Gergs Ulrich, Jung Franziska, Buchwalow Igor B, Hofmann Britt, Simm Andreas, Treede Hendrik, Neumann Joachim
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany;
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Am J Physiol Heart Circ Physiol. 2017 Dec 1;313(6):H1087-H1097. doi: 10.1152/ajpheart.00350.2017. Epub 2017 Sep 15.
Using transgenic (TG) mice that overexpress the human serotonin (5-HT) receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias. The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT.
我们利用在心肌细胞中特异性过表达人类血清素（5-羟色胺，5-HT）受体的转基因（TG）小鼠，旨在探究5-HT是否能在哺乳动物心脏中合成与降解，以及这是否同样会在该TG模型中引发变力性和变时性效应。我们注意到，5-HT前体5-羟色氨酸（5-HTP）可在TG小鼠而非野生型（WT）小鼠的心脏制剂中发挥变力性和变时性效应；在人类心房制剂以及使用超声心动图检测的完整TG动物中也发现了类似结果。此外，通过免疫组织化学，我们能够在小鼠心脏以及人类心房中检测到5-HT代谢酶和5-HT转运体。因此，在存在芳香族L-氨基酸脱羧酶抑制剂的情况下，TG和分离的人类心房制剂中5-HTP的正性变力作用消失，而且，参与5-HT降解的酶的抑制剂增强了5-HT在TG心房中的效力。神经递质释放剂可增加分离的TG心房的收缩力，且这种效应可被5-HT受体拮抗剂阻断。5-HT摄取抑制剂氟西汀提高了5-HT在TG心房中增加收缩力的效力。此外，有机阳离子和单胺转运体抑制剂明显降低了5-HT在TG心房中的正性变力效力。因此，我们初步得出结论，5-HT可能在哺乳动物心脏尤其是哺乳动物心肌细胞中进行局部合成和降解。可以想象，5-HT的这种形成以及可能受损的降解在不明原因的心动过速和其他心律失常病例中可能具有临床相关性。目前的研究表明，具有变力活性的血清素（5-HT）能够在小鼠和人类心脏中形成，且可能由心肌细胞自身合成。此外，5-HT的活性降解似乎也发生在哺乳动物心脏中。这些发现可能会再次提高研究人员对5-HT心脏效应的兴趣。
