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

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 394; no. 6; pp. 1251 - 1262
• Main Authors: Neumann, Joachim, Binter, Maximilian Benedikt, Fehse, Charlotte, Marušáková, Margaréta, Büxel, Maren Luise, Kirchhefer, Uwe, Hofmann, Britt, Gergs, Ulrich
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2021; Springer Nature B.V
• Subjects: Amitriptyline; Biomedical and Life Sciences; Biomedicine; Heart; Histamine; Histamine receptors; Muscle contraction; Neurosciences; Original; Original Article; Pharmacology/Toxicology; Phospholamban; Phosphorylation; Rodents; Serine; Transgenic mice; Histamine; Amitriptyline; Human atrium; histamine receptor; Inotropy; Transgenic mice; H; Phospholamban phosphorylation; Chronotropy
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-021-02065-7

We have previously shown that histamine (2-(1 H -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 (H 2 R-TG) mice that overexpress the human H 2 histamine receptor (H 2 R) 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 H 2 Rs. Here, we wanted to determine whether the histamine effects in H 2 R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H 2 R-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 H 2 R-TG. Similarly, in isolated perfused hearts from H 2 R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H 2 R-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 H 2 R-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 H 2 Rs in H 2 R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.