Acute effect of thyroid hormone on the heart: An extranuclear increase in sugar uptake

doi:10.1016/0022-2828(89)90748-7

Journal of Molecular and Cellular Cardiology

Volume 21, Issue 3, March 1989, Pages 323-334

https://doi.org/10.1016/0022-2828(89)90748-7 Get rights and content

Abstract

The thyroid hromone 3,5,3′-triiodo-L-thyronine (T3) produced a rapid increase in [³H]2-deoxyglucose (2-DG) uptake by freshly isolated rat heart slices in vitro, an effect that was evident after 1 min of pre-incubation with the hormone. This stimulatory effect of T3 was dose-related: the lowest effective concentration was 1 pm and maximal effect of about 80% above control was seen at 1 nm. Studies with several thyroid hormone analogues revealed that l-T3 was the most effective analogue which was followed in a decreasing order of potency by l-T4 = d-T3 > d-T4 > 3,5-l-T2 > rT3 > dL-thyronine. Further, the T3-induced increase in 2-DG uptake was independent of new protein synthesis because it was not blocked by the protein synthesis inhibitor cycloheximide under conditions in which [³H] leucine incorporation was inhibited by approximately 95%. Evaluation of the mechanism through which T3 exerts this action revealed that the uptake of 2-DG and 3-0-methyl-d-glucose (30MG) by heart slices was saturable, but that of l-glucose was not, and that T3 produced a similar increase in the uptake of both 2-DG and 30MG but failed to change l-glucose uptake. Saturation curve analysis of 2-DG and 30 MG uptake revealed that T3 increased V_max values but had no effect on $K$ _m values. Moreover, T3, which promoted total 2-DG uptake rate, had no effect on the proportionate phosphorylation rate of 2-DG to 2-DG-6-phosphate by hexokinase.

From this study it is concluded that thyroid hormone produces a direct and acute effect on the heart. This prompt effect of T3 to increase sugar uptake by heart slices, owing to the increase in the V_max of the sugar transport system, is extranuclear in nature, is thyroid hormone specific, and has a physiologic relevance.

References (45)

AH Burns et al.
Direct effect of thyroid hormones on glucose oxidation in isolated rat cardiac myocytes
J Mol Cell Cardiol
(1975)
DR Challoner
Glucose transport in perfused rat hearts: lack of epinephrine stimulation during arrest
Life Sci
(1970)
HY Chang et al.
Short term effects of triiodothyronine on rat heart receptors
Biochem Biophys Res Commun
(1981)
S Kempson et al.
Hormone action at the membrane level. VII Stimulation of dihydroalprenolol binding to beta-adrenergic receptors in isolated rat heart ventricle slices by triiodothyronine and thyroxine
Biochim Biophys Acta
(1978)
I Klein et al.
New perspective of thyroid hormone, catecholamines, and the heart
Am J Med
(1984)
RF Kletzien et al.
Sugar transport in chick embryo fibroblasts. II. Alterations in transport following transformation by a temperature-sensitive mutant of rouse sarcoma virus
J Biol Chem
(1974)
L Landsberg
Catecholamines and hyperthyroidism
Clin Endocrinol Metab
(1977)
OH Lowry et al.
Protein measurement with folin phenol reagent
J Biol Chem
(1951)
E Morkin et al.
Biochemical and physiologic effects of thyroid hormone on cardiac performance
Prog Cardiovasc Dis
(1983)
A Rudinger et al.
Rabbit myocardial membrane Ca²⁺-adenosine triphosphatase activity: stimulation in vitro by thyroid hormone
Arch Biochem Biophys
(1984)

JD Spain

LF Adamson et al.

Selective alteration by triiodothyronine of amino acid transport in embryonic chick bone

Endocrinology

(1967)

LF Adamson et al.

Some properties of the stimulatory effect of thyroid hormone on amino acid transport by embryonic chick bone

Endocrinology

(1967)

A Amtrop

Distribution of inulin, sucrose, and mannitol in rat brain cortex slices following in vivo or in vitro equilibration

J Physiol

(1979)

FB Davis et al.

Role of calmodulin in thyroid hormone stimulation in vitro of human erythrocyte Ca²⁺-ATPase activity

J Clin Invest

(1983)

M El Shahawy et al.

Direct effect of thyroid hormone on intracardiac conduction in acute and chronic hyperthyroid animals

Cardiovasc Res

(1975)

JR Etzkorn et al.

Beta-adrenergic potentiation of the increased in vitro accumulation of cycloleucine by rat thymocytes induced by triiodothyronine

J Clin Invest

(1979)

K Kobayashi et al.

Control of maximum rates of glycolysis in rat cardiac muscle

Circ Res

(1979)

M Kobayashi et al.

Absence of acute cardiac effect of triiodothyronine in isolated, blood-perfused canine heart

Jpn Heart J

(1979)

GS Levey et al.

Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems

J Clin Invest

(1969)

JR Neely et al.

Effect of pressure development on membrane transport of glucose in isolated rat heart

Am J Physiol

(1967)

CS Pittman et al.

Relation of chemical structure to the action and metabolism of thyroactive substances

Cited by (29)

Thyroid dysfunction and cardiovascular disease
2005, EMC - Cardiologie-Angeiologie
Les hormones thyroïdiennes agissent directement sur le cœur et le système circulatoire, ceci par une majoration de l’effet inotrope myocardique, du rythme cardiaque et une vasodilatation périphérique entraînant une augmentation du débit cardiaque. La triiodothyronine (T₃) traverse la membrane myocardiocytaire pour se lier à des récepteurs nucléaires. Le complexe, ainsi formé, intervient dans la régulation de la transcription des gènes dont ceux de la Ca²⁺ adénosine triphosphatase (ATPase) et du phospholamban dans le réticulum endoplasmique, de la myosine, des récepteurs β-adrénergiques, de l’adénylcyclase, des protéines régulatrices de type guanine-nucleotide regulatory proteins, de l’échangeur Na⁺/Ca⁺⁺ et des canaux potassiques voltage-dépendants. Les effets extranucléaires de la T₃ sur les canaux sodiques, potassiques et calciques représentent une voie alternative de l’action des hormones thyroïdiennes. De nombreuses anomalies électriques ont été rapportées dans l’hyperthyroïdie englobant une tachycardie sinusale ou atriale, des extrasystoles ventriculaires et des anomalies de la repolarisation ventriculaire. La fibrillation auriculaire est fréquente dans l’hyperthyroïdie prédisposant à un risque emboligène. Dans l’hyperthyroïdie infraclinique, il est retrouvé une accélération du rythme cardiaque, des arythmies supraventriculaires, une augmentation de l’index de masse ventriculaire gauche, une altération du temps de relaxation ventriculaire et de la performance à l’effort. L’hypothyroïdie déclarée est susceptible d’entraîner une insuffisance coronarienne, un épanchement péricardique, une hypertension artérielle diastolique, une myocardiopathie et une insuffisance cardiaque. L’hypothyroïdie infraclinique peut être associée à une dysfonction ventriculaire gauche diastolique au repos et systolique à l’effort. Le risque d’athérosclérose et d’infarctus du myocarde est majoré.
Thyroid hormone directly affects the heart and the peripheral vascular system. It increases myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. Triiodothyronine (T₃) enters the cardiac monocytes, and binds to nuclear T₃ receptors. The complex then binds to thyroid hormone response elements of the genes for several cell constituents and regulates transcription of these genes, including those for Ca ²⁺ -ATPase and phospholamban in the sarcoplasmic reticulum, myosin, β-adrenergic receptors, adenylyl cyclase, guanine-nucleotide– binding proteins, Na⁺/Ca²⁺ exchanger, Na⁺/K⁺ – ATPase, and voltage-gated potassium channels. Non nuclear T₃ actions on ion channels for sodium (Na⁺), potassium (K⁺), and calcium (Ca²⁺) ions represent an alternative way of action for thyroid hormone. Many electrocardiographic abnormalities have been described in hyperthyroidism including sinus tachycardia, atrial and ventricular extrasystoles, atrial fibrillation (AF), atrioventricular block and ventricular repolarisation abnormalities. AF is common in patients with hyperthyroidism, which predisposes to embolic events. Subclinical hyperthyroidism is associated with increased heart rate atrial arrhythmias, increased left ventricular mass impaired ventricular relaxation and reduced exercise performance. Overt hypothyroidism increases of coronary disease, pericardial effusion, systolic hypertension, myocardiopathy and congestive heart failure. Subclinical hypothyroidism is associated with impaired left ventricular diastolic dysfunction at rest, with systolic dysfunction in case of stress; the risk for atherosclerosis and myocardial infarction is increased.
Hormonal control of cardiac ion channels and transportes
1999, Progress in Biophysics and Molecular Biology
Triiodothyronine reverses depressed contractile performance after excessive catecholamine stimulation
1998, Annals of Thoracic Surgery
Background. Conflicting results have been reported regarding the acute effects of triiodothyronine (T₃) on myocardial contractile performance. The present study analyzes the role of T₃ in reversing the depressant effect of excessive catecholamine stimulation in isolated porcine left ventricular myocardium.
Methods. Thirty-six left ventricular trabeculae (0.4 × 6.0 mm) obtained from 6 pigs were used for measurements of isometric force development, isotonic shortening, and intracellular calcium in three experimental series (measurement conditions: 37°C; optimal length; supramaximal electrical stimulation, 1 Hz; calcium measurement, fura-2 ratio method; frequency, 225 Hz). In series 1, isometric force development was measured before and after a 60-minute incubation with 10⁻⁷ mol/L epinephrine in preparations with (n = 6) and without (n = 6) preceding fura-2 loading for calcium measurements. In series 2, the acute effects of a 30-minute administration of T₃ (10⁻⁹ mol/L) on isometric force and intracellular calcium were analyzed (n = 6). In series 3, after simultaneous fura-2 loading and a 6-hour 10⁻⁷ mol/L epinephrine exposure the effects of T₃ (10⁻⁹ mol/L, 30 minutes) on force development, shortening, and intracellular calcium transient were analyzed.
Results. Long-term and high-dose epinephrine exposure induced a severe contractile depression with a significant reduction of isometric force development (p < 0.05) and increased diastolic (p < 0.001) and systolic calcium (p < 0.001). In normal porcine myocardium T₃ had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T₃ accelerated the intracellular calcium transients and reduced diastolic calcium. Triiodothyronine increased the shortening amplitude and the force amplitude (p < 0.01).
Conclusions. Triiodothyronine reverses depressed contractile performance after preceding high-dose epinephrine exposure in isolated porcine myocardium. Increased force amplitudes and unaltered or even reduced intracellular calcium transients argue in favor of a resensitization of the contractile apparatus for calcium by T₃. The study supports a potential role for T₃ treatment in depressed myocardium after previous excessive catecholamine exposure (eg, brain death, catecholamine treatment, ischemia).
Effects of amiodarone on beating rate and Na-K-ATPase activity in cultured neonatal rat heart myocytes
1995, General Pharmacology
- 1.
  1. The purpose of this study was to examine the possibility that the cellular action of amiodarone is mediated by inhibition of thyroid hormone regulatory functions within the myocardial cell. We measured the rate of cell beating and the activity of Na-K-ATPase in cultured neonatal rat heart myocytes.
- 2.
  2. Amiodarone (0.25 and 1 μg/ml) reduced beating rate up to 75% within 20 min, and Na-K-ATPase activity up to 40% within 2 hr. No toxic effects were detected in the treated cells.
- 3.
  3. The inhibitory actions of amiodarone on beating rate and Na-K-ATPase activity were the same in myocytes grown in the presence or absence of 3-iodothyronine (T3, 5 nM).
- 4.
  4. These data indicate that amiodarone affects beating rate and Na-K-ATPase activity independently of thyroid hormone. It is suggested that interference of amiodarone with thyroid hormone action is not the only mechanism by which this drug modulates some functions of the myocardial cell.
Acute cellular actions of thyroid hormone and myocardial function
1993, The Annals of Thoracic Surgery
The mechanisms of actions of thyroid hormone in various tissues are largely viewed as cell nucleus-mediated. However, several actions of this hormone are definitively extranuclear, and these include effects on the activities of Ca²⁺-adenosine triphosphatases (ATPases) of myocardial sarcolemma and, apparently, sarcoplasmic reticulum in animal models. Both effects would serve to reduce cytoplasmic (sarcoplasmic) [Ca²⁺]. Sarcoplasmic reticulum uptake of Ca²⁺ from sarcoplasm is mediated by Ca²⁺-ATPase and is deficient in end-stage heart failure; thyroid hormone can enhance sarcoplasmic reticulum Ca²⁺-ATPase activity acutely via an extranuclear mechanism or indirectly via the myosin-associated Ca²⁺-ATPase gene. Such actions would serve to improve myocardial relaxation, thus improvement in diastolic dysfunction, and may be cardioprotective if excessive levels of sarcoplasmic [Ca²⁺] develop during reperfusion of previously ischemic tissue. Action of thyroid hormone on sarcolemmal Ca²⁺-ATPase activity will enhance Ca²⁺ efflux, and a recently described effect of the hormone on myocardial Na⁺ inactivation current may serve to increase or reduce sarcoplasmic [Ca²⁺], depending upon the vector of Na⁺/Ca²⁺ exchange. This article reviews acute effects of thyroid hormone on the heart that are extranuclear in mechanism.
Acute thyroid hormone promotes slow inactivation of sodium current in neonatal cardiac myocytes
1991, BBA - Molecular Cell Research
Sodium current (I_Na) inactivation kinetics in neonatal cardiac myocytes were analyzed using whole cell voltage clamp before and after acute treatments with thyroid hormone (3,5,3′-triido-l-thyronine, T3). In untreated neonatal myocytes, I_Na inactivation was predominantly mono-exponential, with 93 ± 3% (S.D.; n = 9) of the peak amplitude decaying with a time constant, τ_h1, of 1.8 ± 0.5 ms at −30 mV. The remaining 7% of control I_Na decayed more slowly, with a time constant, τ_h2, of 9.3 ± 3.0 ms at −30 mV. The contribution of slowly-inactivating channels to peak current was increased from 7% to 43 ± 27% within 5 min of exposure to 5–20 nM T3 (nine cells; P < 0.005). The time constants for both the fast- and slow-inactivating components of peak current (τ_h1 and τ_h2) were not significantly changed by acute T3 treatment, nor was steady-state I_Na inactivation (h_∞) affected. Thyroid hormone action on sodium inactivation was partially reversible by lidocaine. These findings indicate that T3 acts at the neonatal cardiac cell membrane to promote slow inactivation kinetics in sodium channels.

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Original articleAcute effect of thyroid hormone on the heart: An extranuclear increase in sugar uptake

Abstract

J Mol Cell Cardiol

Life Sci

Biochem Biophys Res Commun

Biochim Biophys Acta

Am J Med

J Biol Chem

Clin Endocrinol Metab

J Biol Chem

Prog Cardiovasc Dis

Arch Biochem Biophys

Selective alteration by triiodothyronine of amino acid transport in embryonic chick bone

Endocrinology

Some properties of the stimulatory effect of thyroid hormone on amino acid transport by embryonic chick bone

Endocrinology

Distribution of inulin, sucrose, and mannitol in rat brain cortex slices following in vivo or in vitro equilibration

J Physiol

Role of calmodulin in thyroid hormone stimulation in vitro of human erythrocyte Ca2+-ATPase activity

J Clin Invest

Direct effect of thyroid hormone on intracardiac conduction in acute and chronic hyperthyroid animals

Cardiovasc Res

Beta-adrenergic potentiation of the increased in vitro accumulation of cycloleucine by rat thymocytes induced by triiodothyronine

J Clin Invest

Control of maximum rates of glycolysis in rat cardiac muscle

Circ Res

Absence of acute cardiac effect of triiodothyronine in isolated, blood-perfused canine heart

Jpn Heart J

Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems

J Clin Invest

Effect of pressure development on membrane transport of glucose in isolated rat heart

Am J Physiol

Relation of chemical structure to the action and metabolism of thyroactive substances

Original article
Acute effect of thyroid hormone on the heart: An extranuclear increase in sugar uptake

Role of calmodulin in thyroid hormone stimulation in vitro of human erythrocyte Ca²⁺-ATPase activity