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Histamine can be Formed and Degraded in the Human and Mouse Heart
Joachim Neumann1, Juliane M Grobe1, Jacqueline Weisgut1
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
Insights
Histamine metabolism in the heart is significant, as inhibiting histamine-degrading enzymes (DAO and MAO) potentiates histamine's effects on heart function. This reveals potential drug targets for modulating heart rate and contractility.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Biochemistry
Background:
- Histamine exerts positive inotropic and chronotropic effects via H2-histamine receptors in humans.
- The role of histamine metabolism in the mammalian heart remains largely uncharacterized.
- Histamine and its precursor, histidine, are present in cardiomyocytes.
Purpose of the Study:
- To investigate the physiological relevance of histamine-metabolizing enzymes in the mammalian heart.
- To explore the impact of histamine metabolism on histamine-induced cardiac effects.
- To identify potential therapeutic targets for modulating cardiac function.
Main Methods:
- Utilized transgenic mice (H2-TG) overexpressing human H2 receptors in cardiomyocytes.
- Assessed histamine's effects on isolated atrial preparations from H2-TG and wild-type mice.
- Measured force of contraction and phosphorylation of phospholamban.
- Investigated the impact of inhibiting diamine oxidase (DAO) and monoamine oxidase (MAO) on histamine's effects.
Main Results:
- Histamine induced positive inotropic and chronotropic effects in H2-TG atrial preparations.
- Histidine administration increased force of contraction in human atrial preparations.
- Histamine increased phospholamban phosphorylation in human atrium.
- Inhibition of DAO and MAO shifted concentration-response curves for positive inotropic effects to the left in H2-TG atria.
- Histamine-metabolizing enzyme activity was detected in both mouse and human cardiac samples.
Conclusions:
- Histamine is subject to degradation in the mammalian heart.
- Inhibiting histamine-metabolizing enzymes enhances histamine's positive inotropic effects in the heart.
- These findings suggest that drugs affecting histamine metabolism (e.g., antidepressants) can alter cardiac function.
- Enzymes involved in histamine metabolism represent potential targets for therapeutic intervention in cardiovascular conditions.
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.
