Action of thyroid hormones at the cellular level: the mitochondrial target. (1/63)

Thyroid hormones exert profound effects on the energy metabolism. An inspection of the early and more recent literature shows that several targets at the cellular level have been identified. Since their effects on the nuclear signalling pathway have already been well-defined and extensively reviewed, this article focuses on the regulation of mitochondrial activity by thyroid hormones. Mitochondria, by virtue of their biochemical functions, are a natural candidate as a direct target for the calorigenic effects of thyroid hormones. To judge from results coming from various laboratories, it is quite conceivable that mitochondrial activities are regulated both directly and indirectly. Not only triiodo-L-thyronine, but also diiodothyronines are active in regulating the energy metabolism. They influence the resting metabolism in rats with 3,5-diiodo-L-thyronine seeming to show a clearer effect.  (+info)

Fetal-to-maternal transfer of 3,3',5-triiodothyronine sulfate and its metabolite in sheep. (2/63)

Earlier studies have shown that sulfoconjugation is a major pathway of thyroid hormone metabolism in fetal mammals. To assess the placental transfer of sulfoconjugates in the pregnant sheep model, we measured 3,3',5-triiodothyronine (T(3)) sulfate (T(3)S), 3, 3'-diiodothyronine sulfate (T(2)S), and T(3) concentrations in fetal serum and in maternal serum and urine after T(3)S infusion to the fetus (n = 5) or the ewe (n = 6). Maternal infusion of T(3)S did not increase fetal serum T(2)S, T(3)S, or T(3) concentrations. In contrast, fetal infusion of T(3)S produced significant increases in maternal serum T(2)S and T(3)S but not T(3) concentrations. Fetal T(3)S infusion also increased maternal urine excretion of T(3)S. However, the 4-h cumulative maternal urinary excretion of T(2)S and T(3)S after fetal T(3)S infusion was less than the excretion observed after fetal infusion of equimolar amounts of T(3) in our previous study. It is concluded that fetal serum T(2)S and T(3)S can be transferred to maternal compartments. However, compared with T(3), these sulfoconjugates may be less readily transferred.  (+info)

Maternal compound W serial measurements for the management of fetal hypothyroidsm. (3/63)

OBJECTIVE: The diagnosis of fetal hypothyroidism is based at present on measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by cordocentesis. The measurement of maternal serum and urinary concentrations of compound W, immunologically similar to but chromatographically distinct from diiodothyronine sulfate (T2S), has been advocated as a new possible marker for fetal hypothyroidism. DESIGN: In this paper, we measured serum compound W levels in 84 pregnant women, 20 with and 64 without thyroid disorders before and during specific treatment. Compound W was also assessed in fetal blood obtained by cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism due to transplacental passage of propylthiouracil (PTU). Compound W levels were measured by T2S RIA in maternal and fetal serum. To assess the possible usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal hypothyroidism we evaluated the transplacental passage of TRIAC by administering the drug to four pregnant women before therapeutic abortion. RESULTS: In normal pregnancies, both maternal and fetal compound W levels increased progressively during gestation with a significant direct correlation (P<0.001, in both mothers and fetuses). Moreover, a significant positive correlation was observed between fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was observed between maternal serum compound W and maternal FT4 in either euthyroid or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid fetuses of PTU-treated mothers showed low compound W levels, and maternal compound W values were in the low normal range and did not show the typical increase during progression of gestation. A significant increase of maternal compound W was observed when the PTU dose was reduced. TRIAC was documented to cross the placental barrier and the treatment of a hyperthyroid pregnant woman on PTU caused the high fetal TSH levels and goiter to normalize. CONCLUSIONS: Serial measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'-diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC to the mother may represent a useful and safe alternative to invasive techniques for the diagnosis and therapy of fetal hypothyroidism.  (+info)

DITPA prevents the blunted contraction-frequency relationship in myocytes from infarcted hearts. (4/63)

Loss of the positive force-frequency relationship is a characteristic finding in failing hearts. The mechanisms of this change are not well understood. Myocardial infarction (MI) was induced in rabbits to produce left ventricular (LV) dysfunction. Beginning 1 day after MI, a subgroup of rabbits received diiodothyropropionic acid (DITPA) (3.75 mg x kg(-1) x day(-1) sc) for 3 wk. We measured contractions, Ca(2+) transients, action potentials, and sarcoplasmic reticulum (SR) Ca(2+) content at different stimulation rates in single LV myocytes. The shortening-frequency relationship was markedly flattened in MI myocytes compared with control myocytes. In addition, Ca(2+) transients, action potentials, and contractions were prolonged. Myocytes from DITPA-treated MI rabbits had preserved inotropic responses to increased stimulation rate and normal duration of action potentials and Ca(2+) transients. SR Ca(2+) content increased significantly when stimulation rate was increased from 0.5 to 2.0 Hz in control myocytes but did not change significantly in MI myocytes. Myocytes from DITPA-treated MI rabbits had a greater frequency-dependent increase in SR Ca(2+) content compared with the untreated MI rabbits. Thus single myocytes from infarcted rabbit hearts have frequency-dependent abnormalities of contractility, Ca(2+) cycling, and action potential repolarization. The flattened contraction-frequency relationship can be partially explained by an attenuation of the normal enhancement of SR Ca(2+) content that occurs when stimulation rate is increased. Chronic DITPA administration after MI largely prevents the development of these abnormalities.  (+info)

The thyroid hormone analog DITPA restores I(to) in rats after myocardial infarction. (5/63)

Previous studies have established that reductions in repolarizing currents occur in heart disease and can contribute to life-threatening arrhythmias in myocardium. In this study, we investigated whether the thyroid hormone analog 3, 5-diiodothyropropionic acid (DITPA) could restore repolarizing transient outward K(+) current (I(to)) density and gene expression in rat myocardium after myocardial infarction (MI). Our findings show that I(to) density was reduced after MI (14.0 +/- 1.0 vs. 10.2 +/- 0.9 pA/pF, sham vs. post-MI at +40 mV). mRNA levels of Kv4.2 and Kv4.3 genes were decreased but Kv1.4 mRNA levels were increased post-MI. Corresponding changes in Kv4.2 and Kv1.4 protein were also observed. Chronic treatment of post-MI rats with 10 mg/kg DITPA restored I(to) density (to 15.2 +/- 1.1 pA/pF at +40 mV) as well as Kv4.2 and Kv1.4 expression to levels observed in sham-operated controls. Other membrane currents (Na(+), L-type Ca(2+), sustained, and inward rectifier K(+) currents) were unaffected by DITPA treatment. Associated with the changes in I(to) expression, action potential durations (current-clamp recordings in isolated single right ventricular myocytes and monophasic action potential recordings from the right free wall in situ) were prolonged after MI and restored with DITPA treatment. Our results demonstrate that DITPA restores I(to) density in the setting of MI, which may be useful in preventing complications associated with I(to) downregulation.  (+info)

Characterization of uptake and compartmentalization of 3,5,3'-tri-iodothyronine in cultured neonatal rat cardiomyocytes. (6/63)

The uptake of tri-iodothyronine (T(3)) in cultured neonatal rat cardiomyocytes was investigated and compared with the uptake of reverse T(3 )(rT(3)) and thyroxine (T(4)). Cellular compartmentalization of T(3) was studied by distinguishing T(3) activity associated with the plasma membrane from that in the cytosol or incorporated in the cell nucleus. T(3) and T(4) uptake displayed similar temperature dependencies which, in magnitude, differed from that of rT(3) uptake. T(3) uptake was Na(+ )independent, and sensitive to oligomycin and monodansylcadaverine (42-49% and 25% inhibition of 15-min cellular uptake respectively). Furthermore, T(3) uptake could be inhibited by tryptophan (20%) and tyrosine (12%), while 2-aminobicyclo[2,2,1]heptane-carboxylic acid had no effect. Co-incubation with tryptophan and oligomycin resulted in an additive inhibition of T(3) uptake (77%). We therefore conclude that (i) T(3) uptake is energy dependent, (ii) receptor-mediated endocytosis may be involved and (iii) the aromatic amino acid transport system T may play a role, while system L is not involved in T(3) transport in cardiomyocytes. Co-incubation with unlabeled iodothyronines showed that 3,3'-di-iodothyronine and T(3) itself were the most effective inhibitors of T(3) uptake (30% and 36% inhibition of 15-min cellular uptake respectively). At 15-min incubation time, 38% of the total cell-associated T(3) was present in the cytosol and nucleus, and 62% remained associated to the plasma membrane. Unidirectional uptake rates did not saturate over a free T(3) concentration range up to 3.9 microM. We have concluded that T(3) uptake in neonatal rat cardiomyocytes occurs by an energy- and temperature-dependent mechanism that may include endocytosis and amino acid transport system T, and is not sensitive to the Na(+) gradient. Elucidation of the molecular basis for the T(3) transporter is the subject of current investigation.  (+info)

Uptake of triiodothyronine and triiodothyroacetic acid in neonatal rat cardiomyocytes: effects of metabolites and analogs. (7/63)

Cellular and nuclear uptake of [125I]tri-iodothyronine (T3) and [125I]triiodothyroacetic acid (Triac) were compared in cardiomyocytes of 2-3 day old rats, and the effect of thyroid hormone analogs on cellular T(3) uptake was measured. Cells (5-10 x 10(5) per well) were cultured in DMEM-M199 with 5% horse serum and 5% FCS. Incubations were performed for from 15 min to 24 h at 37 degrees C in the same medium, 0.5% BSA and [125I]T3 (100 pM), or [125I]Triac (240 pM). Expressed as % dose, T(3) uptake was five times Triac uptake, but expressed as fmol/pM free hormone, Triac uptake was at least 30% (P<0.001) greater than T3 uptake, whereas the relative nuclear binding of the two tracers was comparable. The 15 min uptake of [125I]T3 was competitively inhibited by 10 microM unlabeled T3 (45-52%; P<0.001) or 3,3'- diiodothyronine (T2) (52%; P<0.001), and to a smaller extent by thyroxine (T(4)) (27%; 0.05+info)

DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. (8/63)

Previous studies from our laboratory and those of others have shown thyroxine to be a stimulator of coronary microvascular growth. The present study tested the hypothesis that 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog with inotropic but not chronotopic characteristics, is angiogenic in the nonischemic heart. Daily injections (3.75 mg/kg sc) of DITPA to Sprague-Dawley rats affected protein increases in vascular endothelial growth factor (VEGF)(164), VEGF(188,) basic fibroblast growth factor (bFGF) (FGF-2), angiopoietin-1, and Tie-2 during the first few days of treatment. After 3 wk of treatment, arteriolar length density and the relative number of terminal arterioles (<10 microm diameter) increased in the left ventricle as determined by image analysis of perfuse-fixed hearts. These findings occurred in hearts that did not undergo changes in mass nor in increases in capillary length density. We conclude that DITPA, which is known to improve ventricular function after infarction, is angiogenic in normal nonischemic hearts.  (+info)