treatment to rats also resulted in the augmentation of total and CN-sensitive superoxide dismutase (SOD) activities of the mitochondria, which was reduced when hypothyroid rats were challenged with T(3). Although CN-resistant SOD activity of the mitochondria remained unaltered in response to hypothyroidism induced by PTU treatment, its activity decreased when hypothyroid rats were injected with T(3). The catalase activity of the mitochondria decreased significantly by PTU treatment and was restored to normal when PTU-treated rats were given T(3). Total, Se-independent and Se-dependent glutathione peroxidase activities of the mitochondria were increased following PTU treatment and reduced when T(3) was administered to PTU-treated rats. The reduced and oxidised glutathione contents of the mitochondria of liver increased significantly in hypothyroid rats and their level was restored to normal when hypothyroid rats were injected with T(3). The results of the present study suggest that the mitochondrial antioxidant defence system is considerably influenced by the thyroid states of the body.     

Activities of glycolytic enzymes in some brain areas of thyroidectomized rats and their response to replacement therapy

Glycolytic metabolism has been assessed by studying a set of key enzymes, in anterior cortex, amygdala, hypothalamus septum and hippocampus, in thyroidectomized rats. The reversibility of the changes induced by the thyroidectomy has been assessed by replacement therapy. In thyroidectomized rats the hexokinase activity was significantly decreased in anterior cortex and hypothalamus. The increase in phosphofructokinase and pyruvate kinase activity was probably due to an increase in cellular energy requirements. Hexokinase activity was best restored by treatment with L-thyroxine (T4) or T4+ propylthiouracil (PTU). The low response of pyruvate kinase activity in all treated animals could suggest that this metabolic step is the least reversible.     

Lipid and carbohydrate metabolism in euthyroid and hypothyroid chick embryo (Gallus domesticus).

1. The effect of propylthiouracil (PTU)-induced hypothyroidism on carbohydrate and lipid metabolism was studied in the chick embryo. 2. A single dose of PTU (250 micrograms/embryo) was administered on day 11 and embryos sacrificed on day 20 of incubation. 3. Thyroid glands were significantly enlarged (6 fold) by PTU administration. 4. Increased thyroid weight was associated with growth retardation and decreased plasma thyroxine levels. 5. Plasma glucose level was lower and phospholipids were significantly higher in the hypothyroid embryo. 6. Liver lipid concentrations in the control and hypothyroid embryos were not different but were significantly higher in both groups when compared to previously reported values in the young chick. 7. In contrast to PTU treatment after hatching, liver glycogen levels were not increased in the hypothyroid chick embryo. This was attributed to the high lipid nutrient condition of the chick embryo since a high lipid diet in the young chick decreased hepatic glycogen accumulation significantly.     

Study of the factors influencing cardiac growth. I. Comparison of cardiomegaly induced by isoproterenol in euthyroid and thyroidectomized rats

The purpose of the present work was to study the cardiac growth-stimulating effect of IPR in hypothyroid animals, in which the in vitro sensitivity of the myocardium to beta-adrenergic agonists is significantly decreased. To determine the degree of myocardial enlargement, wet and dry ventricle weight and myocardial RNA, DNA and protein were measured. IPR administered to euthyroid rats in a dosage of 5 mg/kg/day for 4 days induced cardiomegaly. In thyroidectomized rats, a consistent depression of IPR-induced cardiomegaly was observed. This phenomenon appears to be in accordance with earlier observations showing a marked decrease in maximal beta-receptor level of ventricular membranes after thyroidectomy or PTU treatment.     

Thyroid Hormone Influences Antioxidant Defense System in Adult Rat Brain

The objective of the current study was to find out whether thyroid hormone influences antioxidant defense parameters of rat brain. Several oxidative stress and antioxidant defense parameters of mitochondrial (MF) and post-mitochondrial (PMF) fractions of cerebral cortex (CC) of adult rats were compared among euthyroid (control), hypothyroid [6-n-propylthiouracil (PTU)-challenged], and hyperthyroid (T3-treatment to PTU-challenged rats) states. Oxidative stress parameters, such as thiobarbituric acid-reactive substances (TBA-RS) and protein carbonyl content (PC), in MF declined following PTU challenge in comparison to euthyroid rats. On the other hand, when PTU-challenged rats were treated with T3, a significant increase in the level of oxidative stress parameters in MF was recorded. Hydrogen peroxide content of MF as well as PMF of CC was elevated by PTU-challenge and brought to normal level by subsequent treatment of T3. Although mitochondrial glutathione (reduced or oxidized) status did not change following PTU challenge, a significant reduction in oxidized glutathione (GSSG) level was noticed in PMF following the treatment. T3 administration to PTU-challenged rats had no effect on mitochondrial glutathione status. Total and CN-resistant superoxide dismutase (SOD) activities in MF of CC augmented following PTU challenge. CN-resistant SOD activity did not change when PTU-challenged rats were treated with T3. Although CN-sensitive SOD activity of PMF remained unaltered in response to PTU challenge, its activity increased when PTU-challenged rats were treated with T3. Catalase activity in PMF of CC of PTU-challenged rats increased, whereas the activity was decreased when hypothyroid rats were treated with T3. Similarly, total and Se-dependent glutathione peroxidase (GPx) activities of MF increased following PTU challenge and reduced following administration of T3. Se-independent GPx activity of MF and PMF and glutathione reductase activity of PMF decreased following PTU challenge and did not change further when rats were treated with T3. On the other hand, glutathione S-transferase activity of MF and PMF of CC did not change following PTU challenge but decreased below detectable level following T3 treatment. Results of the current investigation suggest that antioxidant defense parameters of adult rat brain are considerably influenced by thyroid states of the body.     

Influence of chronic treatment with iopanoic acid on thyroxine metabolism in the newborn rat

Parameters of the peripheral metabolism of thyroxine (T4) were studied in the early postnatal period. Iopanoic acid (IOP) was administered to newborn rats that were either euthyroid or rendered hypothyroid in utero by propylthiouracil (PTU) or methimazole (MMI) administration to the mothers during gestation and injected with thyroxine on postnatal days 6 and 7. In euthyroid newborn rats given IOP from postnatal day 6, the plasma T4 level increased (+50%) while the plasma 3,3',5'-triiodothyronine (T3) level slightly decreased (-18%). Peripheral deiodination of T4 was also reduced (about -50%) as estimated by thyroid 125I uptake after injection of 125I (3'-5')L-T4. In the newborn rats rendered hypothyroid in utero and given T4 on postnatal days 6 and 7, IOP treatment started on day 4 decreased the constant rate of elimination (-50%), the distribution volume (-43%) and the metabolic clearance (-74%) of plasma T4. The results were the same in PTU- and MMI-treated newborn rats. The differences between newborn and adult animals under IOP treatment are discussed.     

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

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

Impaired growth hormone secretion in neonatal hypothyroid rats: hypothalamic versus pituitary component

In 10-day-old rats made hypothyroid by giving dams propylthiouracil (PTU) in the drinking water since the day of parturition, simultaneous radioimmunoassay (RIA) determinations of basal and stimulated growth hormone (GH) secretion, hypothalamic GH-releasing hormone (GHRH)-like immunoreactivity (LI) content, immunocytochemical localization of somatotrophs, and hypothalamic GHRH-LI-positive structures were performed. The frequency of somatotrophs was also determined. One-day-old hypothyroid rats, whose mothers had been given PTU since the 14th day of pregnancy, were also used for comparison. In 10-day-old hypothyroid rats, pituitary and plasma GH levels and the number of somatotrophs were considerably lower and plasma TSH levels were significantly higher than those in age-matched control rats; however, GHRH-LI titers in the mediobasal hypothalamus and the morphology of GHRH-LI-positive structures were unaltered. In 1-day-old rats the only alteration present, in addition to elevated plasma TSH levels, was a clear-cut decrease in plasma GH levels. An acute challenge with GHRH (20 ng/100 g body wt, sc) or clonidine (15 micrograms/100 g body wt, sc) induced a clear-cut rise in plasma GH levels 15 min postinjection in 10-day-old control rats but failed to do so in age-matched hypothyroid rats. Both compounds failed to rise plasma GH in both hypothyroid and control 1-day-old rats. Taken together these data indicate that in neonatal and infant rats deprivation of thyroid hormones acts primarily to depress pituitary somatotroph function and that possible changes in GHRH-secreting structures represent a later postnatal event.     

Suckling ability and maternal prolactin levels in hypothyroid rats

Long-Evans rats and their offspring were made hypothyroid by addition of the antithyroid goitrogen 6-N-propylthiouracil (PTU) to the drinking water (0.1%) from the day of parturition. Serum concentrations of prolactin (PRL), thyroid-stimulating hormone (TSH) and thyroxine (T4) were determined by double radioimmunoassay (RIA). From the fifth postnatal day, body weight of PTU-treated pups was significantly lower than that of control rats, and a strikingly elevated serum TSH level and nondetectable amount of T4 were measured both in PTU-exposed mothers and their offspring at Day 10 postpartum. To test the youngs' suckling capability and the amount of maternal milk production, 10- and 15-day-old normal and PTU-treated pups were separated from their mothers for 4 hr in the morning and then reunited and allowed to suckle. Normal pups gained body weight at the end of both the first and second hour postreunion, while PTU pups gained only during the first hour and lost weight in the second hour of testing. When the pups were exchanged between normal and PTU mothers, opposite results were obtained, indicating that the reduced gain in hypothyroid rats was not due to impaired suckling capability, or insufficient sensory stimulation for milk secretion but to a decreased milk production of PTU mothers. In accordance with this, in lactating hypothyroid rats both the basal (presuckling) level and the suckling-induced rise of serum PRL were found significantly depressed.     

Activity of lipoprotein lipase in thyroidectomized rats

Total plasma postheparin lipolytic activity as well as lipoprotein lipase activity in plasma was higher after heparin injection in thyroidectomized rats than in controls. In contrast, the activity of liver lipase was lower in thyroidectomized rats. Adipose tissue from thyroidectomized rats contained more lipoprotein lipase activity than adipose tissue from controls as measured both in extracts of tissue homogenates and medium from in vitro incubations of tissue pieces. There were no differences between control and hypothyroid rats in the disappearance of intravenously injected 125I-labeled lipoprotein lipase, but when a low dose of heparin was injected before the labeled enzyme, the disappearance of 125I-labeled lipoprotein lipase was more retarded in thyroidectomized rats. The elimination of heparin itself was slightly retarded by thyroidectomy.     

Experimental hypothyroidism inhibits delta-aminolevulinate dehydratase activity in neonatal rat blood and liver

The aim of this study was to investigate the potential relationship between hypothyroidism and delta-aminolevulinate dehydratase (delta-ALA-D) activity in rat blood and liver. Experimental hypothyroidism was induced in weanling rats by exposing their mothers to propylthiouracil (PTU) diluted in tap water (0.05% w/ v), ad libitum, during the lactational period (PTU group). Control (euthyroid) group included weanling rats whose mothers received just tap water, ad libitum, during the lactational period. Reverted-hypothyroid group (PTU + 3,3',5-triiodo-L-thyronine [T(3)]) included weanling rats whose mothers were exposed to PTU similarly to those in the hypothyroid group, but pups received daily subcutaneous injections of T(3) (20 microg/kg, from Postnatal Days 2-20). After the treatment, serum T(3) levels were drastically decreased (around 70%) in the PTU group, and this phenomenon was almost reverted by exogenous T(3). PTU decreased blood delta-ALA-D activity by 75%, and T(3) treatment prevented such phenomena. Erythrocytes and hemoglobin levels were increased by 10% in PTU-treated animals and higher increments (around 25%) were observed in these parameters when exogenous T(3) was coadministered. Dithiothreitol did not change blood delta-ALA-D activity of PTU-exposed animals when present in the reaction medium, suggesting no involvement of the enzyme's essential thiol groups in PTU-induced delta-ALA-D inhibition. PTU did not affect blood delta-ALA-D activity in vitro. These results are the first to show a correlation between hypothyroidism and decreased delta-ALA-D activity and point to this enzyme as a potential molecule involved with hypothyroidism-related hematological changes.     

Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats

Hyperalphalipoproteinemia, characterized by increased plasma concentrations of apoA-I and of HDL lipid and protein, was observed in rats treated with triiodothyronine (T(3)) for 7 days. The increase in the plasma HDL apoproteins was general for apoC, apoE plus A-IV, and apoA-I, as determined by isoelectric focusing. Hypotriglyceridemia, characterized by decreased concentrations of VLDL and apoB, was also observed in the hyperthyroid state. Although in the mildly hypothyroid animals (propylthiouracil-treated), hepatic metabolism of free fatty acid is shifted toward esterification to triglyceride and VLDL formation, as we reported previously, plasma HDL and apoA-I concentrations were not different from control plasma values, while the d 1.006-1.063 g/ml (IDL + LDL) lipoprotein fraction tended to be increased. In general, the proportion of apoE in the (IDL + LDL) fraction of the hypothyroid rat was greater than in controls and hyperthyroid animals, while the proportion of apoE tended to be lower in VLDL from both hypo- and hyperthyroid rats than in VLDL from controls. An enhanced release of apoA-I by perfused livers isolated from rats treated with T(3) was also observed; this enhanced output of apoA-I may explain, in part, the hyperalphalipoproteinemia observed in these rats. The depressed net output of apoA-I in vitro by perfused livers from rats treated with propylthiouracil (PTU) was not expressed in a statistically significant diminished plasma concentration of HDL or apoA-I in the intact animals. Treatment with T(3) also resulted in modification of the content of essential fatty acids in various lipid classes. Linoleic acid residues were significantly reduced and arachidonic acid content was increased in plasma phospholipids and esterified cholesterol in T(3)-treated rats. However, the relative fatty acid composition of unesterified fatty acids and triglyceride fatty acids was not altered by T(3) treatment. PTU treatment had no effect on fatty acid distribution in any of the plasma lipids. Secretion of biliary lipids was increased in perfused livers from T(3)-treated rats, while treatment with PTU did not affect release of lipids in the bile. These observations suggest a regulatory role for thyroid hormones that determine concentration and composition of plasma HDL and other lipoproteins.-Wilcox, H. G., W. G. Keyes, T. A. Hale, R. Frank, D. W. Morgan, and M. Heimberg. Effects of triiodothyronine and propylthiouracil on plasma lipoproteins in male rats.     

Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate

S-adenosylmethionine, formed by the adenylation of methionine via S-adenosylmethionine synthase, is the methyl donor in virtually all known biological methylations. These methylation reactions produce a methylated substrate and S-adenosylhomocysteine, which is subsequently metabolized to homocysteine. The methylation of guanidinoacetate to form creatine consumes more methyl groups than all other methylation reactions combined. Therefore, we examined the effects of increased or decreased methyl demand by these physiological substrates on plasma homocysteine by feeding rats guanidinoacetate- or creatine-supplemented diets for 2 wk. Plasma homocysteine was significantly increased (~50%) in rats maintained on guanidinoacetate-supplemented diets, whereas rats maintained on creatine-supplemented diets exhibited a significantly lower (~25%) plasma homocysteine level. Plasma creatine and muscle total creatine were significantly increased in rats fed the creatine-supplemented or guanidinoacetate-supplemented diets. The activity of kidney L-arginine:glycine amidinotransferase, the enzyme catalyzing the synthesis of guanidinoacetate, was significantly decreased in both supplementation groups. To examine the role of the liver in mediating these changes in plasma homocysteine, isolated rat hepatocytes were incubated with methionine in the presence and absence of guanidinoacetate and creatine, and homocysteine export was measured. Homocysteine export was significantly increased in the presence of guanidinoacetate. Creatine, however, was without effect. These results suggest that homocysteine metabolism is sensitive to methylation demand imposed by physiological substrates.     

The effects of hypothyroidism on nerve growth factor and norepinephrine concentrations in weight-bearing and non-weight-bearing bones of rats

Thyroid hormones affect bone remodelling directly via receptors in osteoblasts. Previously, however, we have shown that the euthyroid and hyperthyroid states significantly influence the concentrations of both nerve growth factor (NGF) and norepinephrine (NE) in particular bones. Both NGF and NE directly affect bone metabolism and therefore it is possible that thyroid hormone action on bone may also be indirect via its actions on these two neural-related substances. In light of previous studies, the current experiments aimed to investigate whether hypothyroidism also influenced NGF and NE concentrations in weight-bearing and non-weight-bearing rat bones. Hypothyroidism was induced by oral ingestion of propylthiouricil (PTU; 3.8+/-0.2 mg/kg/day) for 21 days. Histological examination on distal femurs and microparticle enzyme immunoassayed plasma concentrations of T3 and T4 verified the hypothyroid status in treated rats. NGF concentrations were assayed via enzyme-linked immunosorbent assay (ELISA) and NE concentrations were measured via high performance liquid chromatography (HPLC) with electrochemical detection (ECD). NGF concentrations: Femoral NGF concentrations were 207% higher in hypothyroid rats (674.9+/-88.3 ng/g) than in euthyroid rats (326.7+/-63.6 ng/g; p < 0.05). Rib NGF concentrations in hypothyroid rats (3125.1+/-450.2 ng/g) were increased by 342% compared to euthyroid ribs (914.5+/-128.6 ng/g; p < 0.01). Rib NGF concentrations in hypothyroid rats were 463% higher than in femurs of hypothyroid rats (p < 0.001). NE concentrations: In hypothyroid rats, NE concentrations were reduced by approximately 50% in both ribs (38.9 ng/g) and calvaria (41.5 ng/g) compared to euthyroid rats (74.7 ng/g and 87.4 ng/g respectively; p < 0.05 for both). These findings on hypothyroid rats may be taken in conjunction with our companion work on hyperthyroid rats (Yao et al., 2002, JMNI 2:327-334) and put in context with other reports, to indicate that (i) there are several sources of NGF in bone, some of which are stimulated by hypothyroidism and others by hyperthyroidism and (ii) the concentrations of both NGF and NE in bone are sensitive to weight-bearing and thyroid hormone status.     

Reduced Axoplasmic Somatostatin Transport in Hypothyroid Rats

The effect of hypothyroidism on neuronal function was studied by measuring axoplasmic transport of immunoreactive somatostatin in rat sciatic nerve by the ligation technique. Accumulation of immunoreactive somatostatin proximal to a ligature was linear up to 8 h in normal, in thyroidectomized, and in parathyroidectomized rats. The transport rate was decreased by 38% in thyroidectomized rats as compared to normal rats and was unchanged in parathyroidectomized rats. Sciatic nerve content of somatostatin in hypothyroid rats did not differ from control. Reduced accumulation of immunoreactive somatostatin in hypothyroid rats may be due to a decrease in somatostatin synthesis or in axoplasmic transport, or to an increase in the degradation rate of the peptide.     

应激对同型半胱氨酸代谢的负性调节

基于应激对高同型半胱氨酸血症具有诱导作用,本文探索了应激致同型半胱氨酸(homocysteine,HCY)代谢变化的关键环节,并初步揭示了该作用的意义。以束缚应激法建立大鼠应激模型,采用高压液相-荧光检测法测定血浆HCY水平,用放射性酶学法检测不同组织中胱硫醚β合成酶(cystathionine beta-synthase,CBS)活性的变化,以及RT-PCR法和Northern blot法检测CBS mRNA水平的变化。结果可见,束缚应激可导致大鼠高同型半胱氨酸血症的发生;CBS在肝脏具有最强的代谢活性,肾脏其次,而心脏和血液中活性极低;应激大鼠肝脏CBS活性和mRNA水平均显著降低(P<0.05),应激3周时分别为对照组的70.6％±5.9％和55.9％±4.3％。以上研究结果表明,应激对HCY转硫代谢途径存在负性调节作用,其对肝脏CBS基因转录水平的调控是应激所致高同型半胱氨酸血症发生的重要诱因;肝脏是应激对HCY代谢调节的主要场所。     

The influence of thyroid hormones on homocysteine and atherosclerotic vascular disease

Several reports have appeared in the literature proving that hypothyroidism is associated with increased risk for cardiovascular disease, especially coronary heart disease. This increased risk for premature atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. Hypothyroid patients have increased diastolic blood pressure (as a result of increased systemic vascular resistance), altered lipid profile (elevated levels of total cholesterol, LDL-cholesterol and apolipoprotein B). More recently homocysteine, C-reactive protein, increased arterial stiffness, endothelial dysfunction and altered coagulation parameters have been recognized as a "new" risk factors for atherosclerosis in patients with thyroid hormone deficiency. The plasma total homocysteine concentration, an independent risk factor for atherosclerosis, is moderately elevated in overtly hypothyroid patients and it decreases with thyroid replacement therapy. Several experimental study have shown that hypothyroidism affects folate metabolism and the enzymes involved in the remetylation pathway of homocysteine (particularly 5,10-methylenotetrahydrofolate reductase - MTHFR). In hypothyroid condition the hepatic activity of flavoenzyme - MTHFR, is decreased. Thyroid hormone may affect the availability of FMN and FAD - necessary for stabilizing MTHFR. An impairment of enzyme involved in transsulfuration pathway is suggested. The increased serum creatinine level in hypothyroidism probably reflects a reduced glomerular filtration rate, which is linked to impaired renal homocysteine clearance and hyperhomocysteinemia.     

Effects of thyroid hormone on Leydig cell regeneration in the adult rat following ethane dimethane sulphonate treatment

We tested the effects of thyroid hormone on Leydig cell (LC) regeneration in the adult rat testis after ethane dimethyl sulphonate (EDS) treatment. Ninety-day-old, thyroid-intact (n = 96) and thyroidectomized (n = 5) male Sprague-Dawley rats were injected intraperitoneally (single injection) with EDS (75 mg/kg) to destroy LC. Thyroid-intact, EDS-treated rats were equally divided into three groups (n = 32 per group) and treated as follows: control (saline-injected), hypothyroid (provided 0.1% propyl thiouracil in drinking water), and hyperthyroid (received daily subcutaneous injections of tri-iodothyronine, 100 microg/kg). Testing was done at Days 2, 7, 14, and 21 for thyroid-intact rats and at Day 21 for thyroidectomized rats after the EDS treatment. Leydig cells were absent in control and hyperthyroid rats at Days 2, 7, and 14; in hypothyroid rats at all ages; and in thyroidectomized rats at Day 21. The LC number per testis in hyperthyroid rats was twice as those of controls at Day 21. 3beta-Hydroxysteroid dehydrogenase (LC marker) immunocytochemistry results agreed with these findings. Mesenchymal cell number per testis was similar in the three treatment groups of thyroid-intact rats on Days 2 and 7, but it was different on Days 14 and 21. The highest number was in the hypothyroid rats, and the lowest was in the hyperthyroid rats. Serum testosterone levels could be measured in control rats only on Day 21, were undetectable in hypothyroid rats at all stages, and were detected in hyperthyroid rats on Days 14 and 21. These levels in hyperthyroid rats were twofold greater than those of controls on Day 21. Serum androstenedione levels could be measured only in the hyperthyroid rats on Day 21. Testosterone and androstenedione levels in the incubation media showed similar patterns to those in serum, but with larger values. These findings indicate that hypothyroidism inhibits LC regeneration and hyperthyroidism results in accelerated differentiation of more mesenchymal cells into LC following the EDS treatment. The observations of the EDS-treated, thyroidectomized rats confirmed that the findings in hypothyroid rats were, indeed, due to the deficiency of thyroid hormone.     

Influence of thyroid states on stress gastric ulcer formation

Thyroid hormones exert a critical developmental and regulatory role on the morphology and biochemistry of gastrointestinal mucosal cells. However, the relationship between thyroid function and stress gastric lesion formation remains undetermined. This study was designed to test the hypothesis that thyroid states may affect the acute development of gastric lesions induced by cold-restraint stress. Normal (euthyroid), hyperthyroid (200 micrograms of T4 i.p. x 7 days) and hypothyroid (thyroidectomized) rats were used. Gastric lesion incidence and severity was significantly (p less than 0.05) increased in hypothyroid rats, whereas in contrast hyperthyroid rats developed significantly less gastric lesions. As anticipated, plasma levels of thyroxin (T4) were significantly (p less than 0.01) elevated in hyperthyroid rats, and undetectable in hypothyroid rats. Acute pretreatment with i.p. cimetidine (100 mg/Kg), but not T4 (200 micrograms/Kg) 1 h prior to stress completely prevented gastric lesions formation in hypothyroid rats. Finally, binding of 3H-dihydroalprenolol to beta-adrenergic receptors on brain membranes prepared from frontal cortex was reduced by 20% in hypothyroid rats after 3 h of stress. These and other data contained herein suggest that thyroid hormones contribute to modulate the responsiveness of the gastric mucosa to stress. The increased rate of ulcerogenesis observed in hypothyroid rats appears to be mediated by gastric acid secretion. The central mechanism of this response may involve decreased brain nonadrenergic receptor function.