Neumann Joachim, Grobe Juliane M, Weisgut Jacqueline, Schwelberger Hubert G, Fogel Wieslawa Agnieszka, Marušáková Margaréta, Wache Hartmut, Bähre Heike, Buchwalow Igor B, Dhein Stefan, Hofmann Britt, Kirchhefer Uwe, Gergs Ulrich
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
Department of Visceral, Transplant and Thoracic Surgery, Molecular Biology Laboratory, Medical University Innsbruck, Innsbruck, Austria.
Front Pharmacol. 2021 May 11;12:582916. doi: 10.3389/fphar.2021.582916. eCollection 2021.
Histamine is metabolized by several enzymes and . The relevance of this metabolism in the mammalian heart is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H-histamine receptors. In transgenic mice (H-TG) that overexpress the human H receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H-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 H-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.
组胺可被多种酶代谢。这种代谢在哺乳动物心脏中的相关性尚不清楚。然而，组胺可通过H组胺受体对人类产生正性肌力作用（PIE）和正性变时作用（PCE）。在心肌细胞中过表达人H受体但野生型同窝小鼠（WT）心肌细胞中未过表达的转基因小鼠（H-TG）中，组胺在分离的左心房或右心房制剂中诱导了PIE和PCE。这些H-TG被用于研究组胺降解酶在哺乳动物心脏中的假定相关性。组胺的前体组氨酸可增加人心房制剂中的收缩力（FOC）。此外，组胺可增加人心房中受磷蛋白的磷酸化状态。在此，我们在小鼠心脏的心肌细胞中检测到了组氨酸脱羧酶（HDC）和组胺本身。此外，我们的数据表明组胺在哺乳动物心脏中会被降解。抑制组胺代谢酶二胺氧化酶（DAO）和单胺氧化酶（MAO）可使H-TG心房中PIE的浓度反应曲线左移。此外，组胺代谢酶的活性在小鼠心脏样本以及人心房样本中均有存在。因此，用于其他适应症的药物（如抗抑郁药）可改变心脏中的组胺水平。我们的结果加深了我们对组胺在小鼠和人类心脏中生理作用的理解。我们的发现可能具有临床相关性，因为我们展示了可用于改变人类心脏跳动速率和力量的药物的酶靶点。
