5-Hydroxytryptamine synthesis in HL-1 cells and neonatal rat cardiocytes

Ikeda, Keiichi; Tojo, Katsuyoshi; Otsubo, Chikara; Udagawa, Takashi; Kumazawa, Kensuke; Ishikawa, Masahiro; Tokudome, Goro; Hosoya, Tatsuo; Tajima, Naoko; Claycomb, William C.; Nakao, Kazuwa; Kawamura, Masahiro

doi:10.1016/j.bbrc.2005.01.018

Cited by 23 publications

(16 citation statements)

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“…Recently, the ability of neonatal rat cardiac myocytes to synthesize 5-HT has been reported (23). Therefore, one can ask whether overexpression of a 5-HT 4 receptor changes the concentrations of 5-HT in heart tissue or plasma.…”

Section: Resultsmentioning

confidence: 99%

Cardiac overexpression of the human 5-HT₄receptor in mice

Gergs¹,

Baumann²,

Böckler³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT4 receptors, which are expressed in the human atrium and in ventricular tissue. However, a true animal model to study these receptors in more detail has been hitherto lacking. Therefore, we generated, for the first time, a transgenic (TG) mouse with cardiac myocyte-specific expression of the human 5-HT4 receptor. RT-PCR and immunohistochemistry revealed expression of the receptor at the mRNA and protein levels. Stimulation of isolated cardiac preparations by isoproterenol increased phospholamban phosphorylation at Ser 16 and Thr 17 sites. 5-HT increased phosphorylation only in TG mice but not in wild-type (WT) mice. Furthermore, 5-HT increased contractility in isolated perfused hearts from TG mice but not WT mice. These effects of 5-HT could be blocked by the 5-HT 4 receptor-selective antagonist GR-125487. An intravenous infusion of 5-HT increased left ventricular contractility in TG mice but not in WT mice. Similarly, the increase in contractility by 5-HT in isolated cardiomyocytes from TG mice was accompanied by and probably mediated through an increase in L-type Ca 2ϩ channel current and in Ca 2ϩ transients. In intact animals, echocardiography revealed an inotropic and chronotropic effect of subcutaneously injected 5-HT in TG mice but not in WT mice. In isolated hearts from TG mice, spontaneous polymorphic atrial arrhythmias were noted. These findings demonstrate the functional expression of 5-HT4 receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT4 receptorexpressing mice might be a useful model to mimic the human heart, where 5-HT 4 receptors are present and functional in the atrium and ventricle of the healthy and failing heart, and to investigate the influence of 5-HT in the development of cardiac arrhythmias and heart failure. serotonin; arrhythmia; transgenic mice; signal transduction MOST OF THE SEROTONIN (5-HT) in the blood originates from enterochromaffine cells of the gastrointestinal tract (53). 5-HT is released by these cells and is avidly taken up by platelets. Platelets seem to be the main source of 5-HT that influences the cardiovascular system. These influences include vasoconstriction, an increase in platelet aggregation, apoptosis of cardiac cells, augmentation in beating rate, the generation of arrhythmias (27), valvular heart disease (49), and positive inotropic and relaxant effects (for an overview, see Ref. 29).At present, seven groups of 5-HT-receptors have been distinguished (5-HT 1 -5-HT 7 ) (29). The 5-HT 4 receptor mediates the positive inotropic effect in humans (8,31,33,51). In the human atrium and ventricle, mRNAs of several splice variants of the 5-HT 4 receptor have been found (6, 2, 9).In isolated multicellular preparations from human atria, 5-HT exerts a positive inotropic effect and a relaxant (or lusitropic) effect (31, 33). These effects were accompanied by increases in cAMP content and ele...

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Section: Resultsmentioning

confidence: 99%

Cardiac overexpression of the human 5-HT₄receptor in mice

Gergs¹,

Baumann²,

Böckler³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…23,24 It is also likely to exhibit this function in the heart, because we found that serotonin uptake by HL-1 cardiomyocytes, which possess the transporter, is at least partially inhibited by known inhibitors of hENT4/ PMAT. The physiological significance of such transport is suggested by the finding that serotonin is not only produced by cardiac myocytes 25 but also regulates cardiac development and function. 26 Although hENT4/PMAT was previously reported not to interact with nucleosides, 23,24 a striking finding of the present study was that although transport activities were slight at pH 7.5, both hENT4 and mENT4 exhibited robust adenosine transport activity at lower pH values, with hENT4 exhibiting maximal activity in the pH range 5.5 to 6.5 ( Figure 3A).…”

Section: Discussionmentioning

confidence: 99%

“…24 Although most highly expressed in brain and skeletal muscle, Northern blotting revealed significant expression in heart. Serotonin is produced by cardiac myocytes 25 and, by acting on 5-HT 2B receptors, regulates cardiac development as well as cardiac structure and function in adults. 26 Given the potential importance of serotonin in the heart, and our preliminary finding that ENT4 transported adenosine at acidic pH but not at pH 7.4, the present study was undertaken to examine the functional properties of the human and rodent transporters and their tissue distributions in more detail.…”

mentioning

confidence: 99%

Distribution and Functional Characterization of Equilibrative Nucleoside Transporter-4, a Novel Cardiac Adenosine Transporter Activated at Acidic pH

Barnes

Dobrzynski

Foppolo

et al. 2006

Circulation Research

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181

201

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Abstract-Adenosine plays multiple roles in the efficient functioning of the heart by regulating coronary blood flow, cardiac pacemaking, and contractility. Previous studies have implicated the equilibrative nucleoside transporter family member equilibrative nucleoside transporter-1 (ENT1) in the regulation of cardiac adenosine levels. We report here that a second member of this family, ENT4, is also abundant in the heart, in particular in the plasma membranes of ventricular myocytes and vascular endothelial cells but, unlike ENT1, is virtually absent from the sinoatrial and atrioventricular nodes. Originally described as a monoamine/organic cation transporter, we found that both human and mouse ENT4 exhibited a novel, pH-dependent adenosine transport activity optimal at acidic pH (apparent K m values 0.78 and 0.13 mmol/L, respectively, at pH 5.5) and absent at pH 7.4. In contrast, serotonin transport by ENT4 was relatively insensitive to pH. ENT4-mediated nucleoside transport was adenosine selective, sodium independent and only weakly inhibited by the classical inhibitors of equilibrative nucleoside transport, dipyridamole, dilazep, and nitrobenzylthioinosine. We hypothesize that ENT4, in addition to playing roles in cardiac serotonin transport, contributes to the regulation of extracellular adenosine concentrations, in particular under the acidotic conditions associated with ischemia. Key Words: nucleoside Ⅲ adenosine Ⅲ transport Ⅲ ischemia Ⅲ pH T he purine nucleoside adenosine is produced by the action of both endo-and ecto-nucleotidases on adenine nucleotides in the heart and plays key roles in the regulation of coronary blood flow and myocardial O 2 supply-demand balance. 1-4 For example, action of adenosine on A 2A receptors on vascular smooth muscle and endothelial cells causes coronary vasodilatation. 1,5 In contrast, the negative inotropic and dromotropic effects of adenosine on the heart are mediated primarily by A 1 receptors. 2 Similarly, the negative chromotropic effect of adenosine involves action of A 1 receptors in the sinoatrial (SA) node on the inwardly rectifying potassium channel current I K-Ado and the hyperpolarization-activated pacemaker current I f . 2,6 Endogenous adenosine, acting on mitochondrial K ATP channels via A 1 and A 3 receptors, also makes a major contribution to the phenomenon of ischemic preconditioning. 5,7 Extracellular adenosine concentrations in the heart are governed both by action of ecto-5Ј-nucleotidase on adenine nucleotides released from cells and by transporter-mediated flux of adenosine across cell membranes. 3,4 Although most adenosine production occurs intracellularly, under normoxic conditions, metabolism maintains a low intracellular concentration and, therefore, the net flux of adenosine is into cardiomyocytes and endothelial cells. Under such conditions, administration of transport inhibitors increases extracellular concentrations of adenosine, leading to vasodilatation. 8 However, increased adenine nucleotide breakdown and inhibition of adenosine kinase duri...

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“…5-Hydroxytryptamine Synthesis and Handling. 5-HT has been found in the heart (Sole et al, 1979), and Ikeda et al (2005) demonstrated the ability of neonatal rat cardiomyocytes to synthesize 5-HT. 5-HT is a survival factor for cardiomyocytes, as demonstrated by Nebigil et al (2003a).…”

Section: -Hydroxytryptamine Presence and Function In The Heartmentioning

confidence: 98%