Altered sinus nodal and atrioventricular nodal function in freely moving  mice overexpressing the A<sub>1</sub> adenosine receptor

Kirchhof, Paulus; Fabritz, Larissa; Fortmüller, Lisa; Matherne, G. Paul; Lankford, Amy; Baba, Hideo A.; Schmitz, Wilhelm; Breithardt, Günter; Neumann, Joachim; Boknı́k, Peter

doi:10.1152/ajpheart.01036.2002

Cited by 53 publications

(53 citation statements)

References 36 publications

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“…Purinergic A 1 receptor activation and heart rate control. A cardiac A 1 -specific overexpressing mouse line has resting bradycardia and heart block that is pertussis toxin sensitive, setting a precedent for the identification of the physiologically relevant inhibitory G␣ subunit that couples this response (22). In contrast to the muscarinic system, in which we observed selectivity of inhibitory G␣-subunit responses, we did not see any clear effects of inhibitory G protein deletion on the negative chronotropic response after the addition of an A 1 adenosine receptor agonist.…”

Section: Tachycardia In Mice With Global G Protein Deletion In G␣ I2contrasting

confidence: 60%

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Zuberi

Birnbaumer²,

Tinker³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Section: Tachycardia In Mice With Global G Protein Deletion In G␣ I2contrasting

confidence: 60%

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Zuberi

Birnbaumer²,

Tinker³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The heart was excised under anesthesia and retrogradely perfused on a vertical Langendorff apparatus, and monophasic action potentials were recorded from the right atrial epicardium and LV epicardium as previously described (16,35). After an initial stabilization period, the intrinsic ventricular rhythm was observed after atrioventricular nodal block for 10 min to detect bradycardia-dependent arrhythmias.…”

Section: Isolation Of 5-ht4a Receptor Cdna and Generation Of Transgenmentioning

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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“…␣ 2ABC -Knockout (KO) mice were injected 16 hour antemortem with pertussis toxin 150 g/kg IP (Sigma, Munich, Germany). 23 …”

Section: Organ Bath Experimentsmentioning

confidence: 99%

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

et al. 2007

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Background-Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic ␣ 2 -adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine. Methods and Results-To test whether clonidine elicits pharmacological effects independent of ␣ 2 -adrenoceptors, we have generated mice with a targeted deletion of all 3 ␣ 2 -adrenoceptor subtypes (␣ 2ABC Ϫ/Ϫ ). ␣ 2ABC Ϫ/Ϫ mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in ␣ 2ABC Ϫ/Ϫ mice by up to 150 bpm. Clonidine-induced bradycardia in conscious ␣ 2ABC Ϫ/Ϫ mice was 32.3% (10 g/kg) and 26.6% (100 g/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from ␣ 2ABC -knockout and wild-type mice. Clonidine inhibited the native pacemaker current (I f ) in isolated sinoatrial node pacemaker cells and the I f -generating hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I f , clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and ␣ 2ABC -knockout mice. Conclusions-Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.

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Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Cited by 53 publications

References 36 publications

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Cardiac overexpression of the human 5-HT₄receptor in mice

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

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Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor

Cited by 53 publications

References 36 publications

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Cardiac overexpression of the human 5-HT4receptor in mice

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

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Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Cardiac overexpression of the human 5-HT₄receptor in mice