The effect of elevated levels of thyroxine on the aerobic capacity of locomotor muscles of the tufted duck,Aythya fuligula

Following extended periods of relative inactivity, or prior to migration, birds are able to increase the aerobic capacity of their locomotory muscles. Thyroid hormones may influence this process. A preliminary study was undertaken to assess the ability of elevated levels of thyroxine to increase the aerobic capacity of the locomotory and cardiac muscles of adult tufted ducks. Administration of thyroxine in the food for 8 weeks had little effect on body mass or on the masses of the pectoralis, semitendinosus and iliofibularis muscles, although there were increases in resting oxygen consumption and in the mass of the cardiac ventricles. The maximum activity of the aerobic enzyme, citrate synthase, was significantly greater in the left ventricle, liver, and iliofibularis muscles (P<0.005) of treated birds. However, while there was clearly no difference in activity in the semimembranosus leg muscle, that of the pectoralis was not quite significant (P=0.078). It is concluded that addition of supra-physiological levels of exogenous thyroxine may induce a differential increase in the maximum activity of citrate synthase in the locomotor muscles of the tufted duck, which is correlated with the fibre type composition of these muscles. These results are consistent with those found in studies on rats, with slow oxidative fibres being the most sensitive, and fast glycolytic fibres the least sensitive, to thyroxine treatment.Abbreviations BM body mass - CS citrate synthase - CYTOX cytochrome c oxidase - FG last glycolytic - FOG fast oxydative glycolytic - VO₂ oxygen consumption - SO slow oxidative - T₄ thyroxine - T₃ triiodothyronine     

Effects of thyroxine on the synthesis of folate coenzymes in rat liver

1. The effects of thyroidectomy and of ;acute' and ;chronic' administration of thyroxine on the synthesis of folate coenzymes were studied by determining the liver contents of folate active derivatives and the enzymic activities involved in their biosynthesis. The effect of thyroxine on the same enzymes in vitro was also studied. 2. In thyroidectomized rats the liver contents of folate coenzymes did not change except for a slight decrease in the contents of 5-formyltetrahydrofolate and tetrahydrofolate compared with those in control rats. 3. In the same animals serine hydroxymethyltransferase and formyltetrahydrofolate synthetase activities decreased markedly. 4. The ;chronic' administration of thyroxine to thyroidectomized rats caused more evident variations in the liver contents of folate coenzymes and in particular a decrease in the contents of 5-formyltetrahydrofolate, tetrahydrofolate, 5(or 10)-formyl derivatives of tetrahydropteroylpolyglutamate and of 5(or 10)-formyl derivatives of pteroylpolyglutamate. 5. The enzymic activities did not show significant variations. 6. The ;acute' administration of thyroxine caused changes in the liver contents of some folate derivatives such as 10-formyldihydrofolate, 10-formylfolate, tetrahydrofolate and the 10-formyl derivative of dihydropteroylpolyglutamate. In these animals also the enzymic activities were unchanged. 7. No effect of thyroxine on enzymic activities in vitro was observed.     

Regulation of NAD- and NADP-linked isocitrate dehydrogenase by thyroxine in the brain and liver of female rats of various ages

The specific activity of NAD- and NADP-linked isocitrate dehydrogenase and their regulation by thyroxine in the brain and liver of female rats of various ages were studied with the ultimate goal of better understanding the decreased physiological functioning of the brain and liver during old age. Both thyroidectomy and thyroxine treatment have differential age-dependent effects on the activities of these enzymes in both tissues. The activity of NAD-ICDH decreases whereas both cytoplasmic and mitochondrial NADP-ICDH increase simultaneously following thyroidectomy. Thyroxine administration induces NAD-ICDH and depresses NADP-ICDH. The degree of induction and/or repression is lowest in old rats. These effects of thyroxine are actinomycin D sensitive in both the tissues of rats.     

Effects of thyroxine and cold exposure on hypothalamic TRH levels in rats with various pituitary-thyroid states.

The hypothalamic content and concentration of thyrotropin-releasing hormone (TRH) were determined by radioimmunoassay in normal, thyroidectomized, hypophysectomized and cold-exposed rats with or without thyroxine. In normal animals, the single administration of thyroxine (1,5 and 20 microgram/100 g B.W.) altered neither the content nor the concentration of TRH in the hypothalamus. However, seven days' administration of this hormone resulted in the dose-dependent increase in the hypothalamic TRH levels. In thyroidectomized rats the hypothalamic TRH levels were slightly reduced in spite of the marked increase of plasma TSH levels and decrease of pituitary TSH levels. In the animals given thyroxine (10 microgram/100 g B.W.) for 7 days in addition to thyroidectomy, however, the TRH levels exceeded that in the animals which underwent throidectomy alone. The hypothalamic TRH levels were markedly reduced in hypophysectomized rats. Conversely, in hypophysectomized rats given 7 days' thyroxine (1 and 5 microgram/100 g B.W.), the levels were increased dose-dependently. In cold-exposed rats, the plasma TSH levels roughly doubled, but the TRH levels remained unchanged. These findings strongly suggest that the feedback site of thyroxine extends not only to the pituitary gland but also to the hypothalamus, and that thyroxine has an increasing effect of the hypothalamic TRH level, though the mechanism(s) remain to be clarified.     

Brain levels and turnover rates of presumptive neurotransmitters as influenced by administration and withdrawal of ethanol in mice

—Effects of acute or chronic administration of ethanol and its withdrawl on the steady-state levels and turnover rates of certain neurotransmitters have been investigated in mice. The influence of long-term administration of ethanol on the activities of enzymes involved in the metabolism of these transmitters has also been studied. Acute administration of ethanol or acetaldehyde or chronic administration of ethanol resulted in a decrease in the cerebral contents of acetylcholine, acetylCoA and CoA. Brain levels of 5-hydroxytryptamine, norepinephrine and choline remained unchanged after acute administration of ethanol. However, chronic administration of ethanol resulted in a decrease in the norepinephrine content without significantly affecting 5-hydroxytryptamine or choline contents. Cerebral levels of γ-aminobutyric acid increased with both acute or chronic administration of ethanol. The total incorporation of [³H]choline into acetylcholine in brain was depressed upon acute administration of ethanol. After withdrawal of ethanol for one day cerebral levels of norepinephrine returned to normal; however, γ-aminobutyric acid and acetylcholine returned to normal levels at 2 and 4 days after ethanol withdrawal, respectively. Pretreatment of mice with pyrazole, an inhibitor of alcohol dehydrogenase, prevented the ethanol-induced decrease in cerebral acetylcholine levels. The activities of cerebral choline acetyltransferase and glutamic decarboxylase were decreased after 2 weeks of chronic ethanol administration. However, the activities of acetyl cholinesterase and GABA-transaminase remained unaffected after 2 weeks of ethanol treatment     

Effects of triiodothyronine on turnover rate and metabolizing enzymes for thyroxine in thyroidectomized rats

Aim

Previous studies in rats have indicated that surgical thyroidectomy represses turnover of serum thyroxine (T₄). However, the mechanism of this process has not been identified. To clarify the mechanism, we studied adaptive variation of metabolic enzymes involved in T₄ turnover.

Main methods

We compared serum T₄ turnover rates in thyroidectomized (Tx) rats with or without infusion of active thyroid hormone, triiodothyronine (T₃). Furthermore, the levels of mRNA expression and activity of the metabolizing enzymes, deiodinase type 1 (D1), type 2 (D2), uridine diphosphate-glucuronosyltransferase (UGT), and sulfotransferase were also compared in several tissues with or without T₃ infusion.

Key findings

After the T₃ infusion, the turnover rate of serum T₄ in Tx rats returned to normal. Although mRNA expression and activity of D1 decreased significantly in both liver and kidneys without T₃ infusion, D2 expression and activity increased markedly in the brain, brown adipose tissue, and skeletal muscle. Surprisingly, hepatic UGT mRNA expression and activity in Tx rats increased significantly in comparison with normal rats, and returned to normal after T₃ infusion.

Significance

This study suggests that repression of the disappearance of serum T₄ in rats after Tx is a homeostatic response to decreased serum T₃ concentrations. Additionally, T₄ glucuronide is a storage form of T₄, but may also have biological significance. These results suggest strongly that repression of deiodination of T₄ by D1 in the liver and kidneys plays a major role in thyroid hormone homeostasis in Tx rats, and that hepatic UGT also plays a key role in this mechanism.     

Sensitivity of the Bothrops jararaca snake uterus to oxytocin and acetylcholine

The influence of hormones on the uterine smooth muscle sensitivity has been demonstrated in mammals; however in nonmammalian species much remains to be clarified. This study investigated the sensitivity of the snake (Bothrops jararaca) uterus to oxytocin and acetylcholine. The snakes were divided into three experimental groups: snakes with uterine segments weighing ≤20.00 mg (A), snakes with uterine segments weighing between 20.01 and 35.00 mg (B) and snakes with uterine segments weighing ≥35.01 mg (C). The histomorphometric analysis of the uterus showed an increase in the smooth muscle layer thickness in groups B and C, when compared with group A, suggesting different hormonal conditions of the animals. Cumulative concentration-effect curves to oxytocin and acetylcholine were obtained in uteri of the three experimental groups and the pD₂ values determined. The sensitivity of the snake uterus to oxytocin increased in groups B and C (concentration-effect curves shifted to the left and pD₂ values increased) when compared with group A. The concentration-effect curves to acetylcholine were biphasic and shifted to the left, suggesting two binding sites (low and high affinity binding sites) in snake uteri of groups B and C. These results suggest that sex steroids may modulate the sensitivity of the snake uterus to oxytocin and acetylcholine.     

Studies on Histaminergic Compounds,Part VII.1 Histamine H2-Binding on Guinea-Pig Cerebral Cortex Compared to Histamine (ANT)Agonism

Abstract

The pK_D values of series of H₂-active compounds, obtained from displacement curves of ³H-tiotidine from a guinea-pig cerebral cortex homogenate were compared with the pA₂/pD₂ values of these compounds on the right atrium of the same animal species. A good correlation was found between the cortex pK_D value and the pharmacological activity on the right atrium, especially with the antagonists, the partial agonists and the agonistic impromidine analogues (guanidines). The poor correlation between cortex pK_D and atrium pD₂ of some other agonists (the amines) might be explained by the presence of spare receptors for these compounds. The different number of spare receptors for the guanidines and the amines might be explained by the differences in base strength of these compounds.     

Effect of thyroxine administration to the mother on postnatal radioiodine uptake by the thyroid of partially thyroidectomized rats.

The experiment was carried out on 35 litters of infant rats aged 4-17 days. The animals in each litter were always divided into two groups: control (sham operation) and experimental (hemithyroidectomy). Starting with the day on which the young were operated on, the mothers received daily subcutaneous injections of either saline or of thyroxine in doses of 50, 100 or 200 mug. At the end of the experiment, the young were injected intraperitoneally with 1 muCi 131I. One hour later they were decapitated and the radioactivity in their thyroid was expressed as the percentage of the administered dose per mg thyroid. The following age groups were used, according to the interval between thyroidectomy and decapitation: 4 to 8, 9 to 13, 13 to 15 and 15 to 17 days. 131I uptake by the residue of the thyroid in partially thyroidectomized animals was always compared with the values in the animals from the same litter subjected to sham operation. The results showed that partial thyroidectomy significantly stimulated 131I uptake in all age groups in which the mother was only given saline. In the 4- to 8-day-old group, the administration of 50 or 100 mug thyroxine to the mother inhibited this compensatory increase. In the 9- to 13-day-old group, inhibition occurred only after a dose of 100 mug thyroxine. In animals with an interval from the 13th to the 15th days old the dose of thyroxine administered to the mother had to be raised to 200 mug/day to achieve an inhibitory effect. In the last group (interval 15th to 17th day), not even administration of the maximum thyroxine dose to the mother from the 13th postnatal day succeeded in inhibiting the significant increase in 131I uptake. These results show that thyroxine administered to lactating female rats can be transmitted via the milk to the organism of the young in amounts which can be demonstrated in a physiological tests.     

Purinoreceptors are involved in the control of acute morphine withdrawal.

The effects exerted by P1 and P2 purinoceptor agonists and antagonists on the acute opiate withdrawal induced by morphine were investigated in vitro. Following a 4 min in vitro exposure to morphine, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. The P1 purinoceptor agonist, adenosine, was able dose-dependently to reduce morphine withdrawal whereas alpha,beta-methylene ATP (APCPP), a P2 purinoceptor agonist, increased morphine withdrawal. Caffeine, a P1 purinoceptor antagonist, was able significantly and in a concentration dependent manner to increase morphine withdrawal whereas quinidine, a P2 receptor antagonist, reduced it. The results of our experiments indicate that both P1 and P2 purinoceptor agonists and antagonists are able to influence opiate withdrawal in vitro, suggesting an important functional interaction between the purinergic system and opioid withdrawal.     

Effect on wool growth of thyroxine replacement in thyroidectomized merino rams

The effect on wool growth of thyroidectomy with subsequent thyroxine replacement at subnormal and supranormal levels has been investigated in Merino rams fed a restricted basal diet. Thyroidectomy without thyroxine replacement caused a greater than 60% reduction in wool growth. Provision of 30% of normal plasma thyroxine concentrations was sufficient to return wool growth to normal. Similarly, complete replacement of plasma thyroxine levels gave normal wool growth while increasing thyroxine concentrations to three times normal increased wool growth to levels slightly above normal. These results provide a possible explanation for the inability of other workers to correlate seasonal thyroxine patterns and annual wool growth variations.     

Modification of the effects of naloxone in morphine-dependent mice

Mice were rendered dependent on morphine by mixing morphine with their food (2 mg/g) for three days. Increasing doses of naloxone precipitated dose-dependent withdrawal reactions such as weight loss and jumping. These withdrawal reactions were antagonized by morphine pretreatment. Effects of morphine, such as increased locomotor activity, inhibition of intestinal transport, and analgesia were antagonized by naloxone in both non-dependent and dependent subjects. The antagonist actions of naloxone were increased in dependent subjects; lower doses of naloxone were sufficient to antagonize effects of morphine. The present results confirm earlier studies indicating that precipitation of withdrawal can be antagonized by morphine pretreatment suggesting that withdrawal reactions are due to actions of naloxone at the same receptor at which opioid agonists act. The increased antagonist potency of naloxone in dependent subjects extends earlier results obtained with analgesic effects to several other agonist effects of morphine and is consistent with the interpretation that exposure to an opioid agonist induces a change in the conformation of opioid receptors.     

Metabolic responses of folic acid and related compounds to thyroxine in rats

This study deals with the effects of thyroidectomy and feeding thyroid powder on histidine and folic acid metabolism. Normal rats maintained on a soy protein diet, low in methionine but supplemented with vitamin B-12, oxidize approx. 10% of an injected dose of [2-¹⁴C]histidine in 3 h and excrete low levels of formiminoglutamic acid. Addition of methionine increases histidine oxidation to approx. 20%. The feeding of thyroid powder or the injection of high levels of thyroxine decreases histidine oxidation and increases formiminoglutamic acid excretion. Surgical thyroidectomy at weaning increases histidine oxidation to approx. 45% and, thus, resembles the effect of methionine in promoting histidine oxidation and decreasing formiminoglutamic acid excretion. The feeding of methionine to the thyroidectomized animal further increases histidine oxidation to 65%. The distribution of folate forms in the liver was determined by column chromatography following administration of a dose of tritiated folic acid. In the normal animal, tetrahydrofolate accounts for 38% of the total folate present. The feeding of methionine increases this to 48%, which is consistent with the observed increase in histidine metabolism. Thyroidectomy increases the percentage of tetrahydrofolate to 63% and the feeding of methionine further increases it to 68%. The percentage of tetrahydrofolate relative to total folate is in proportion to the observed rate of histidine metabolism. The action of thyroidectomy in increasing histidine oxidation may be accounted for by its effect in increasing the proportion of tetrahydrofolate.     

The effects of thyroxine and methimazole treatment on the synthesis of prostacyclin (PGI2) in the rat

The effects of thyroxine (T4) and methimazole administration on plasma prostacyclin (PGI₂) levels $\text{in vivo}$ and on PGI₂ release by aortic rings incubated $\text{in vitro}$ were investigated in rats. Male rats were given single injection of T4 (200 μg/100 g body wt) ip every 24 h for either 3, 7 or 14 days for hyperthyroid rats. For hypothyroid rats, a group of rats were given methimazole (0.01 % in drinking water) for 14 days. PGI₂ concentrations were determined in plasma and also in the medium in which aortic rings were incubated. PGI₂ was measured as 6-keto-PGF1α by RIA. Plasma PGI₂ levels in T₄-treated groups were found to be significantly higher than those of control animals. Aortic rings obtained from rats given single injection of T₄ for 7 and 14 days showed significant increases in release of PGI₂ into the incubation medium. In contrast, rats given methimazole for 14 days showed a significant decrease in the production of PGI₂ by aortic rings without any significant changes in plasma levels. Direct addition of T₄ into the incubation medium did not cause any significant changes in PGI₂ release by aortic rings obtained from control rats.These results suggest the regulatory role of thyroid hormone in PGI₂ synthesis $\text{in vivo}$.     

Cholinesterase inhibition by vecuronium and pancuronium in human airways

Vecuronium (100 ωM) but not pancuronium (100 ωM) increased the sensitivity of human isolated bronchial preparations (HBP) to exogenous acetylcholine (ACh). The pD₂ values obtained from concentration-dependent contractions were : control, 4.59±0.29 vecuronium, 5.86±0.31. Vecuronium or pancuronium (100 ωM) significantly decreased (50%) the neostigmine contractions in HBP. In addition, vecuronium was more potent than pancuronium in preventing exogenous ACh degradation. These results suggest that vecuronium and pancuronium may have physiological effects in human airways by inhibiting both the tissue cholinesterases and muscarinic (M₃) receptors.     

Hyperbaric Oxygen Attenuates Withdrawal Symptoms by Regulating Monoaminergic Neurotransmitters and NO Signaling Pathway at Nucleus Accumbens in Morphine-Dependent Rats

In this study, we examined whether hyperbaric oxygen (HBO₂) plays a detoxification role in withdrawal symptoms in a morphine-dependent rat model. The model was established through injections of morphine at increasing doses for 7 days. Withdrawal symptoms were induced by naloxone injection on the 8th day. The detoxification effect of HBO₂ was evaluated using the withdrawal symptom scores, biochemical indices and neurotransmitters. Compared with the model group, HBO₂ therapy significantly attenuated the withdrawal symptom scores, body weight loss and the level of norepinephrine level, whereas it increased the dopamine level and tyrosine hydroxylase expression in the nucleus accumbens. Moreover, HBO₂ therapy substantially alleviated the NO, NOS, cAMP, and cGMP levels. Our findings indicate that HBO₂ can effectively alleviate withdrawal symptoms induced by morphine dependence, and these effects may be attributed to the modulation of monoaminergic neurotransmitters and the suppression of the NO–cGMP signaling pathway.     

Effect of sulphur dioxide (SO2) and heat (35°C) stressors on plasma glucocorticoids and thyroxine levels in mice

The objective of this study was to determine acute effects of SO₂ and simultaneous exposure to SO₂ and heat on plasma glucocorticoids and thyroxine levels. Male mice (160) were divided into four treatment groups: control, heat, SO₂, SO₂ and heat. These groups were further divided into four time exposures, 30 min, 1, 12 and 24 hours. The effect of heat and SO₂ as compared to heat or SO₂ alone appears to be a more rapid and prolonged elevation of glucocorticoids, while thyroxine levels showed a more rapid depression compared to heat and a greater depression as compared to the SO₂ treatment group.     

Influence of adenosine analogs on morphine tolerance and dependence in mice

A number of adenosine agonists were investigated for possible actions on tolerance to morphine withdrawal in mice. The induction of tolerance to a sustained release preparation of morphine was assessed by measuring the analgesic effect induced by a test dose of the drug. The concomitant treatment with L- and D-phenylisopropyl adenosine, (L- and D-PIA), cyclopentyladenosine (CPA) or chloroadenosine (CADO) during the period of morphine absorption did not alter the induction of the process. In contrast cyclohexyladenosine (CHA) significantly decreased the intensity of tolerance. The administration of naloxone 30 hrs, after the priming dose of morphine induced an intense withdrawal reaction. The intensity of the abstinence syndrome was decreased by the administration of L-PIA, CHA or CADO; CPA and D-PIA were ineffective. These results suggest that adenosine analogs may interfere with the known morphine effects on calcium disposition in nerve terminals.     

Influence of opiates on the levels of adenosine 3':5'-cyclic monophosphate in neuroblastoma X glioma hybrid cells.

In neuroblastoma x glioma hybrid cells prostaglanddin E₁ (PGE₁) increases the level of adenosine 3′: 5′-cyclic monophosphate. This response to PGE₁ is strongly enhanced in cells that were incubated with morphine, methadon, noradrenaline or carbamylcholine for several hours. All these compounds increase the level of cyclic GMP in the cells. As in untreated cells, the effect of PGE₁ can be inhibited by morphine or noradrenaline. The development of the increased response to PGE₁ is dependent on protein synthesis. The increased response to PGE₁ is discussed in connection with morphine tolerance and withdrawal.