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

Neumann, Joachim; Grobe, Juliane M.; Weisgut, Jacqueline; Schwelberger, H. G.; Fogel, W. A.; Marušáková, Margaréta; Wache, Hartmut; Bähre, Heike; Buchwalow, Igor; Dhein, Stefan; Hofmann, Britt; Kirchhefer, Uwe; Gergs, Ulrich

doi:10.3389/fphar.2021.582916

Cited by 27 publications

(37 citation statements)

References 91 publications

(140 reference statements)

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“…Under normal conditions, 5-HT is stored in thrombocytes, so the heart receives 5-HT from the blood (Verbeuren 1990;1992). In the past, we presented evidence that 5-HT and histamine can also be produced by and found in considerable amounts in isolated cardiomyocytes (Neumann et al 2021, Pönicke et al 2012. The cardiovascular effects of 5-HT have been reviewed in detail elsewhere Levy, 2006, Neumann et al 2017).…”

Section: Introductionmentioning

confidence: 98%

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Neumann

Schwarzer

Fehse

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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In the past, we generated transgenic mice that overexpress the human histamine 2 (H2)-receptor (H2-TG) or that overexpress the human serotonin 4 (5-HT4)-receptor (5-HT4-TG) in the heart. Here, we crossbred these lines of mice to generate double transgenic mice that overexpress both receptors (DT). This was done to study a conceivable interaction between these receptors in the mouse heart as a model for the human heart. When in left atria, initially, force of contraction was elevated maximally with 1 µM serotonin, and subsequently, histamine was cumulatively applied; a biphasic effect of histamine was noted: the force of contraction initially decreased, maximally at 10 nM histamine, and thereafter, the force of contraction increased again at 1 µM histamine. Notably, functional interaction between 5-HT and histamine was also identified in isolated electrically stimulated trabeculae carneae from human right atrium (obtained during cardiac surgery). These functional and biochemical data together are consistent with a joint overexpression of inotropically active H2-receptors and 5-HT4-receptors in the same mouse heart. We also describe an antagonistic interaction on the force of contraction of both receptors in the mouse atrium (DT) and in the human atrial muscle strips. We speculate that via this interaction, histamine might act as a “brake” on the cardiac actions of 5-HT via inhibitory GTP-binding proteins acting on the activity of adenylyl cyclase.

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Section: Introductionmentioning

confidence: 98%

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Neumann

Schwarzer

Fehse

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Mast cells, present also in human hearts, contain large concentrations of histamine, but minor levels of histamine are found in most cells investigated (Jutel et al 2009). More recently, we presented evidence that histamine can be formed and degraded in cardiomyocytes (Gergs et al 2016;Neumann et al 2021b). Histamine can be taken up into the body via the gastrointestinal tract to some extent, but can also be formed from histidine by the enzyme histidine decarboxylase which is present in many cells of the human body.…”

Section: Introductionmentioning

confidence: 73%

“…Animals were maintained and handled according to approved protocols of the animal welfare committees of the Martin Luther University of Halle-Wittenberg, Germany. The generation and initial characterization of mice with cardiac-specific overexpression have been reported from our group (Gergs et al 2019(Gergs et al , 2020Neumann et al 2021b). We used an α-myosin heavy chain promoter to overexpress the human H 2 -histamine receptor in the mouse heart and tested the offspring for transgenes using the polymerase chain reaction (Gergs et al 2019(Gergs et al , 2020Neumann et al 2021b).…”

Section: Transgenic Micementioning

confidence: 99%

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Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Gergs

Weisgut

Griethe

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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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.

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“…1) and subsequently to an increase in the phosphorylation state of phospholamban (PLB, compare scheme in Fig. 1) and the inhibitory subunit of troponin (Neumann et al, 2021b). In isolated human atrial or ventricular preparations, besides histamine other histamine receptor agonists like amthamine (pD 2 = 5.38) or the more potent agonist impromidine (pD 2 = 6.59) have been studied (Bristow et al, 1982;Poli et al, 1994;Coruzzi et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Gergs

Büxel

Bresinsky

et al. 2021

J Pharmacol Exp Ther

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In an integrative approach, we studied cardiac effects of recently published novel H 2 receptor agonists in the heart of mice that overexpress the human H 2 receptor (H 2 -TG), littermate wild type control mice (WT) and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H 2 receptor agonists UR-Po563, UR-MB-158 and UR-MB-159 increased force of contraction in left atrium from H 2 -TG with pEC 50 values of 8.27, 9.38, and 8.28, respectively, but not in WT. Likewise, UR-Po563, UR-MB-158 and UR-MB-159increased the beating rate in right atrium from H 2 -TG with pEC 50 values of 9.01, 9.24, and 7.91, respectively, but not in WT. These effects could be antagonized by famotidine, a H 2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff perfused hearts from H 2 -TG but not WT. Similarly, UR-Po563, UR-MB-158 or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H 2 -TG. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H 2 -TG were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H 2 receptors in vitro and in vivo.We speculate that these compounds might be of some merit to treat neurological disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients.

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

Cited by 27 publications

References 91 publications

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Cardiac Effects of Novel Histamine H₂ Receptor Agonists

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

Cited by 27 publications

References 91 publications

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

Cardiac Effects of Novel Histamine H2 Receptor Agonists

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Cardiac Effects of Novel Histamine H₂ Receptor Agonists