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.

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

“…Two different pharmacological effects would be in play: the proarrhythmic effect of more sensitive H 2 -histamine receptors and the anti-arrhythmic effect of the β-adrenoceptor antagonist, which might cancel each other out in a living patient with an intact vegetative nervous system. Mechanistically, it seems relevant that the overexpression of H 2 -histamine receptors in mouse heart increased the incidence of supraventricular arrhythmias in isolated right atrial preparations in these animals in an organ bath ( Neumann et al, 2021b ). This finding suggests that the increased density of H 2 -histamine receptors in patients might be caused by supraventricular arrhythmias.…”

“…Mice with the overexpression of H 2 -histamine receptors may be a better choice ( Gergs et al, 2019 , 2020 ). They have been successfully used to predict the effects of H 2 -histamine receptor agonists or H 2 -histamine receptor antagonists on human hearts ( Neumann et al, 2021b , c ).…”

“…However, such data indicate that these psychiatric drugs could clinically interfere with cardiac H 2 -histamine receptors. Based on these reports, amitriptyline was recently shown to antagonise the effects of histamine on the force of contraction in isolated atrial preparations from human hearts, indicating that old data on psychiatric drugs are still clinically relevant, and they have not been considered seriously in the past ( Neumann et al, 2021b ).…”

Possible Association between the Use of Proton Pump Inhibitors and H2 Receptor Antagonists, and Esophageal Cancer: A Nested Case–Control Study Using a Korean National Health Screening Cohort

“…The disparity in effects of H2RA at different exposure histories might be mediated by certain risk factors, including the presence of GERD and old age. Theoretically, H 2 receptors are mainly distributed in the myocardium of the right atrium and ventricle in animal studies [ 36 ]. Functional or structural alterations of H 2 receptors in cardiomyocytes may lead to cardiac arrhythmias [ 37 ].…”

Cardiac effects of ephedrine, norephedrine, mescaline, and 3,4-methylenedioxymethamphetamine (MDMA) in mouse and human atrial preparations

“…The homogenization of the samples, protein measurements, electrophoresis, primary and secondary antibody incubation, and quantification were performed following our previously established protocols (Boknik et al 2019 ; Gergs et al 2021 ; Neumann et al 2021a , 2021b ). The following primary antibodies were used: anti-phosphorylated troponin inhibitor (P-TnI; #4004, Cell Signaling Technology Europe, Leiden, Netherlands) and anti-calsequestrin (CSQ) used as loading control (#ab3516, Abcam, Cambridge, UK).…”