Single-channel activity and expression of atrial L-type Ca(2+) channels in patients with latent hyperthyroidism.
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Patients with "latent hyperthyroidism" (suppressed thyroid-stimulating hormone and normal circulating thyroid hormones) are at risk to develop atrial fibrillation. In animal models, hyperthyroidism is associated with increased cardiac L-type Ca(2+) current. Therefore, we assessed L-type channel function and expression in right atria from patients undergoing cardiac surgery. Single L-type channels were studied in the cell-attached condition. Voltage dependence of gating was similar in patients with and without latent hyperthyroidism. With use of a pulse protocol leading to maximum channel availability, single-channel activity was further analyzed. Average peak current was significantly enhanced in latent hyperthyroidism, mainly because of an increased channel availability (P < 0.05). Protein expression was analyzed by Western blot. In latent hyperthyroidism, expression of Ca(2+) channel alpha(1)-subunits was increased more than threefold (P < 0.01). In contrast, sarco(endo)plasmic reticulum Ca(2+)-ATPase and phospholamban levels were not significantly changed. We only observed a trend toward increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression (P = 0.085). Function and expression of human atrial L-type Ca(2+) channels are increased in latent hyperthyroidism. These endocrine effects on the heart may be clinically relevant. (+info)
Regulation of beta 1- and beta 3-adrenergic agonist-stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes.
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1. This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to beta-adrenoceptor (beta-AR) stimulation. The beta 1- and beta 3-AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non-selective and selective beta 1/beta 3-AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, triiodothyronine (T3)-treated and thyroidectomized rats. 2. The beta 3-AR density was enhanced (72%) by T3-treatment and reduced (50%) by introduction of a hypothyroid state while beta 1-AR number remained unaffected. The beta 1- and beta 3-AR density was correlated with the specific mRNA level in all thyroid status. 3. The lipolytic responses to isoprenaline, noradrenaline (beta 1/beta 3/beta 3-AR agonists) and BRL 37344 (beta 3-AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism. 4. T3-treatment increased the maximal lipolytic response to the partial beta 3-AR (CGP 12177) and beta 1-AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy. 5. In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17 +/- 0.03 versus 0.41 +/- 0.08 mumol glycerol/10(6) adipocytes; 0.048 +/- 0.005 versus 0.114 +/- 0.006 pmol cyclic AMP min-1 mg-1) but not changed with xamoterol. 6. The changes in lipolytic responses to postreceptor-acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states. 7. Thyroid status affects lipolysis by modifying beta 3-AR density and postreceptor events without changes in the beta 1-AR functionality. (+info)
Gestational thyrotoxicosis with acute Wernicke encephalopathy: a case report.
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A 35-year-old hyperthyroid woman who developed nausea, vomiting, tachycardia, nystagmus and mental disturbance, was referred to our hospital with a suspected diagnosis of thyroid storm. However, the thyroid gland was only slightly palpable, bruits were not audible, and exophthalmos was not present. Serum levels of thyroid hormone were increased, but TSH receptor antibodies were negative. Echography and color flow doppler ultrasonography revealed a slightly enlarged thyroid gland and a slightly increased blood flow, both of which were much less milder than those expected for severe hyperthyroid Graves' disease. Under the diagnosis of hyperthyroidism due to gestational thyrotoxicosis associated with Wernicke encephalopathy, vitamin B1 was administered on the first day of admission. Her consciousness became nearly normal on the second day except for slight amnesia. Her right abducent nerve palsy rapidly improved, but horizontal and vertical nystagmus, diminished deep tendon reflexes and gait ataxia improved only gradually. MRI findings of the brain were compatible with acute Wernicke encephalopathy. We concluded that history taking and physical findings are important to make a differential diagnosis of gestational thyrotoxicosis with acute Wernicke encephalopathy from Graves' thyroid storm, and that Wernicke encephalopathy should be treated as soon as possible to improve the prognosis. (+info)
Tables to estimate total binding capacity of thyroxine-binding globulin from the in vitro thyroid function tests.
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Equations for an estimate of the total binding capacity of serum thyroxine-binding globulin (TBG-TC) were developed relating this parameter to serum thyroxine concentration (T4) and in vitro uptake (T3U). This extimate demonstrated a highly significant, positive correlation with TBG-TC as measured by electrophoresis in ten normal subjectdividuals with altered TBG-TC but without thyroid dysfunction (ten normal pregnant women, ten healthy women receiving anovulatories, ten nephrotics, and ten patients with severe malnutrition). True-positive (sensitivity) and true-negative (specificity) ratios were calculated for total and free T4 in serum, T3U, Free T4 Index, and both measured and calculated TBG-TC. False-positive results for free T4 index (12%) were due to altered TBG-TC. In such cases, 93% were recognized by the calculated TBG-TC from the calues of the invitro tests. It is concluded that this estimates should be added to the in vitro thyroid tests for their proper interpretation in cases where altered TBG-TC could be misleading. This estimate applies only to the particular in vitro testing system used herein. (+info)
Effect of thyroid hormone on mtHsp70 expression, mitochondrial import and processing in cardiac muscle.
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Mitochondrial heat shock protein 70 (mtHsp70), an important mitochondrial chaperone, is increased in cardiac muscle mitochondria of hyperthyroid rats. To determine the mechanism(s) underlying this increase, we used variations in thyroid status. In Series I, rats were made hyperthyroid by injecting them with 3,3', 5-triiodo-l-thyronine (T(3)) for 5 days, or by treating them with vehicle. In Series II, animals were given 6-n-propyl-2-thiouracil in their drinking water (0.05% w/v) for a period of 32-42 days to make them hypothyroid. During the last 5 days of treatment these animals received injections of either T(3) or vehicle. T(3) treatment resulted in parallel increases in mtHsp70 protein and mRNA levels in a variety of tissues, suggesting transcriptional regulation. However, evidence of tissue-specific post-transcriptional regulation was also apparent. In isolated heart mitochondria, T(3) treatment resulted in a 1.8-fold increase in mtHsp70. This was due to the 1. 6-fold greater import of mtHsp70 into mitochondria in T(3), compared with hypothyroid animals, and it could not be attributed to an altered rate of intramitochondrial mtHsp70 degradation. The rate of processing of mtHsp70 to its mature form, reflecting mitochondrial processing peptidase activity, was unaffected by T(3), but was more rapid than mtHsp70 import. These data indicate a novel mechanism by which T(3) modifies the mitochondrial phenotype via the adaptations in the protein import pathway. (+info)
Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone sulfate concentrations in patients with hyperthyroidism and hypothyroidism.
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BACKGROUND: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to have protective effects against cardiovascular disease, cancer, immune-modulated diseases, and aging. We examined serum concentrations of DHEA, DHEA-S, and pregnenolone sulfate (PREG-S) in patients with thyroid dysfunction. METHODS: Steroids extracted with methanol from serum sample were separated into an unconjugated fraction (DHEA) and a monosulfate fraction (DHEA-S and PREG-S), using a solid-phase extraction and an ion-exchange column. After separation of unconjugated steroids by HPLC, the DHEA concentration was measured by enzyme immunoassay. The monosulfate fraction was treated with arylsulfatase, and the freed steroids were separated by HPLC. The DHEA and PREG fractions were determined by gas chromatography-mass spectrometry, and the concentrations were converted into those of DHEA-S and PREG-S. RESULTS: Serum concentrations of DHEA, DHEA-S, and PREG-S were all significantly lower in patients with hypothyroidism (n = 24) than in age- and sex-matched healthy controls (n = 43). By contrast, in patients with hyperthyroidism (n = 22), serum DHEA-S and PREG-S concentrations were significantly higher, but the serum DHEA concentration was within the reference interval. Serum concentrations of these three steroids correlated with serum concentrations of thyroid hormones in these patients. Serum albumin and sex hormone-binding globulin concentrations were not related to these changes in the concentration of steroids. CONCLUSIONS: Serum concentrations of DHEA, DHEA-S, and PREG-S were decreased in hypothyroidism, whereas serum DHEA-S and PREG-S concentrations were increased but DHEA was normal in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these steroids, and DHEA sulfotransferase might be increased in hyperthyroidism. (+info)
Mitochondrial protonophoric activity induced by a thyromimetic fatty acid analogue.
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Calcium-dependent uncoupling of liver mitochondrial oxidative phosphorylation by a non-metabolizable long chain fatty acyl analogue was compared with uncoupling induced by in vivo thyroid hormone treatment. beta,beta'-Methyl-substituted hexadecane alpha, omega-dioic acid (Medica 16) is reported here to induce a saturable 20-30% decrease in liver mitochondrial DeltaPsi, DeltapH and protonmotive force which proceeds in the presence of added Ca(2+) to cyclosporin A-sensitive mitochondrial permeabilization. Ca(2+)-dependent uncoupling by Medica 16 was accompanied by atractylate-enhanced, bongkrekic-inhibited activation of mitochondrial Ca(2+) efflux. The direct mitochondrial effect exerted in vitro by Medica 16 is similar to that induced by in vivo thyroid hormone treatment. Hence, the thyromimetic protonophoric activity of Medica 16 and the uncoupling activity of TH converge onto components of the mitochondrial permeabilization transition pore. (+info)
Thyroid hormone-induced overexpression of functional ryanodine receptors in the rabbit heart.
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Modifications in the Ca(2+)-uptake and -release functions of the sarcoplasmic reticulum (SR) may be a major component of the mechanisms underlying thyroid state-dependent alterations in heart rate, myocardial contractility, and metabolism. We investigated the influence of hyperthyroid state on the expression and functional properties of the ryanodine receptor (RyR), a major protein in the junctional SR (JSR), which mediates Ca(2+) release to trigger muscle contraction. Experiments were performed using homogenates and JSR vesicles derived from ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism, with attendant cardiac hypertrophy, was induced by the injection of L-thyroxine (200 microg/kg body wt) daily for 7 days. Western blotting analysis using cardiac RyR-specific antibody revealed a significant increase (>50%) in the relative amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca(2+)-dependent, high-affinity [(3)H]ryanodine binding was also significantly greater ( approximately 40%) in JSR from hyperthyroid rabbits. The Ca(2+ )sensitivity of [(3)H]ryanodine binding and the dissociation constant for [(3)H]ryanodine did not differ significantly between euthyroid and hyperthyroid hearts. Measurement of Ca(2+)-release rates from passively Ca(2+)-preloaded JSR vesicles and assessment of the effect of RyR-Ca(2+)-release channel (CRC) blockade on active Ca(2+)-uptake rates revealed significantly enhanced (>2-fold) CRC activity in the hyperthyroid, compared with euthyroid, JSR. These results demonstrate overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy. Relative abundance of RyR may be responsible, in part, for the changes in SR Ca(2+) release, cytosolic Ca(2+) transient, and cardiac systolic function associated with thyroid hormone-induced cardiac hypertrophy. (+info)