Lysergic acid diethylamide stimulates cardiac human H 2 histamine receptors

doi:10.21203/rs.3.rs-2898645/v1

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Lysergic acid diethylamide stimulates cardiac human H 2 histamine receptors

https://doi.org/10.21203/rs.3.rs-2898645/v1

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published 04 Jul, 2023

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Introduction: Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT₄ serotonin receptors and/or H₂ histamine receptors.

Methods: We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT₄ receptor (5-HT₄-TG) or of the H₂-histamine receptor (H₂-TG). For comparison, we used wild type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium obtained from patients during bypass surgery.

Results: LSD (up to 10 µM) concentration dependently increased force of contraction and beating rate in left or right atrial preparations from 5-HT₄-TG (n=6, p<0.05) as a partial agonist in 5-HT₄-TG atrial preparations. The inotropic and chronotropic effects of LSD were antagonized by 10 µM tropisetron in 5-HT₄-TG. In contrast, LSD (10 µM) increased force of contraction and beating rate in left or right atrial preparations, from H₂-TG as a full agonist. After pre-stimulation with cilostamide (1 µM), LSD (10 µM) increased force of contraction in human atrial preparations (n = 6, p < 0.05). The contractile effects of LSD in human atrial preparations could be antagonized by by 10 µM cimetidine.

Conclusion: LSD leads to H₂-histamine receptor mediated cardiac effects in humans.

Significance: LSD is undergoing a revival in clinical studies. New indications for LSD especially in psychiatric patients are being found. Hence, there is a clinical need to understand its cardiac effects and possibly cardiac side effects better. The present work uses a translational approach to address this research need.

Lysergic acid diethylamide

H2-histamine receptor

heart

inotropy

chronotropy

Lysergic acid diethylamide (LSD, Fig. 1) was studied for use in psychiatry in the 1960s but was largely used in illicit ways and therefore removed from the market worldwide (review: Schlag et al. 2022). Currently, LSD is predominantly used for recreational purposes, and intoxications are recorded (review: Schlag et al. 2022).

Histamine acts via histamine H₁, H₂, H₃ and H₄ receptors (Panula et al. 2015, Neumann et al. 2021). In the heart of mammals, all four histamine receptor subtypes have been described at RNA and/or protein level.

However, species differences exist in the cardiac effects of histamine (Neumann et al. 2021). In the mouse, rat, dog and cat heart, a direct histamine receptor mediated inotropic or chronotropic effect is missing: inotropic effects of histamine were found to be indirect via release of endogenous catecholamines (Flacke et al., 1967; Dai et al., 1976; Laher and McNeill, 1980a, 1980b, Gergs et al. 2019).

Moreover, even regional differences in the actions of histamine in the mammalian heart are known: in the rabbit atrium, H₁ receptors are more prevalent and a positive inotropic effect mediated by H₁ and phospholipase C activation has been described (Hattori et al., 1988). In contrast, in the rabbit ventricle a positive inotropic effect by H₂ receptor activation via activation of adenylyl cyclase, a subsequent increase in cAMP and elevation of the activity of a cAMP dependent protein kinase (PKA) was noted by the same group (Hattori et al., 1990, 1991). In humans, H₂ receptors were measurable in both the atrium and ventricle (radioligand binding: Baumann et al., 1982, 1983, 1984, antibody and RNA expression: Matsuda et al., 2004). In humans, the cardiac H₂ receptors mediate a positive inotropic effect in isolated human atrial cardiac preparations (Levi et al., 1981, Genovese et al., 1988, Zerkowski et al., 1993, Thoren et al., 2011, Sanders et al., 1996). Infusion of histamine in patients led to an increase in heart beat and an increase in the first derivative of pressure development in the left ventricle (Vigorito et al., 1983). These effects of histamine in the human heart are not due to a release of noradrenaline: the human H₂ receptor mediates the cardiac actions of histamine in isolated human cardiomyocytes in vitro where a release of noradrenaline from nerve cells was excluded (Sanders et al., 1996).

LSD is a partial agonist at rabbit and guinea pig cardiac H₂ receptors: at low concentrations LSD increases beating rate, and at high concentrations decreases beating rate, in isolated right atrial preparations from rabbits in a cimetidine sensitive fashion (Angus and Black 1980). Moreover, LSD antagonized the positive inotropic effect of histamine in isolated guinea pig papillary muscles (Angus and Black 1980). To the best of our knowledge, the effects of LSD on human cardiac H₂ receptors have not been reported.

LSD can also act as an agonist at serotonin receptors. 5-HT_2A receptors mediate the hallucinogenic effects of LSD (Schlag et al. 2022). In the human heart, all inotropic and chronotropic effects of serotonin (5-HT) are 5-HT₄ receptor mediated (reviews: Neumann et al 2017, 2023). We generated and characterized a mouse model with cardiomyocyte-specific overexpression of the human 5-HT₄ receptor (5-HT₄-TG) to investigate the actions of the receptor better (Gergs et al. 2010). In a similar fashion as described above for histamine, 5-HT in the heart of wild type littermate mice (WT) has no receptor mediated inotropic effects. However, in 5-HT₄-TG, 5-HT exerted positive inotropic effects both in vivo and in vitro (Gergs et al. 2010, 2013). Based on this work from our group, we decided to use 5-HT₄-TG to study a putative cardiac role of LSD via 5-HT₄-receptors (Fig. 1). To test the clinical relevance of our findings, we set out to measure the effects of LSD under isometric conditions on the force of contraction in the human heart. To this end, we used electrically stimulated right atrial strips obtained rapidly from the surgical theatre.

In summary, we studied the following hypotheses: firstly, LSD stimulates contractility in H₂-TG. Secondly, LSD stimulates contractility in 5-HT₄-TG. Thirdly, LSD increases the force of contraction in the isolated human atrium via H₂–histamine and/or 5-HT₄–serotonin receptors. A progress report of our work has been reported in abstract form (Jacob et al. 2023).

2.1. Transgenic mice

The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the National Research Council (2011). Animals were maintained and handled according to approved protocols of the animal welfare committees of the University of Halle-Wittenberg, Germany. The generation and initial characterization of the transgenic mice has been described before (Gergs et al. 2010, 2019). In brief, for generation of transgenic mice by pronuclear DNA injection, human H₂ -receptor cDNA or human 5-HT₄ receptor cDNA were inserted into a mouse cardiac α-myosin heavy chain promoter expression cassette. For all experiments, adult transgenic mice and WT littermates of both sexes were used.

2.2. Contractile studies in mice

As described before, the right or left atrial preparations from the mice were isolated and mounted in organ baths (Gergs et al. 2013; Neumann et al. 1998). The bathing solution of the organ baths contained 119.8 mM NaCI, 5.4 mM KCI, 1.8 mM CaCl₂, 1.05 mM MgCl₂, 0.42 mM NaH₂PO₄, 22.6 mM NaHCO₃, 0.05 mM Na₂EDTA, 0.28 mM ascorbic acid and 5.05 mM glucose. The solution was continuously gassed with 95% O₂ and 5% CO₂ and maintained at 37°C and pH 7.4 (Neumann et al. 1998, Kirchhefer et al. 2004). Spontaneously beating right atrial preparations from mice were used to study any chronotropic effects. After equilibration was reached, ergometrine was cumulatively added to left atrial or right atrial preparations to establish concentration-response curves. Then, where indicated, either serotonin or histamine was additionally applied to the preparations. In separate experiments, concentration-response curves to ergotamine in mouse left atrial preparations were obtained and, after the effect of 10 µM ergotamine had reached a plateau, the atrial strips were rapidly brought to the temperature of liquid nitrogen for further study.

2.3. Contractile studies on human preparations

The contractile studies on human preparations used the same setup and buffer as in the mouse studies. The samples were obtained from 3 male patients and 4 female patients, 78–82 years old. Drug therapy included metoprolol, furosemide, apixaban and acetyl salicylic acid. Our methods used for atrial contraction studies in human samples have been previously published and were not altered in this study (Gergs et al. 2009, 2021b).

2.4. Langendorff-perfused Hearts

Heart preparations were utilized as described previously (Kirchhefer et al., 2014; Gergs et al., 2020). Mice were anesthetized intraperitoneally pentobarbital sodium (50 mg kg-1 body weight) and treated with 1.5 units of heparin. The hearts were removed from the opened chest, immediately attached by the aorta to a 20-gauge cannula, and perfused retrogradely under constant flow of 2 ml min^− 1 with oxygenized buffer solution (37°C) containing (in mM): NaCI 119.8, KCI 5.4, CaCl₂ 1.8, MgCl₂ 1.05, NaH₂P0₄ 0.42, NaHCO₃ 22.6, Na₂EDTA 0.05, ascorbic acid 0.28 and glucose 5.0 in an in-house built isolated heart system equipped with a PowerLab system (ADInstruments, Oxford, United Kingdom). The heart preparations were allowed to equilibrate for 30 min before measurements. Hearts contracted spontaneously in sinus rhythm, and heart rate and force of contraction were measured and monitored continuously. The first derivative of left ventricular contraction (+ dF/dt and − dF/dt) was calculated (LabChart, ADInstruments, Oxford, United Kingdom).

2.5. Western Blot Analysis

Homogenates from ventricular tissue samples were prepared in 300 µl of 10 mM NaHCO₃ and 100 µl 20% SDS. Crude extracts were incubated at 25°C for 30 min before centrifugation to remove debris and thereafter, the supernatants (= homogenates) were separated and stored at -80°C until further use. Western blot analysis was performed as previously described (Abella et al., 2023). Briefly, aliquots of 20 µg of protein were loaded per lane and finally, bands were detected using enhanced chemiluminescence (ECL, Amersham (Cytiva), Freiburg, Germany) together with an Amersham ImageQuant 800 imager (Cytiva, Freiburg, Germany). The following primary antibodies were used in this study: polyclonal rabbit anti phospho-PLB (antibody was raised against PLB-peptide phosphorylated at serine-16, Badrilla, Leeds, UK) and polyclonal rabbit anti calsequestrin (CSQ, abcam, Cambridge, UK). The characteristics and use of these antibodies has been reported repeatedly by our group (Kirchhefer et al., 2002). The antibody against calsequestrin was used as loading control.

2.6. Radioligand Competition Binding.

Radioligand competition binding experiments were performed as previously described by using the HEK293-SP-FLAG-hH2R cell line and [³H]DE257 (K_d = 66.9 nM, c = 40 nM) (Baumeister et al., 2015; Pockes et al., 2018; Rosier et al., 2021). Ligand dilutions were prepared 10-fold concentrated in L-15 with 1% BSA, and 10 µL/ well was transferred to a flat-bottom polypropylene 96-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), as well as 10 µL/ well of the respective radioligand. The cells were adjusted to a density of 1.25 × 10⁶ cells/mL, and 80 µL of the cell suspension was added to each well (total volume of 100 µL). All data were analyzed using GraphPad Prism 9 software (San Diego, CA, USA). The normalized competition binding curves were then fitted with a four-parameter logistic fit yielding pIC₅₀ values. These were transformed into pK_i values using the Cheng − Prusoff equation (Cheng and Prusoff 1973).

2.7. Data Analysis

Data shown are means ± SEM. Statistical significance was estimated by analysis of variance followed by Bonferroni´s t-test. A p-value < 0.05 was considered as significant.

2.8. Drugs and materials

LSD was supplied as a stock solution from Merck, Germany. All other chemicals were of analytical grade. Demineralized water was used throughout the experiments. Stock solutions were freshly prepared daily.

2.5. Western Blot Analysis

2.6. Radioligand Competition Binding.

2.7. Data Analysis

Data shown are means ± SEM. Statistical significance was estimated by analysis of variance followed by Bonferroni´s t-test. A p-value < 0.05 was considered as significant.

2.8. Drugs and materials

1. Left atrium from H₂-TG

We first cumulatively applied LSD (0.1 µM to 10 µM). Subsequently, histamine was additionally and cumulatively applied. In left atrial preparations from H₂-TG (Fig. 2A) but not from WT (Fig. 2B), LSD exhibited a time- and concentration-dependent positive inotropic effect that was not stimulated further by histamine (Fig. 2A). In WT, neither histamine nor LSD had a positive inotropic effect (Fig. 2B). These data are summarized with regard to the force of contraction for H₂-TG (Fig. 2C). Moreover, in the same samples, LSD shortened the time to peak tension (Fig. 2D) and the time of relaxation Fig. 2E). Furthermore, LSD also augmented the absolute values of the rate of tension development (Fig. 2F) and the rate of relaxation (Fig. 2G). Subsequently applied histamine (1 nM to 10 µM) did not add to the effect of previously applied LSD.

2. Right atrium from H₂-TG

Next, we were interested in right atrial function, under the same experimental conditions used in the left atrium. LSD time- and concentration-dependently increased the beating rate of right atrial preparations from H₂-TG but not from WT. This is displayed in an original muscle strip in Fig. 3A (H₂-TG). Summarized data for the beating rates can be found in Fig. 3B (H₂-TG).

3. Left atrium from 5-HT₄-TG

In separate studies, we first cumulatively applied LSD (0.1 µM to 10 µM). Subsequently, serotonin was cumulatively applied. In left atrial preparations from 5-HT₄-TG, LSD exhibited a concentration- and time-dependent positive inotropic effect that was stimulated further by serotonin (Fig. 4A). These data are summarized in Fig. 4B with regard to force of contraction. Moreover, in the same samples, LSD shortened the time to peak tension (Fig. 4C) and the time of relaxation (Fig. 4D) in 5-HT₄-TG. Furthermore, LSD also augmented the absolute values of the rate of tension development (Fig. 4E) and the rate of relaxation (Fig. 4F). Subsequently applied serotonin (1 nM to 10 µM) added to the effect of previously applied LSD.

4. Right atrium from 5-HT₄-TG

Next, we were interested in right atrial function under the same experimental conditions as used in the left atrium. LSD time- and concentration-dependently increased the beating rate of right atrial preparations from 5-HT₄-TG (original muscle strip in Fig. 5A). While LSD increased the beating rate in 5-HT₄-TG, additionally applied serotonin did not stimulate the beating rate any further (Fig. 5A).

5. Antagonists

To confirm the role of the H₂ receptor and the 5-HT₄ serotonin receptor in transgenic mice, we used antagonists: cimetidine antagonized the positive inotropic effect or the positive chronotropic effect of LSD in H₂-TG (original recording: Fig. 6A, Fig. 6B). Likewise, tropisetron antagonized the positive inotropic effect or the positive chronotropic effect of LSD in 5-HT₄-TG (data not shown).

6. Langendorff perfused hearts

Next, it was of interest to investigate ventricular effects of LSD. To this end, we used isolated retrogradely perfused hearts (Langendorff preparations), allowed to beat spontaneously. We recorded force of contraction from the apex and measured ventricular function under these conditions. We noted that 10 µM LSD increased force of contraction in hearts from H₂-TG and, to a lesser extent, 5-HT₄-TG, but not in hearts from WT (Table 1).

Table 1

Maximum effect of LSD (10 µM) on force of contraction in milli Newton (mN) and the rate of tension relaxation mN/seconds (mN/s) in isolated perfused hearts from H₂-TG, 5-HT₄-TG and WT. # indicate p < 0.05 versus pre-drug (10 µM LSD) value. N = number of animals.
	WT	H₂-TG	5-HT₄-TG
N=	5	5	5
Basal force (mN)	12.6 ± 2.7	9.0 ± 1.8	11.6 ± 3.4
Force after LSD (mN)	14.9 ± 2.6	15.1 ± 2.6#	14.8 ± 3.5#
Basal rate of relaxation (mN/s)	176 ± 38.7	165 ± 33.3	215 ± 63.6
Rate of relaxation after LSD (mN/s)	186 ± 38.5	315 ± 55.6#	308 ± 85.6#

7. Protein phosphorylation in mouse samples

In freeze-clamped isolated atrial preparations, LSD increased the phosphorylation state of phospholamban at amino acid serine 16 in preparations from H₂-TG and, to a lesser extent, 5-HT₄-TG. Figure 7A displays a typical Western blot. Data are statistically analyzed in Fig. 7B.

8. Effects in human atrium

In isolated human atrial preparations, we usually measured the effect of LSD in the presence of 1 µM cilostamide. Initially cilostamide on its own increased force of contraction. Thereafter, additionally applied LSD raised force of contraction further. This positive inotropic effect of LSD was completely reversed by additionally applied cimetidine (Fig. 8A, bottom). In one sample, however, we noted a pronounced positive inotropic effect of LSD alone in a human atrial muscle strip (Fig. 8, top). The inotropic effects can be seen in Fig. 8B. Similarly, cilostamide and additionally applied LSD raised the absolute maximum rates of tension development (Fig. 8C) and of relaxation development (Fig. 8D). In contrast to cimetidine, tropisetron failed to antagonize the positive inotropic effect of LSD in human atrial preparations (data not shown).

Moreover, LSD could activate human H₂-receptors in cell culture (using a recombinant expression system (pKi 4.49 ± 0.09, n = 3), suggesting a direct agonistic action of LSD at human H₂-receptors.

LSD has a role as a recreational drug or drug of abuse (De Gregorio et al. 2016). LSD is used for these purposes probably because LSD is very potent agonist a 5-HT_2A receptors, where binding is thought to lead to hallucinations that some users crave for. In conjunction, it is almost certain that more than one receptor is involved in the central nervous system actions of LSD because it has long known that LSD has a high affinity for many G-protein coupled receptors (Roth et al. 2002). For instance, LSD binds with high affinity to all five dopamine receptors and most serotonin receptors (Roth et al. 2002). Hence, the signal transduction of LSD is complex (review: Olson 2022). However, LSD binding to 5-HT₄ receptors appears to be unreported.

The first evidence for LSD action at H₂ receptors was found in membranes from guinea pig brains, where LSD increased the activity of adenylate cyclase in a cimetidine sensitive manner, and thus proved to be H₂ receptor mediated (Green et al. 1978). Indeed, our data in transgenic animals indicate that LSD is an agonist at human H₂ receptors as the effects of a high concentration of LSD reached a plateau, indicating full receptor saturation. Under these conditions, exogenous histamine was ineffective.. The evidence that LSD exerted these actions via H₂ receptors is several fold. Firstly, LSD was only active in H₂-TG samples and not in WT simples. Secondly, the effect of LSD on force and beating rate in H₂-TG samples could be antagonized by cimetidine, known as a selective antagonist at H₂ receptors. Thirdly, LSD led to an increase in phosphorylation of PLB (Fig. 1), a pathway expected for H₂ receptor agonists (Gergs et al. 2019). Fourthly, in transfected cells, LSD could bind to H₂ receptors. Moreover, our findings are in line with previous animal studies where LSD could increase force or/and beating rate in rabbit or guinea-pig cardiac muscle strips (Angus and Black 1980). These effects were blocked by cimetidine (Angus and Black 1980).

We proved that stimulation of H₂ receptors is clinically relevant in humans when the inotropic effect of LSD in isolated human heart samples was blocked by cimetidine, thus demonstrating a H₂ receptor mediated response. Moreover, we would argue the fact that we usually required phosphodiesterase III inhibition by cilostamide argues that also in the human heart H₂ receptors couple LSD to force generation. There are data that H₂ stimulation in human heart samples leads to cAMP increases and activation of cAMP dependent protein kinase (Fig. 1, review: Neumann et al. 2021).

PLB is only expressed in cardiomyocytes and not in non-cardiomyocytes. The fact that we measured an increase in PLB phosphorylation in atrial samples is strongly indicative that the H₂ receptors are present and functional in cardiomyocytes. We also used the alpha myosin promotor, which drives expression in the heart only in cardiomyocytes (Subramaniam et al., 1993).

H₂ activation is expected to activate PKA, which only phosphorylates PLB on serine 16 (Simmerman et al., 1986). This augmented phosphorylation of PLB explains at least in part the relaxant effects and inotropic effects of LSD in the human atrium.

Clinical relevance:

Our data have at least two clinical applications. Firstly, intoxications with LSD have been well reported. Intoxication with LSD were accompanied with tachycardia by 40% of recreational users, demonstrating that cardiac side effects of LSD are clinically relevant (Leonard et al. 2018, Passie et al. 2008).

Should these intoxications be accompanied by cardiac arrhythmias, our data suggest that it might be worthwhile to test cimetidine as an antidote. Cimetidine is an approved drug and, when given intravenously, should block any effects of LSD on cardiac H₂ receptors that may have directly caused an arrhythmia.

As well as intoxication treatment options, our data might supply evidence for LSD to be used as a therapeutic drug. Recently, efforts have been renewed to treat psychiatric patients with LSD (Gasser et al. 2015). Indeed, there are currently 148 studies on clinicaltrials.gov for LSD. Our data will allow calculations for safe plasma concentrations of LSD, to act on high affinity brain receptors but not on cardiac H₂ receptors. We also show that 5-HT₄ receptors should not cause cardiac arrhythmias in users of LSD. Reported therapeutic plasma levels after taking 100 µg perorally LSD is 1.3 ng/ml (about 4 nM, Dolder et al. 2018), and for recreational purposes about 5 fold higher doses were reported, leading to 20 nM plasma concentrations of LSD (Dolder et al. 2018). However, these plasma concentrations might be higher if the metabolism of LSD is impaired either by additionally applied drugs or when (for genetic reasons) patients exhibit low metabolism of LSD (Luethi et al. 2019).

Limitations

We have not had the opportunity to study human ventricular samples in our contraction study due to lack of access to that tissue. Hence, we can only extrapolate from our Langendorff data in H₂-TG that LSD will also have effects on the human ventricle.

In conclusion, LSD is a full agonist at human H₂ histamine receptors and a partial agonist at 5-HT₄ receptors in transgenic mice. LSD acts as an agonist at H₂ receptors but not as an agonist at 5-HT₄ receptors in the isolated human atrium.

Acknowledgements

The authors thank Pia Willmy for expert technical assistance. This work contains parts of theses of JH and PB.

Authors´s contributions: JN and UK devised the study, JN wrote the first draft, draft was improved written by LH, SP, UK, UG, BH. Supplied material (UK) and clinical data (BH), performed experiments: HJ, JN, LH, PB. Analyzed data: UK, PB, HJ, SP. Graphed data: UG, SP, HJ. All authors have read and approved the submission of this version. . All authors have read and agree with the submission of the present version of the work. The authors declare that all data were generated in-house and that no paper mill was used.

Funding: no external funding

Availability of data and materials: The data of this study are available from the corresponding author upon reasonable request.

Ethical Approval Animals: The investigation conformed to the Guide for the Care and Use of Laboratory Animals as published by the National Research Council (2011). The animals were handled and maintained according to the approved protocols of the Animal Welfare Committee of the University of Halle-Wittenberg, Halle, Germany. Humans: This study complies with the Declaration of Helsinki and has been approved by the local ethics committee (hm-bü 04.08.2005).

Consent to Participate: Informed consent was obtained from all patients included in the study.

Consent to Publish: All authors declare that they have seen and approved the submitted version of this manuscript.

Competing Interests:

The authors declare no competing interests of financial or personal nature.

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Lysergic acid diethylamide stimulates cardiac human H 2 histamine receptors

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

2.1. Transgenic mice

2.2. Contractile studies in mice

2.3. Contractile studies on human preparations

2.4. Langendorff-perfused Hearts

2.5. Western Blot Analysis

2.7. Data Analysis

2.8. Drugs and materials

2.5. Western Blot Analysis

2.7. Data Analysis

2.8. Drugs and materials

Results

1. Left atrium from H₂-TG

2. Right atrium from H₂-TG

3. Left atrium from 5-HT₄-TG

4. Right atrium from 5-HT₄-TG

5. Antagonists

6. Langendorff perfused hearts

7. Protein phosphorylation in mouse samples

8. Effects in human atrium

Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1

Lysergic acid diethylamide stimulates cardiac human H 2 histamine receptors

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

2.1. Transgenic mice

2.2. Contractile studies in mice

2.3. Contractile studies on human preparations

2.4. Langendorff-perfused Hearts

2.5. Western Blot Analysis

2.7. Data Analysis

2.8. Drugs and materials

2.5. Western Blot Analysis

2.7. Data Analysis

2.8. Drugs and materials

Results

1. Left atrium from H2-TG

2. Right atrium from H2-TG

3. Left atrium from 5-HT4-TG

4. Right atrium from 5-HT4-TG

5. Antagonists

6. Langendorff perfused hearts

7. Protein phosphorylation in mouse samples

8. Effects in human atrium

Discussion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1

1. Left atrium from H₂-TG

2. Right atrium from H₂-TG

3. Left atrium from 5-HT₄-TG

4. Right atrium from 5-HT₄-TG