Triiodothyronine Treatment Research Articles

Pre-translational control of hepatic malic enzyme expression during the development of the rat

The expression of hepatic cytosolic malic enzyme in the developing rat has been studied by molecular-biological techniques. Malic enzyme mRNA was barely detectable throughout the neonatal period, but increased to significant levels immediately before weaning. Northern-blot analysis demonstrated that the two major malic enzyme mRNA species displayed non-co-ordinate control during development, with the 2.0 kb form accumulating to a greater extent than the 3.1 kb form. A novel 1.6 kb mRNA species was found to predominate in foetal samples. Tri-iodothyronine treatment of neonatal rats caused premature induction of all three malic enzyme mRNA species. Dietary studies also showed precocious induction of the mRNA with diets high in carbohydrate, but not with those high in fat.

Regulation by thyroid status of c-myc, c-fos and H-ras mRNAs in the rat myocardium

Effects of thyroid status on expression of a variety of myocardial genes, such as those encoding contractile proteins, have been reported, as well as interactions between thyroid hormones and developmental and haemodynamic regulation of contractile protein synthesis. In addition, it is clear that developmental and haemodynamic factors regulate expression of specific proto-oncogenes, including c-myc, c-fos and H-ras, in the myocardium but the effect of thyroid status on such proto-oncogene products, which are proposed to play a critical signal-transducing role in the heart, has been previously unexplored. In order to determine whether changes in thyroid status are associated with changes in expression of these putative intracellular signals, we examined the effect of hypothyroidism and tri-iodothyronine (T3) treatment on myocardial levels of c-myc, c-fos and H-ras mRNAs in the rat. The induction of hypothyroidism was associated with a marked increase in myocardial c-myc, c-fos and H-ras mRNAs, changes reversed by 72 h of T3 replacement. Administration of T3 to euthyroid rats had no significant effect on myocardial c-myc or c-fos mRNAs, but inhibition of H-ras mRNA by T3 was evident. These observations demonstrating influences of thyroid status on expression of specific proto-oncogenes suggest that thyroid hormones, as well as exerting direct effects on expression of functionally important myocardial genes, also interact with the cellular transduction pathways mediated by the products of the c-myc, c-fos and H-ras genes.

Studies on the decrease of liver cytochrome P-450 content by triiodothyronine

In the rat liver, the microsomal content of cytochrome P-450 decreased by 50% after triiodothyronine (T3) administration. The molecular basis for the decreased cytochrome P-450 levels was investigated. The activities of the enzymes involved in heme synthesis or degradation were not altered by thyroid hormone administration. The incorporation of 3H-delta-aminolaevulinate into the liver microsomal heme was markedly reduced in T3-treated rats. The latter appeared not to reflect a lowered binding affinity of the apoprotein moiety of cytochrome P-450 for heme. The sodium dodecyl sulfate gel electrophoresis of the microsomal preparation showed a decrease in apocytochrome P-450. It is suggested that the amount of the apocytochrome may be the primary event affected in the formation of cytochrome P-450, by triiodothyronine treatment of thyroidectomized rats.

Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor

Hyperthyroidism, induced in rat pups by the daily intraperitoneal administration of 1 μg/g body weight triiodothyronine, facilitated the development of ChAT fiber plexuses in brain regions innervated by basal forebrain cholinergic neurons, leading to an earlier and increased expression of cholinergic markers in those fibers in the cortex, hippocampus and amygdala. A similar enhancement was seen in the caudate-putamen complex. This histochemical profile was correlated with an accelerated appearance of ChAT-positive telencephalic puncta, as well as with a larger total number of cholinergic terminals expressed, which persisted throughout the eighth postnatal week, the longest time examined in the present study. Hypothyroidism was produced in rat pups by adding 0.5% propylthiouracil to the dams' diet beginning the day after birth. This dietary manipulation resulted in the diminished expression of ChAT in forebrain fibers and terminals. Hypothyroid treatment also reduced the quantity of ChAT puncta present during postnatal weeks 2 and 3, and, from week 4 and continuing through week 6, the number of ChAT-positive terminals in the telencephalic regions examined was actually less than the amount extant during the former developmental epoch. Immunostaining for nerve growth factor receptor (NGF-R), which is associated almost exclusively with ChAT-positive somata and fibers in the basal forebrain, demonstrated a different time course of postnatal development. Forebrain fibers and terminals demonstrating NGF-R were maximally visualized 1 week postnatally, a time at which these same neuronal elements evinced minimal ChAT-like immunopositivity. Thereafter and correlated with increased immunoreactivity for ChAT, fine details of NGF-R stained fibers were observed less frequently. Although propylthiouracil administration decreased NGF-R immunodensity, no alteration in the development of that receptor was observed as a function of triiodothyronine treatment. Cholinergic terminals in the ventrobasal thalamus, which derive from ChAT-positive neurons in the pedunculopontine and laterodorsal tegmental nucleus, were unaffected by either hyperthyroid or hypothyroid conditions. These cells also do not demonstrate NGF-R. We conclude from these experiments (1) that cholinergic fiber plexuses eventually exhibiting ChAT positivity in the telencephalon demonstrate NGF-R prior to the cholinergic synthetic enzyme, (2) that susceptibility to thyroid hormone manipulations may involve sensitivity to NGF, at least in some forebrain cholinergic systems and (3) that the effects of thyroid hormone imbalances on brain cholinergic neurons are regionally selective.

Cardiac function of the diabetic renovascular hypertensive rat: effects of insulin and thyroid hormone treatment

The influences of hypertension and hypothyroidism on diabetic cardiomyopathy are not clear. We studied this problem further by characterizing the effects of chronic triiodothyronine (T3) treatment on cardiac performance of diabetic renovascular hypertensive (RVH) rats. Hypertension was effected by clipping the left renal artery of Wistar-Kyoto (WKY) rats, and diabetes was induced 2 weeks later by streptozotocin (STZ; 55 mg/kg i.v.). The WKY strain was selected because it is relatively resistant to the cardiodepressant effects of diabetes, so that the influence of superimposed hypertension would be more apparent. Performance of working Krebs-Henseleit buffer perfused hearts was quantified by measuring left ventricular pressure and flow characteristics. The results showed that renovascular clipping caused a marked hypertension and left ventricular hypertrophy (LVH) but had no effect on perfused heart performance after 10 weeks. They also showed that diabetes during the final 8 weeks (i) caused a marked impairment in the performance of perfused hearts ex vivo of hypertensive rats but had no measurable effect in the normotensive WKY, (ii) had no effect on arterial pressure of either the normotensive or the hypertensive rats but reduced heart rate of hypertensive animals in vivo, and (iii) caused equivalent hyperglycemia, hypoinsulinemia, and hypothyroidism (depressed serum T3 and T4 levels) of hypertensive and normotensive rats. Treatment of diabetic RVH rats with T3 (10 micrograms.kg-1.day-1) in vivo was nearly as effective as insulin therapy (10 U.kg-1.day-1) in preventing the cardiac dysfunction ex vivo and was as effective as insulin therapy in preventing the bradycardia in vivo and the decline loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nutrients and hormones on transcriptional and post‐transcriptional regulation of fatty acid synthase in rat liver

The effects of nutrients and hormones on transcriptional and post-transcriptional regulation of fatty acid synthase in rat liver were investigated following cDNA cloning. When fasted rats were fed a carbohydrate/protein diet, the transcriptional rate was greatly increased even in 1 h. The transcriptional rate, mRNA concentration and enzyme induction reached maximum levels in 4 h, 8-16 h and 48 h, respectively. Although dietary carbohydrate increased each level more than protein did, both carbohydrate and protein were required to reach a high level. Corn oil feeding markedly decreased the transcriptional rate. In diabetic rats, the transcriptional rate, mRNA concentration and enzyme induction were very low in comparison with the normal. By treating the diabetic rats with insulin, however, the transcriptional rate was increased 5-fold in 1 h and 15-fold in 6 h, preceding a great increase in the mRNA and enzyme levels. On the other hand, fructose feeding or triiodothyronine treatment of diabetic rats abundantly increased the mRNA concentration and somewhat increased the transcriptional rate. Thus, it is suggested that insulin mainly stimulates the transcription of the fatty acid synthase gene, whereas triiodothyronine and fructose mainly increase the mRNA stability.

Ventricular relaxation of diabetic spontaneously hypertensive rat.

Diabetes, and possibly the hypothyroidism that attends diabetes, impairs mechanical relaxation of ventricular muscle, in part by depressing the rate of Ca2+ uptake by sarcoplasmic reticulum. Left ventricular hypertrophy exacerbates the adverse effects of diabetes on cardiac performance, but its effects on relaxation variables have not been well characterized. We examined the impact of streptozotocin-induced diabetes (8 weeks) on ventricular pressure load-dependent relaxation and sarcoplasmic reticular calcium uptake of hearts from spontaneously hypertensive rats and Wistar-Kyoto rats. Subsets of diabetic hypertensive rats were treated with either insulin (10 units/kg/day) or triiodothyronine (8-10 micrograms/kg/day). Diabetes impaired load-dependent relaxation and depressed sarcoplasmic reticular calcium uptake only in spontaneously hypertensive rat hearts. Either insulin or triiodothyronine treatment prevented the diabetes-induced depressions of both mechanical and biochemical indexes of relaxation. The results suggest that 1) hypertrophic ventricles of spontaneously hypertensive rats are more susceptible to the detrimental effects of diabetes on relaxation indexes than are the nonhypertrophic Wistar-Kyoto rat ventricles, and 2) the hypothyroidism that attends diabetes may contribute to the impaired relaxation of diabetic spontaneously hypertensive rat left ventricle.

Insulin, thyroid hormone, and heart function of diabetic spontaneously hypertensive rat.

Diabetes impairs cardiac performance more extensively in hypertensive rats than it does in nonhypertensive strains. A "low thyroid state" may contribute to the adverse cardiovascular effects of diabetes in spontaneously hypertensive rats (SHR). We tested this hypothesis by comparing the effects of thyroid hormone with those of insulin treatment on cardiac performance of diabetic SHR. Diabetes was induced with streptozotocin (45 mg/kg). Subsets of diabetic rats were treated with either insulin (10-20 units/kg/day) or triiodothyronine (8-10 micrograms/kg/day). Heart rate and systolic arterial pressure were obtained at weekly intervals. After 8 weeks, cardiac function was assessed using an isolated working heart preparation. Diabetes reduced arterial pressure and heart rate in vivo and markedly depressed cardiac performance under volume and pressure loading conditions ex vivo, confirming previous observations. As expected, insulin treatment prevented the bradycardia and depressor effect in vivo and the impairment of cardiac performance ex vivo caused by diabetes. The triiodothyronine treatment duplicated the effects of insulin on the hemodynamic measurements in vivo, and corrected nearly all depressed indexes of performance of diabetic SHR hearts ex vivo. Both treatment regimens successfully reduced 8-week mortality when compared with the untreated diabetic group. The results support the hypothesis that a low thyroid state may contribute to the cardiovascular dysfunction in diabetic SHR. Left ventricular hypertrophy may be an important factor in this phenomenon.

Effects of nutrients and hormones on transcriptional and post‐transcriptional regulation of acetyl‐CoA carboxylase in rat liver

The effects of nutrients and hormones on transcriptional and post-transcriptional regulation of acetyl-CoA carboxylase in rat liver were investigated following a cDNA cloning. After refeeding a carbohydrate/protein diet to fasted rats, the transcriptional rate was increased 2.5-fold in only 1 h. The mRNA concentration reached a maximal level of 9-12-fold increase in 8-16 h, and the enzyme induction increased 10-fold in 48 h. By a carbohydrate diet without protein, the transcriptional rate, mRNA concentration and enzyme induction were similarly increased to the levels in the carbohydrate/protein diet. It appears that protein feeding is not necessary to induce acetyl-CoA carboxylase. Corn oil feeding decreased the transcriptional rate. In diabetic rats, the transcriptional rate, mRNA concentration and enzyme induction were very low in comparison with the normal. After insulin treatment, the transcriptional rate was increased 2-fold (the normal level) in 2 h in diabetic rats. By fructose feeding to diabetic rats, the transcriptional rate and mRNA concentration were increased similarly to the levels reached by insulin treatment, while the enzyme induction was increased by only 60%. Thus, it is suggested that insulin is importantly involved in the transcription and also translation of acetyl-CoA carboxylase. On the other hand, triiodothyronine treatment increased the mRNA and enzyme levels in diabetic and normal rats, and somewhat increased the transcriptional rate only in diabetic rats. Triiodothyronine appears to stabilize the mRNA besides having an insulin-like action in acetyl-CoA carboxylase transcription.

Effects of thyroid hormone on Ca 2+ efflux and Ca 2+ transport capacity in rat skeletal muscle

The present study was undertaken to investigate the effects of 3,5,3′-triiodothyronine (T 3) treatment on passive Ca 2+ efflux, Ca 2+-dependent Mg 2+-ATPase (Ca 2+-ATPase) concentration and active Ca 2+ transport in isolated rat skeletal muscle. In addition, the question was examined whether changes in Ca 2+ efflux at rest and during electrical stimulation in the hyperthyroid state were accompanied by parallel changes in 3-O-methylglucose efflux. The resting Ca 2+ efflux from rat soleus muscle was increased by 25% after 8 days of treatment with T 3 ( 20 μg 100 g body weight). This was associated with a 78% increase in the basal efflux of 3-O-methylglucose. Electrical stimulation resulted in a rapid stimulation of Ca 2+ efflux and 3-O-methylglucose efflux in the two groups of rats, and the levels obtained were significantly higher in the T 3-treated group. The stimulating effect of the alkaloid veratridine on Ca 2+ efflux was 60% larger in 8-day hyperthyroid rats. Within 24 h after the start of T 3 treatment, a significant (21%) increase in Ca 2+-ATPase concentration was detected. Significant increases in active Ca 2+ uptake and passive Ca 2+ efflux were not observed until after 2 and 3 days of T 3 treatment, respectively. It is concluded that T 3 stimulates the synthesis of Ca 2+ ATPase and augments the intracellular Ca 2+ pools (sarcoplasmic reticulum and mitochondria). The latter results in enhancement of the passive Ca 2+ leak, which in turn, may lead to activation of substrate transport systems. The suggested increase in intracellular Ca 2+ cycling after T 3 treatment may, at least partly, explain the T 3-induced stimulation of energy metabolism.

Effects of ageing on transcriptional and post‐transcriptional regulation of malic enzyme and glucose‐6‐phosphate dehydrogenase in rat liver

We previously found an age-dependent impairment of induction of lipogenic enzymes in rat liver [Iritani et al. (1981) Biochim. Biophys. Acta 665, 636-639]. Further, we have found that after refeeding a fat-free diet to fasted rats, increases in transcriptional rate, mRNA concentration and enzyme induction of hepatic malic enzyme and glucose-6-phosphate dehydrogenase were always lower in 18-month-old rats than in 1.5-month-old rats. In the young rats, the transcriptional rates reached the maximum level in 4 h and the mRNA reached maximum levels in 16 h. The peaks tended to delay in the older rats. The half-lives of the mRNAs were not significantly longer in the old than in the young animals. The incorporation of [3H]leucine into the enzyme proteins was also decreased roughly in proportion to the enzyme induction. The mRNA concentrations in the liver polysomes were roughly proportional to the total mRNA. Thus, no effects of ageing on mRNA stability or on the translational activity of the enzymes could be found. It is suggested that the age-dependent decreases of malic enzyme and glucose-6-phosphate dehydrogenase induction can be mainly ascribed to the transcriptional steps. Moreover, the transcriptional rate, mRNA concentration and induction of malic enzyme were increased by triiodothyronine treatment at a similar rate in both the young and old rats, but the absolute increments were lower in the old animals. The triiodothyronine response to malic enzyme induction also appeared to be primarily decreased at the transcription level.

Effect of hypophysectomy, replacement therapy with ovine prolactin, and cortisol and triiodothyronine treatment on prolactin receptors of the tilapia ( Oreochromis mossambicus)

The effects of hypophysectomy and subsequent replacement therapy with ovine prolactin (oPRL) on specific binding of 25I-oPRL to gill, kidney, and liver membranes of male tilapia were examined. The possible control of prolactin receptors by cortisol (F) and triiodothyronine (T 3) was also studied using intact animals. In gill and kidney, hypophysectomy resulted in a significant decrease in specific binding that was partially restored (threefold increase) by three injections of oPRL, suggesting a role of the pituitary in the control of prolactin receptors. However, removal of the pituitary and replacement therapy with oPRL had no effect on binding by liver membranes. Cortisol and T 3 treatment, alone or in combination, did not significantly affect prolactin binding by any of the tissues tested.

Noradrenaline and thyroid function regulate (Na +,K +)-adenosine triphosphatase independently in vivo

We investigated interactions between noradrenaline and thyroid hormone status in the regulation of (Na +,K +)-ATPase in vivo. Treatment with the β-adrenoceptor antagonist propranolol or with the neurotoxin 6-hydroxydopamine did not prevent the increases in heart (Na +,K +)-ATPase associated with triiodothyronine treatment. Administration of methimazole did not prevent the increase in (Na +,K +)-ATPase indices in cerebral cortex and heart associated with subacute noradrenergic stimulation by yohimbine. There was no evidence for synergistic effects between thyroid hormone administration and noradrenergic stimulation by yohimbine. Thyroid hormone, unlike noradrenaline, mainly increased (Na +,K +)-ATPase activity with low affinity for ouabain. These results show that noradrenaline and thyroid hormone regulate (Na +,K +)-ATPase by largely independent mechanisms, and may regulate different populations of enzyme molecules.

Differential regulation by thyroid hormones of myosin heavy chain alpha and beta mRNAs in the rat ventricular myocardium.

The effect of tri-iodothyronine (T3) treatment on myocardial levels of alpha and beta myosin heavy chain (MHC) mRNAs in the rat was defined in vivo and in vitro. Dose-response experiments were performed in intact hypothyroid and euthyroid rats; in addition, studies in vitro examined the effect of T3 on MHC mRNAs in neonatal cardiac myocytes in primary culture. Specific alpha and beta MHC mRNAs were determined by Northern blot and dot hybridization to oligonucleotide probes complementary to the 3' untranslated regions of the MHC genes. An increase in myocardial beta MHC mRNA was demonstrated in hypothyroidism, accompanied by a reduction in alpha MHC mRNA. Marked differences in the sensitivity of alpha and beta MHC mRNAs to T3 replacement were found; a dose-dependent increase in alpha mRNA was evident at 6 h after T3 treatment, in the absence of consistent effects on beta mRNA, whereas 72 h after T3 replacement was commenced, stimulatory effects of T3 on alpha MHC mRNA, evident at all doses, were accompanied by a dose-dependent inhibition of beta MHC mRNA. No effect of thyroid status on actin mRNA was found, indicating the specificity of MHC gene regulation. T3 treatment of cardiac myocytes in vitro exerted similar actions on MHC mRNAs to those found in vivo, with a more marked influence on alpha than beta MHC mRNA. These studies of the action of T3 in vivo and in vitro have thus demonstrated specific effects of T3 on pretranslational regulation of the alpha and beta MHC genes, influences which differ not only in terms of stimulation or inhibition, but also in magnitude of effect.

The influence of dexamethasone on serum thyrotrophin and thyrotrophin synthesis in the rat

Glucocorticoid hormones suppress circulating concentrations of thyrotrophin (TSH), but their effect on synthesis of TSH in the pituitary gland is unclear. We have examined the influence of the glucocorticoid dexamethasone on serum TSH, pituitary TSH content and TSHβ- and α-subunit mRNA concentrations in pituitary cytoplasm in both the euthyroid and hypothyroid rat, and following triiodothyronine (T 3) treatment in the hypothyroid rat. The rise in serum TSH in hypothyroidism was attenuated in animals treated with dexamethasone; in addition the suppression of serum TSH 6 h after T 3 administration to hypothyroid rats was enhanced by dexamethasone. In contrast to the changes in serum TSH, pituitary TSH content was unaffected by dexamethasone. Furthermore dexamethasone had no significant effect on changes in pituitary cytoplasmic TSHβ- and α-subunit mRNA levels with thyroid status. These findings demonstrate that dexamethasone exerts differential effects on serum TSH levels and TSH biosynthesis which contrast with those of thyroid hormones.

Enhanced survival in striped bass fingerlings after maternal triiodothyronine treatment

Elevation of the triiodothyronine (T3) content of striped bass (Morone saxatilis) eggs by maternal T3 injection confirms the uptake of T3 by oocytes. The resulting offspring were influenced favorably by the T3, as seen in quantitative indices of development. As reported previously, larvae from T3-supplemented eggs raised under laboratory conditions exhibited increased body area, length, dry weight, and rates of swimbladder inflation and survival, compared to controls. Also, the T3 content of unfertilized oocytes correlated positively and highly significantly with survival to two weeks of age within individual cohorts (Brownet al., 1988). In the present study, the survival of experimental and control striped bass was monitored through the fingerling stage, under hatchery production conditions. The rate of recovery of maternally T3-treated cohorts from pond-culture was approximately fourfold that of controls. The striking effects of T3 enrichment of eggs on offspring indicate the potential contribution of maternal hormones in striped bass development, and suggest possible applications in aquaculture.

Acute hypothyroidism has no effect on pulmonary vascular resistance.

The effect of acute hypothyroidism on the pulmonary circulation was studied in 9 nonobese athyreotic patients by right heart catheterization at rest and during exercise. The patients were studied while they were hypothyroid 2 weeks after ceasing triiodothyronine treatment and while they were euthyroid on replacement therapy. At rest, pulmonary blood flow [4.0 +/- 0.6 l/min vs 5.8 +/- 1.0 l/min, p less than 0.01] and systolic pulmonary artery pressure [18 +/- 3 mmHg vs 23 +/- 2 mmHg, p less than 0.01] were lower when the patients were hypothyroid than when they were euthyroid. The mean and diastolic pressures in the pulmonary artery and the pulmonary capillary pressures were not different among the groups. Likewise, thyroid hormone levels had no significant effect on pulmonary vascular resistance [100 +/- 25 dyn-s-cm-5 vs 90 +/- 23 dyn-s-cm-5]. With supine exercise, pulmonary blood flow [10.1 +/- 1.6 l/min vs. 13.2 +/- 2.0 l/min, p less than 0.01], mean pulmonary artery pressure [25 +/- 6 mmHg vs 30 +/- 6 mmHg, p less than 0.02], and systolic pulmonary artery pressure [36 +/- 6 mmHg vs 44 +/- 8 mmHg, p less than 0.01] were lower when the patients were hypothyroid. The diastolic pulmonary artery pressure and the pulmonary capillary pressure were similar in both thyroid states. Again, thyroid deficiency had no effect on pulmonary vascular resistance [81 +/- 23 dyn-s-cm-5 vs 76 +/- 24 dyn-s-cm-5]. The lower systolic pressures in the pulmonary artery seen in hypothyroidism are probably due to the decreased systolic volume load of the pulmonary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

The direct effect of the thyroid hormone on cardiac chronotropism

To establish whether thyroid hormone modifies the heart rate directly or through an action on other neuroendocrine modulators, the authors have examined several animals models differing in the plasma levels of such compounds. Induction of the hypothyroid state in rats produced a slow onset of bradycardia, which may be removed by a prolonged triiodothyronine treatment. The involvement of TSH was excluded as, by comparing thyroidectomized, hypophysectomized and cold exposed rats, the heart rate was found to vary according to the thyroid levels and not to the TSH levels. Moreover growth hormone, corticotropin and gonadotropins do not influence the heart rate, as the bradycardia induced by hypophysectomy was fully removed by triiodothyronine treatment. The lack of influence by ACTH and GnH was confirmed by treatment of thyroidectomized rats with corticosteroids or testosterone, respectively. Finally, thyroid hormone did not act on the heart rate by changing the norepinephrine output at the sympathetic nerve endings in the heart. In fact, thyroidectomy produced a more intense bradycardia than sympathectomy, and such bradycardia was equally removed by triiodothyronine treatment in thyroidectomized rats and in thyroidectomized and then sympathectomized ones. The authors suggest that the direct effect of the thyroid hormone on cardiac chronotropism is due to an early enhancement of beta-adrenoceptors, followed by a late modification of the electrophysiological properties of the myocardium.

Effect of triiodothyronine treatment on thyrotrophin β- and α-messenger RNAs in the pituitary of the euthyroid rat

We have examined the effect of triiodothyronine (T 3) treatment of the euthyroid rat on serum thyrotrophin (TSH) concentration, pituitary content of TSH and on pituitary cytoplasmic levels of TSH β- and α-subunit messenger (m)RNAs, measured using the technique of dot hybridization to radiolabelled complementary (c)DNA probes. Serum concentration of TSH fell rapidly after T 3 treatment of euthyroid rats, but no effect of T 3 treatment was evident on pituitary TSH content. In contrast, marked effects of T 3 on cytoplasmic levels of both TSH β- and a-subunit mRNAs were demonstrated, with reductions in β and α-mRNAs at both early (6 h) and late (72 h) time points after administration of T 3. These observations, which have not been documented previously in the euthyroid state, contrast with earlier findings in hypothyroidism in which stimulatory influences of T 3 on TSH mRNAs are evident at 6 h.

Effects of thyroid hormone on Na+-K+ transport in resting and stimulated rat skeletal muscle.

The effects of hypothyroidism and 3,5,3'-triiodothyronine (T3) treatment on passive Na+-K+ fluxes and Na+-K+ pump concentration were investigated in isolated rat muscle. Within 12 h after a single dose of T3 (20 micrograms/100 g body wt), K+ efflux had increased by 21% in soleus and by 20% in extensor digitorum longus muscle. In the presence of ouabain, even larger effects were observed. These changes were associated with a 12% rise in amiloride-suppressible Na+ influx but no significant increase in [3H]ouabain binding site concentration. After 3 days of T3 treatment, the stimulating effect on K+ efflux and Na+ influx in soleus reached a plateau approximately 80 and 40% above control levels, respectively, whereas the maximum increase in [3H]ouabain binding site concentration (103%) was only fully developed after 8 days. Hypothyroidism decreased 86Rb efflux by 30%. The efflux of K+ and the influx of Na+ per contraction (both approximately 7 nmol/g wet wt) as well as the net loss of K+ induced by electrical stimulation were unaffected by T3 treatment. The rise in resting K+ efflux after 12-24 h of T3 treatment could be partly blocked by dantrolene or trifluoroperazine, indicating that an increase in the cytoplasmic Ca2+ concentration may contribute to the early rise in K+ efflux. It is concluded that the early rise in the resting passive leaks of Na+ and K+ induced by T3 is a major driving force for Na+-K+ pump synthesis.