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.
Highlights
IntroductionCardiac H2Rs have been shown to mediate the positive inotropic effects (PIE) of exogenously applied histamine in isolated human cardiac preparations (Genovese et al 1988; Levi et al 1981; Sanders et al 1996; Zerkowski et al 1993)
Histamine is synthesized by cells, such as mast cells, in many organs of the mammalian body from histidine; histamine can Naunyn-Schmiedeberg's Arch Pharmacol (2021) 394:1251–1262Levi 1978)
Our results showed that histamine exerted a positive inotropic effects (PIE) in isolated electrically stimulated (1 Hz) left atrial preparations from H2R-TG mice; the PIE was concentration and time dependent (–log EC50 = 7.4)
Summary
Cardiac H2Rs have been shown to mediate the PIE of exogenously applied histamine in isolated human cardiac preparations (Genovese et al 1988; Levi et al 1981; Sanders et al 1996; Zerkowski et al 1993). The PIE in the human heart was accompanied by and, may have been mediated by an increase in 3’,5’-cyclic adenosine monophosphate (cAMP) content in human right atrial preparations (Sanders et al 1996) and the opening of L-type calcium channels (Eckel et al 1982, Fig. 1). The mode of action of the H2Rs in the human heart mimics the β-adrenoceptor system in the heart (Fig. 1). Stimulation of H2Rs generates cAMP in the heart, which leads to phospholamban (PLB) phosphorylation (H2R-TG, Gergs et al 2019b)
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