Dataset Information

Amitriptyline functionally antagonizes cardiac H₂ histamine receptors in transgenic mice and human atria.

ABSTRACT: We have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H₂R-TG) mice that overexpress the human H₂ histamine receptor (H₂R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H₂Rs. Here, we wanted to determine whether the histamine effects in H₂R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H₂R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM-10 μM) to higher concentrations (rightward shift) in left atrial preparations from H₂R-TG. Similarly, in isolated perfused hearts from H₂R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H₂R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H₂R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 μM was reduced by 10-μM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H₂Rs in H₂R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.

SUBMITTER: Neumann J

PROVIDER: S-EPMC8208937 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Amitriptyline functionally antagonizes cardiac H2 histamine receptors in transgenic mice and human atria.

Neumann Joachim J Binter Maximilian Benedikt MB Fehse Charlotte C Marušáková Margaréta M Büxel Maren Luise ML Kirchhefer Uwe U Hofmann Britt B Gergs Ulrich U

Naunyn-Schmiedeberg's archives of pharmacology 20210224 6

We have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, wa ...[more]

PMID: 33625558

Similar Datasets

Project description:Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H2-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H2-histamine receptors in a cardiac-specific way (H2-TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H2-TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H2-TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H2-TG could be blocked by the H2-histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H2 and not H1-histamine receptors) more often induced arrhythmias in right atrial preparations from H2-TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H2-TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H2-TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H2-TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H2-TG than from WT. In summary, we noted that overexpression of human H2-histamine receptors in a novel transgenic animal model can lead to arrhythmias. We suggest that this model might be useful to understand the mechanism(s) of histamine-induced cardiac arrhythmias in humans better in a molecular way and may be of value to screen novel antiarrhythmic drugs.

Dataset Information

Amitriptyline functionally antagonizes cardiac H₂ histamine receptors in transgenic mice and human atria.

Publications

Amitriptyline functionally antagonizes cardiac H<sub>2</sub> histamine receptors in transgenic mice and human atria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets