Publications (2)6.36 Total impact
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Article: Human 5-HT(4) receptor stimulation in atria of transgenic mice.
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ABSTRACT: In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT(4) receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT(4(a)) receptor under control of the heart-specific α-myosin heavy chain promoter in the atria (and ventricles). Contractile studies were performed in isolated electrically driven left atrial preparations and spontaneously beating right atrial preparation of TG and littermate control mice (wild type (WT)). 5-HT increased force of contraction and phospholamban phosphorylation on serine 16 only in left atrial preparations from TG but not from WT. In contrast, β-adrenoceptor stimulation of left atrial preparations by isoprenaline increased force of contraction with similar pEC(50) values and to a similar maximum extent in both TG and WT. The contractile effects of 5-HT in left atrial preparations from TG could be blocked by the 5-HT(4) receptor-specific antagonists GR125487 or GR113808. In right atrial preparations from WT and TG, the β-adrenoceptor agonist isoprenaline exerted a positive chronotropic effect with similar pEC(50) values and similar maximum effects. Only in right atrial preparations from TG but not WT, 5-HT exerted a positive chronotropic effect that could be attenuated by 5-HT(4) receptor-specific antagonists. Finally, in left atrial preparations of TG, a higher incidence of arrhythmias was noted compared to WT. The present data indicate that the human 5-HT(4) receptors expressed in mouse atria are functional. This is the first transgenic model to study this human receptor in the atrium ex vivo or in vivo.Archiv für Experimentelle Pathologie und Pharmakologie 01/2013; · 2.65 Impact Factor -
Article: Cardiac overexpression of the human 5-HT4 receptor in mice.
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ABSTRACT: Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT(4) 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-HT(4) 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(2+) channel current and in Ca(2+) 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-HT(4) receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT(4) receptor-expressing 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.AJP Heart and Circulatory Physiology 09/2010; 299(3):H788-98. · 3.71 Impact Factor
