Histamine can be Formed and Degraded in the Human and Mouse Heart.

Joachim Neumann,Wieslawa Agnieszka Fogel,Igor B Buchwalow,Stefan Dhein,Uwe Kirchhefer,Hubert G Schwelberger,Ulrich Gergs,Britt Hofmann,Hartmut Wache,Margaréta Marušáková,Heike Bähre,Juliane M Grobe,Jacqueline Weisgut

doi:10.3389/fphar.2021.582916

Abstract

Histamine is metabolized by several enzymes in vitro and in vivo. The relevance of this metabolism in the mammalian heart in vivo is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H2-histamine receptors. In transgenic mice (H2-TG) that overexpress the human H2 receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H2-TG were used to investigate the putative relevance of histamine degrading enzymes in the mammalian heart. Histidine, the precursor of histamine, increased force of contraction (FOC) in human atrial preparations. Moreover, histamine increased the phosphorylation state of phospholamban in human atrium. Here, we could detect histidine decarboxylase (HDC) and histamine itself in cardiomyocytes of mouse hearts. Moreover, our data indicate that histamine is subject to degradation in the mammalian heart. Inhibition of the histamine metabolizing enzymes diamine oxidase (DAO) and monoamine oxidase (MAO) shifted the concentration response curves for the PIE in H2-TG atria to the left. Moreover, activity of histamine metabolizing enzymes was present in mouse cardiac samples as well as in human atrial samples. Thus, drugs used for other indication (e.g. antidepressants) can alter histamine levels in the heart. Our results deepen our understanding of the physiological role of histamine in the mouse and human heart. Our findings might be clinically relevant because we show enzyme targets for drugs to modify the beating rate and force of the human heart.

Highlights

Histamine was synthesized in a study to compare several monoamines by researchers in organic chemistry (Windaus and Vogt, 1907)
The effects of histidine and histamine (10 μM) on a H2histamine receptors. In transgenic mice (H2-TG) mouse left atrium are shown in Supplementary Figure S1
In a different set of patient samples, a positive inotropic effects (PIE) to single additions of histamine (1, 10, or 100 μM) was recorded which could be blocked by 10 μM cimetidine (Figure 3C)

Summary

Introduction

Histamine was synthesized in a study to compare several monoamines by researchers in organic chemistry (Windaus and Vogt, 1907). It is known that histamine is synthesized from histidine, for instance, in the human gut by bacteria (microbiome) and in many organs of the human body (e.g., enterochromaffine-like cells, neurons or mast cells) and that histamine produced in such a way in the gut or ingested with food can enter the body This is clinically relevant in some patients because they react e.g. with increased more rapid heartbeat (tachycardia) and fall in blood pressure (hypotension) to this orally applied histamine (Maintz et al, 2006; Haas et al, 2008; Schwelberger, 2010; Panula et al, 2015). The putative storage and release of histamine is indicated

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Conclusion