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ABSTRACT: Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine if administration of T3 (instead of T4) improves the relationship between THs in serum and cardiac tissue, and cardiac function over a short-term treatment period. Adult female SD rats were made hypothyroid by seven weeks treatment with the anti-thyroid drug PTU (6-n-propyl-2-thiouracil). After establishing hypothyroidism, rats were assigned to one of five graded T3 (triiodothyronine) dosages plus PTU for a two week dose-response experiment. Untreated, age matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T3 and T4 levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene re-expression, and cardiac dysfunction. Short-term administration of T3 led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T3 levels was not associated with restoration of cardiac tissue T3 levels or cardiac function. In fact, a 3 fold higher T3 dosage was necessary to normalize cardiac tissue T3 levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.
Endocrinology 04/2013; · 4.46 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous thyroid hormone derivative with unknown biosynthetic origins. Structural similarities have led to the hypothesis that T(1)AM is an extrathyroidal metabolite of T(4). This study uses an isotope-labeled T(4) [heavy-T(4) (H-T(4))] that can be distinguished from endogenous T(4) by mass spectrometry, which allows metabolites to be identified based on the presence of this unique isotope signature. Endogenous T(1)AM levels depend upon thyroid status and decrease upon induction of hypothyroidism. However, in hypothyroid mice replaced with H-T(4), the isotope-labeled H-T(3) metabolite is detected, but no isotope-labeled T(1)AM is detected. These data suggest that T(1)AM is not an extrathyroidal metabolite of T(4), yet is produced by a process that requires the same biosynthetic factors necessary for T(4) synthesis.
Endocrinology 09/2012; 153(11):5659-67. · 4.46 Impact Factor
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Maria Elena Manni,
Gaetano De Siena,
Alessandro Saba,
Maja Marchini,
Elisa Landucci,
Elisabetta Gerace,
Marina Zazzeri,
Claudia Musilli,
Domenico Giampietro-Pellegrini,
Rosanna Matucci, Riccardo Zucchi,
Laura Raimondi
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ABSTRACT: Background and purpose: 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behavior and metabolism. Aim: We investigated the effect of central administration of T1AM (0.13, 0.4, 1.32 and 4 µgkg(-1) ) on learning and pain threshold of mice not pre-treated and pre-treated intraperitoneally with clorgyline (2.5 mgkg(-1) ), an inhibitor of amine oxidative metabolism, and whether brain thyroid hormone levels contributed to these effects. Methods: T1AM or vehicle were injected i.c.v. into male mice and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot-plate, movements on the hole-board platform. Plasma glycemia was measured using a glucorefractometer. The brain levels of T3, T4, and T1AM were measured by HPLC coupled to tandem mass spectrometry. ERK1/2 activation and c-fos expression were evaluated by Western-blot analysis in different brain regions. Results: T1AM improved learning capacity, decreased the pain threshold to hot stimuli, enhanced curiosity and raised plasma glycemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. EC50's were on the order of 0.6 - 1 µgkg(-1) . T1AM effects on learning and pain were abolished or deeply affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behavior. Conclusions and Implications: T1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative- induced memory disorders. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
British Journal of Pharmacology 08/2012; · 4.41 Impact Factor
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ABSTRACT: Trace amine-associated receptors (TAARs) have recently been identified in mouse olfactory epithelium (OE) and may be implicated
in the detection of volatile amines, including pheromones. We investigated TAAR expression in human nasal mucosa, evaluating
32 nasal mucosa biopsies obtained from 16 patients with normal olfactory function undergoing routine nasal surgery. OE was
identified on the basis of olfactory marker protein gene expression, and it was included in 11 samples out of 32. With the
exception of TAAR1, which was detected at trace levels in a few samples of both groups, TAAR expression was limited to OE.
TAAR5 was expressed in all OE samples at levels ranging from 15 to 1,480 copies/50ng cDNA; TAAR8 was detected in 5 OE samples
at trace levels and in another 5 OE samples at levels ranging from 11 to 33 cDNA copies/50ng RNA; TAAR9, TAAR2, and TAAR5
were expressed at trace levels in 5, 3, and 3 OE samples, respectively. In conclusion, most TAARs, and particularly TAAR5,
are selectively expressed in human OE. TAAR5 might play a significant functional role since it is known to be activated by
trimethylamine, which is present in human secretions and has been implicated in behavioral responses.
KeywordsHuman Olfactory Epithelium-Olfactory Receptors-Quantitative PCR-TAARs-Trace Amines-Trimethylamine
Chemosensory Perception 04/2012; 3(2):99-107. · 1.64 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3 nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24 h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.
Journal of Endocrinology 03/2012; 213(3):223-30. · 3.55 Impact Factor
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Maria Elena Manni,
Gaetano De Siena,
Alessandro Saba,
Maja Marchini,
Ilaria Dicembrini,
Elisabetta Bigagli,
Lorenzo Cinci,
Maura Lodovici,
Grazia Chiellini, Riccardo Zucchi,
Laura Raimondi
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ABSTRACT: BACKGROUND AND PURPOSE Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO. EXPERIMENTAL APPROACH We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 µg·kg(-1) ) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg·kg(-1) ). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS. KEY RESULTS T1AM, 1.3 µg·kg(-1) , produced a hypophagic effect (-24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (-33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM. CONCLUSIONS AND IMPLICATIONS T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs.
British Journal of Pharmacology 01/2012; 166(2):650-8. · 4.41 Impact Factor
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ABSTRACT: The primary purpose of this study was to detect and quantify 3-iodothyronamine (T(1)AM), an endogenous biogenic amine related to thyroid hormone, in human blood.
T(1)AM, total T(3), and total T(4) were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were related to standard clinical and laboratory variables.
The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2 diabetes, and six patients showed echocardiographic evidence of impaired left ventricular function.
No intervention or any patient selection was performed.
serum T(1)AM, total and free T(3) and T(4), routine chemistry, routine hematology, and echocardiographic parameters were measured.
T(1)AM was detected in all samples, and its concentration averaged 0.219 ± 0.012 pmol/ml. The T(1)AM concentration was significantly correlated to total T(4) (r = 0.654, P < 0.001), total T(3) (r = 0.705, P < 0.001), glycated hemoglobin (r = 0.508, P = 0.013), brain natriuretic peptide (r = 0.543, P = 0.016), and γ-glutamyl transpeptidase (r = 0.675, P < 0.001). In diabetic vs. nondiabetic patients T(1)AM concentration was significantly increased (0.232 ± 0.014 vs. 0.203 ± 0.006 pmol/ml, P = 0.044), whereas no significant difference was observed in patients with cardiac dysfunction.
T(1)AM is an endogenous messenger that can be assayed in human blood. Our results are consistent with the hypothesis that circulating T(1)AM is produced from thyroid hormones and encourage further investigations on the potential role of T(1)AM in insulin resistance and heart failure.
The Journal of clinical endocrinology and metabolism 01/2012; 97(1):E69-74. · 6.50 Impact Factor
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ABSTRACT: 3-iodothyronamine (T(1)AM) is an endogenous compound which shares structural and functional features with biogenic amines and is able to interact with a specific class of receptors, designed as trace amine associated receptors. T(1)AM has significant physiological effects in mammals and produces a reversible, dose-dependent negative inotropic and chronotropic effect in heart. The aim of the present study was to investigate if T(1)AM is able to reduce irreversible tissue injury in isolated rat hearts subjected to ischemia and reperfusion, as evaluated by triphenyltetrazolium chloride staining. We observed that T(1)AM reduced infarct size at concentrations (125 nM to 12.5 μM) which did not produce any significant hemodynamic action. The dose-response curve was bell-shaped and peaked at 1.25 μM. T(1)AM-induced cardioprotection was completely reversed by the administration of chelerythrine and glibenclamide, suggesting a protein kinase C and K (ATP) (+) -dependent pathway, while it was not additive to the protection induced by cyclosporine A, suggesting modulation of mitochondrial permeability transition. At cardioprotective concentration, T(1)AM reduced the time needed for cardiac attest during ischemia, but it did not affect sarcoplasmatic reticulum Ca(2+) handling, as demonstrated by unaltered ryanodine receptor binding properties. In conclusion, in isolated rat heart T(1)AM produces a cardioprotective effect which is mediated by a protein kinase C and K (ATP) (+) -dependent pathway and is probably linked to modulation of mitochondrial permeability transition and/or ischemic arrest time.
Cardiovascular Drugs and Therapy 08/2011; 25(4):307-13. · 3.13 Impact Factor
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Patrizia Agretti,
Giuseppina De Marco,
Laura Russo,
Alessandro Saba,
Andrea Raffaelli,
Maja Marchini,
Grazia Chiellini,
Lucia Grasso,
Aldo Pinchera,
Paolo Vitti,
Thomas S Scanlan, Riccardo Zucchi,
Massimo Tonacchera
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ABSTRACT: 3-Iodothyronamine (T(1)AM), produced from thyroid hormones (TH) through decarboxylation and deiodination, is a potent agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor belonging to the family of TAARs. In vivo T(1)AM induces functional effects opposite to those produced on a longer time scale by TH and might represent a novel branch of TH signaling. In this study, we investigated the action of T(1)AM on thyroid and determined its uptake and catabolism using FRTL5 cells. The expression of TAAR1 was determined by PCR and western blot in FRTL5 cells, and cAMP, iodide uptake, and glucose uptake were measured after incubation with increasing concentrations of T(1)AM for different times. T(1)AM and its catabolites thyronamine (T(0)AM), 3-iodothyroacetic acid (TA(1)), and thyroacetic acid (TA(0)) were analyzed in FRTL5 cells by HPLC coupled to tandem mass spectrometry. The product of amplification of TAAR1 gene and TAAR1 protein was demonstrated in FRTL5 cells. No persistent and dose-dependent response to T(1)AM was observed after treatment with increasing doses of this substance for different times in terms of cAMP production and iodide uptake. A slight inhibition of glucose uptake was observed in the presence of 100 μM T(1)AM after 60 and 120 min (28 and 32% respectively), but the effect disappeared after 18 h. T(1)AM was taken up by FRTL5 cells and catabolized to T(0)AM, TA(1), and TA(0) confirming the presence of deiodinase and amine oxidase activity in thyroid. In conclusion, T(1)AM determined a slight inhibition of glucose uptake in FRTL5 cells, but it was taken up and catabolized by these cells.
Journal of Molecular Endocrinology 04/2011; 47(1):23-32. · 3.48 Impact Factor
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ABSTRACT: We investigated whether acute and chronic administration of zofenopril, an angiotensin converting enzyme inhibitor, may modulate the expression of genes which are involved in the pathophysiology of myocardial ischemia and heart failure. We used an acute and a chronic model. In the former isolated rat hearts were perfused for 120 min in the presence or in the absence of 10 μM zofenoprilat, the active metabolite of zofenopril. In the chronic model one group of rats was treated with zofenopril (15.2 mg/Kg die per os) for 15 days, while control rats were treated with the same diet, except that zofenopril was omitted. Total RNA was extracted from hearts, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of α myosin heavy chain, superoxide dismutase, heat shock protein 70 (HSP70), nitric oxide synthase 2 and 3 (NOS2, NOS3), heme oxygenase 1, atrial natriuretic peptide (ANP), muscle phosphofructokinase. Acute or chronic zofenopril administration did not produce any change in hemodynamic variables. qRT-PCR experiments showed that in the acute model ANP expression was slightly although not significantly increased. In the chronic model, significant changes in gene expression were detected: in particular, HSP70 was upregulated (1.06 ± 0.38 vs. 0.72 ± 0.20 arbitrary units, P = 0.025), while NOS3 was downregulated (0.66 ± 0.06 vs. 0.83 ± 0.18 arbitrary units, P = 0.007). In the chronic model, liver samples were also assayed, but no significant change in the expression of any gene was detected. We conclude that zofenopril can produce heart-specific effects on gene expression. Persistent changes were detected with regard to specific heat shock protein and nitric oxide synthase subtypes. This action might contribute to the therapeutical response, and particularly to the increased resistance to ischemia.
Molecular and Cellular Biochemistry 03/2011; 352(1-2):301-7. · 2.06 Impact Factor
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Christine J Pol,
Alice Muller,
Marian J Zuidwijk,
Elza D van Deel,
Ellen Kaptein,
Alessandro Saba,
Maja Marchini, Riccardo Zucchi,
Theo J Visser,
Walter J Paulus,
Dirk J Duncker,
Warner S Simonides
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ABSTRACT: Similarities in cardiac gene expression in hypothyroidism and left ventricular (LV) pathological remodeling after myocardial infarction (MI) suggest a role for impaired cardiac thyroid hormone (TH) signaling in the development of heart failure. Increased ventricular activity of the TH-degrading enzyme type 3 deiodinase (D3) is recognized as a potential cause. In the present study, we investigated the cardiac expression and activity of D3 over an 8-wk period after MI in C57Bl/6J mice. Pathological remodeling of the noninfarcted part of the LV was evident from cardiomyocyte hypertrophy, interstitial fibrosis, and impairment of contractility. These changes were maximal and stable from the first week onward, as was the degree of LV dilation. A strong induction of D3 activity was found, which was similarly stable for the period examined. Plasma T(4) levels were transiently decreased at 1 wk after MI, but T(3) levels remained normal. The high D3 activity was associated with increased D3 mRNA expression at 1 but not at 4 and 8 wk after MI. Immunohistochemistry localized D3 protein to cardiomyocytes. In vivo measurement of TH-dependent transcription activity in cardiomyocytes using a luciferase reporter assay indicated a 48% decrease in post-MI mice relative to sham-operated animals, and this was associated with a 50% decrease in LV tissue T(3) concentration. In conclusion, pathological ventricular remodeling after MI in the mouse leads to high and stable induction of D3 activity in cardiomyocytes and a local hypothyroid condition.
Endocrinology 02/2011; 152(2):669-79. · 4.46 Impact Factor
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ABSTRACT: 3-Iodothyronamine (Tι AM) is a novel relative of thyroid hormone that plays a role in critical body regulatory processes such as glucose metabolism, thermal regulation, and heart beating. This paper was aimed at characterizing time dynamics of T1AM and its catabolite 3-iodothyroacetic acid (TA1) in different biological scales with linear time-invariant models. Culture medium samples coming from culture of H9c2 murine cells and perfusion liquid samples from perfused rat heart were collected after the injection of a T1AM bolus. T1AM and TA1 concentrations in the samples were assayed with high-performance liquid chromatography coupled to tandem mass spectrometry. Kinetic constants relative to T1AM transport and conversion were estimated with weighted least-squares method. We found that these constants can be related with an allometric power law depending on mass, with a negative exponent of -0.27 ± 0.19, implying that the velocity of conversion and internalization of Ti AM decreases with increasing of system mass.
IEEE Trans. Biomed. Engineering. 01/2011; 58:3513-3517.
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ABSTRACT: 3-iodothyronamine (T1AM) is a novel relative of thyroid hormone, able to interact with specific G protein-coupled receptors, known as trace amine-associated receptors. Significant functional effects are produced by exogenous T1AM, including a negative inotropic and chronotropic effect in cardiac preparations. This work was aimed at estimating endogenous T1AM concentration in different tissues and determining its cardiac metabolism. A novel HPLC tandem mass spectrometry assay was developed, allowing detection of T1AM, thyronamine, 3-iodothyroacetic acid, and thyroacetic acid. T1AM was detected in rat serum, at the concentration of 0.3±0.03 pmol/ml, and in all tested organs (heart, liver, kidney, skeletal muscle, stomach, lung, and brain), at concentrations significantly higher than the serum concentration, ranging from 5.6±1.5 pmol/g in lung to 92.9±28.5 pmol/g in liver. T1AM was also identified for the first time in human blood. In H9c2 cardiomyocytes and isolated perfused rat hearts, significant Na+-dependent uptake of exogenous T1AM was observed, and at the steady state total cellular or tissue T1AM concentration exceeded extracellular concentration by more than 20-fold. In both preparations T1AM underwent oxidative deamination to 3-iodothyroacetic acid. T1AM deamination was inhibited by iproniazid but not pargyline or semicarbazide, suggesting the involvement of both monoamine oxidase and semicarbazide-sensitive amine oxidase. Thyronamine and thyroacetic acid were not detected in heart. Finally, evidence of T1AM production was observed in cardiomyocytes exposed to exogenous thyroid hormone, although the activity of this pathway was very low.
Endocrinology 10/2010; 151(10):5063-73. · 4.46 Impact Factor
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ABSTRACT: Specific tissue responses to thyroid hormone are mediated by the hormone binding to two subtypes of nuclear receptors, TRalpha and TRbeta. We investigated the relationship between TRbeta activation and liver oxidative metabolism in hypothyroid rats treated with equimolar doses of triiodothyronine (T(3)) and GC-1, a TRbeta agonist. T(3) treatment produces increases in O(2) consumption and H(2)O(2) production higher than those elicited by GC-1. The greater effects of T(3) on oxidative processes are linked to the higher hormonal stimulation of the content of respiratory chain components including autoxidizable electron carriers as demonstrated by the measurement of activities of respiratory complexes and H(2)O(2) generation in the presence of respiratory inhibitors. It is conceivable that these differential effects are dependent on the inability of GC-1 to stimulate TRalpha receptors that are likely involved in the expression of some components of the respiratory chain. The greater increases in reactive oxygen species production and susceptibility to oxidants exhibited by mitochondria from T(3)-treated rats are consistent with their higher lipid and protein oxidative damage and lower resistance to Ca(2)(+) load. The T(3) and GC-1 effects on the expression levels of nuclear respiratory factor-1 and -2 and peroxisome proliferator-activated receptor-gamma coactivator-1alpha suggest the involvement of respiratory factors in the agonist-linked changes in mitochondrial respiratory capacities and H(2)O(2) production.
Journal of Endocrinology 04/2010; 205(3):279-89. · 3.55 Impact Factor
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ABSTRACT: Isolated rat hearts were perfused for 120 minutes in the presence or in the absence of 10 microM zofenoprilat, the active metabolite of zofenopril. At the end of perfusion, cardiac tissue was used to assay sarcoplasmic reticulum (SR) (45)Ca uptake and SR calcium release, which was determined by automatized quick filtration technique after SR vesicle loading with (45)Ca. The expression of genes involved in the control of calcium homeostasis was evaluated by polymerase chain reaction after reverse transcription. In chronic experiments, SR (45)Ca uptake and gene expression were measured in hearts derived from rats treated with 15 mg*kg(-1)*day(-1) zofenopril for 15 days. Acute or chronic zofenopril administration did not produce any change in contractile performance. In acute experiments, SR (45)Ca uptake was significantly increased after exposure to zofenoprilat. The rate constant of calcium-induced calcium release was slightly although not significantly higher, and the calcium leak measured under conditions promoting SR channel closure was significantly increased. In the chronic model, significant increase in the rate of SR (45)Ca uptake was confirmed. Gene expression was not modified, except for decreased phospholamban expression, which is observed in the acute but not in the chronic model. In conclusion, zofenopril increases SR calcium cycling and stimulates active calcium uptake into the SR.
Journal of cardiovascular pharmacology 10/2009; 54(5):456-63. · 2.83 Impact Factor
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ABSTRACT: 3-iodothyronamine (T(1)AM) is a novel endogenous relative of thyroid hormone, able to interact with trace amine-associated receptors, a class of plasma membrane G protein-coupled receptors, and to produce a negative inotropic and chronotropic effect. In the isolated rat heart 20-25 microM T(1)AM decreased cardiac contractility, but oxygen consumption and glucose uptake were either unchanged or disproportionately high when compared to mechanical work. In adult rat cardiomyocytes acute exposure to 20 microM T(1)AM decreased the amplitude and duration of the calcium transient. In patch clamped cardiomyocytes sarcolemmal calcium current density was unchanged while current facilitation by membrane depolarization was abolished consistent with reduced sarcoplasmic reticulum (SR) calcium release. In addition, T(1)AM decreased transient outward current (I(to)) and I(K1) background current. SR studies involving 20 microM T(1)AM revealed a significant decrease in ryanodine binding due to reduced B(max), no significant change in the rate constant of calcium-induced calcium release, a significant increase in calcium leak measured under conditions promoting channel closure, and no effect on oxalate-supported calcium uptake. Based on these observations we conclude T(1)AM affects calcium and potassium homeostasis and suggest its negative inotropic action is due to a diminished pool of SR calcium as a result of increased diastolic leak through the ryanodine receptor, while increased action potential duration is accounted for by inhibition of I(to) and I(K1) currents.
Journal of Cellular and Molecular Medicine 03/2009; 13(9B):3082-90. · 4.13 Impact Factor
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ABSTRACT: The bound of thyroid stimulating hormone (TSH) to its receptor elevates intracellular cAMP concentration that accounts for most of the biological actions of TSH. The presence and the patho-physiological role of a TSH receptor (TSHR) in heart is not yet clear. Understanding this question is important in the clinical use of recombinant human TSH (rhTSH) of patients with thyroid cancer. We investigate the acute effect of rhTSH in the Langendorff-perfused rat heart in relation with its receptor function. Compared to control group, no change in the hemodynamic parameters was observed in rat heart perfused with TSH. Western-blot of TSHR was performed evidencing the presence of the receptor and an increased level in cAMP was observed after thirty minute TSH perfusion. In conclusion the role of TSHR in rat heart seems to be marginal, reinforcing the idea of the cardiovascular safety of administered rhTSH in thyroid patients.
International journal of cardiology 02/2009; 144(1):85-6. · 7.08 Impact Factor
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ABSTRACT: The use of anthraquinone antineoplastic agents is limited by their cardiac toxicity, which is largely due to activation of the sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor). MEN 10755 is a new disaccharide analogue of doxorubicin. We have evaluated its effects on SR function and its toxicity in isolated working rat hearts.In rat SR vesicles, doxorubicin stimulated [3H]-ryanodine binding by increasing its Ca2+-sensitivity. At 1 μM Ca2+, ryanodine binding increased by 15.3±2.5 fold, with EC50=20.6 μM. Epirubicin produced a similar effect, i.e. 9.7±0.6 fold stimulation with EC50=11.1 μM. MEN 10755 increased ryanodine binding by 1.9±0.3 fold (P<0.01 vs doxorubicin and epirubicin), with EC50=38.9 μM.Ca2+-induced Ca2+ release experiments were performed by quick filtration technique, after SR loading with 45Ca2+. At 2 μM Ca2+, doxorubicin (50 μM) increased the rate constant of Ca2+ release to 82±5 s−1 vs a control value of 22±2 s−1 (P<0.01), whereas 50 μM MEN 10755 did not produce any significant effect (24±3 s−1).Ca2+-ATPase activity and 45Ca2+-uptake were not significantly affected by doxorubicin, its 13-dihydro-derivative, epirubicin, MEN 10755 and the 13-dihydro-derivative of MEN 10755, at concentrations 100 μM.In isolated heart experiments, administration of 30 μM doxorubicin or epirubicin caused serious contractile impairment, whereas 30 μM MEN 10755 produced only minor effects.In conclusion, in acute experiments MEN 10755 was much less cardiotoxic than equimolar doxorubicin or epirubicin. This result might be accounted for by reduced activation of SR Ca2+ release.British Journal of Pharmacology (2000) 131, 342–348; doi:10.1038/sj.bjp.0703575
British Journal of Pharmacology 01/2009; 131(2):342 - 348. · 4.41 Impact Factor
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ABSTRACT: 3-Iodothyronamine (T(1)AM) is an endogenous compound derived from thyroid hormone through decarboxylation and deiodination, which interacts with a novel G protein-coupled receptor, known as trace amine-associated receptor 1 (TAAR1). TAAR1 and other receptors of this family are expressed in several tissues, including the heart. Functional effects have been observed after administration of exogenous T(1)AM: in the isolated heart, a negative inotropic and chronotropic action was produced, and the resistance to ischemic injury was increased, possibly as a consequence of an action on intracellular calcium homeostasis. Extracardiac effects include reduction of body temperature, increased lipid versus carbohydrate metabolism, and modulation of insulin secretion. T(1)AM might play an important physiological or pathophysiological role, and this signaling system might allow the development of new therapeutical agents.
Heart Failure Reviews 12/2008; 15(2):171-6. · 3.20 Impact Factor
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ABSTRACT: This work was aimed at determining the cardioprotective effect of digitalis glycosides in rat heart, and to relate it with Na, K-ATPase inhibition and ERK1/2 activation. Isolated working rat hearts were perfused in the presence of ouabain or digoxin, which were used at concentrations ranging from 10 to 10 M. The hearts were then subjected to 30 minutes of global normothermic ischemia followed by 120 minutes of retrograde reperfusion; irreversible tissue injury was determined on the basis of triphenyltetrazolium chloride staining. Significant cardioprotection was observed with 10 M and 10 M ouabain (ischemic injury averaged 7.0 +/- 3.5% and 8.3 +/- 0.6% versus 37.3 +/- 2.0% in controls, P < 0.01 in each case). Hearts treated with digoxin showed decreased ischemic injury at 10 M and 10 M (18.0 +/- 1.5% and 14.2 +/- 1.0%, P < 0.01 versus control in both cases). In parallel experiments, ERK2 phosphorylation was increased by 10 to 10 M ouabain, while ERK1 and ERK2 phosphorylation was increased by 10 to 10 M digoxin. The cardioprotective effect was not related to Na, K-ATPase inhibition, since Rbuptake was not significantly different between control and treated hearts.
Journal of cardiovascular pharmacology 10/2008; 52(4):333-7. · 2.83 Impact Factor
