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...

It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT(1) as well MT(2)), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3',5'-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP(3) pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and beta1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin-insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained.

Human cardiac muscarinic receptor activity is diminished with increasing age; such decreased cardiac muscarinic receptor activity could contribute to the decrease in baroreflex activity with aging. In contrast, antimuscarinic drugs seem to have no effect on human cardiac contractility.

In the human heart, ET(A) and ET(B) receptors coexist; however, only ET(A) receptors are of functional importance. In right atria, ET(A) receptors couple to IP formation and inhibition of adenylyl cyclase; in left ventricles, they couple only to IP formation. In end-stage CHF, the functional responsiveness of the cardiac ET(A)-receptor system is not altered.

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In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT4 receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT4(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 pEC50 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-HT4 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 pEC50 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-HT4 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-HT4 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.

This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10-160 ng/kg/min and-in order to release endogenous noradrenaline-tyramine at four incremental doses of 5-20 micrograms/kg/min. Noradrenaline and tyramine were administered in the absence and presence of alpha 1-adrenoceptor blockade with doxazosin (2 mg p.o.), alpha 2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective beta 1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (1.5 micrograms/kg i.v. loading dose followed by 0.15 microgram/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (delta max 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (delta max -22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by biosprolol. I.v. tyramine reduced Pdiast (delta max -7 mmHg), which was not affected by alpha 1-adrenoceptor blockade, and profoundly shortened QS2c (delta max -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (delta max 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by alpha-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS2c induced by i.v. noradrenaline and converted the fall in Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by alpha 1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by beta 1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular "pressor' response.

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