Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Magdeburger Straße 4, 06112, Halle (Saale), Germany.
Department of Cardiac Surgery, Mid-German Heart Center, University Hospital Halle, Ernst-Grube-Straße 40, 06097, Halle (Saale), Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep;397(9):6705-6720. doi: 10.1007/s00210-024-03047-1. Epub 2024 Mar 18.
Mosapride (4-amino-5-chloro-2-ethoxy-N-[[4-[(4-fluorophenyl) methyl]-2-morpholinyl]-methyl] benzamide) is a potent agonist at gastrointestinal 5-HT receptors. Mosapride is an approved drug to treat several gastric diseases. We tested the hypothesis that mosapride also stimulates 5-HT receptors in the heart. Mosapride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac overexpression of human 5-HT-serotonin receptors (5-HT-TG). However, it is inactive in wild-type mouse hearts (WT). Mosapride was less effective and potent than serotonin in raising the force of contraction or the beating rate in 5-HT-TG. Only in the presence of cilostamide (1 μM), a phosphodiesterase III inhibitor, mosapride, and its primary metabolite time dependently raised the force of contraction under isometric conditions in isolated paced human right atrial preparations (HAP, obtained during open heart surgery). In HAP, mosapride (10 μM) reduced serotonin-induced increases in the force of contraction. Mosapride (10 µM) shifted the concentration-response curves to serotonin in HAP to the right. These data suggest that mosapride is a partial agonist at 5-HT-serotonin receptors in HAP.
吗替麦考酚酯（4-氨基-5-氯-2-乙氧基-N-[[4-[(4-氟苯基)甲基]-2-吗啉基]-甲基]苯甲酰胺）是胃肠道 5-HT 受体的有效激动剂。吗替麦考酚酯是一种已批准用于治疗多种胃部疾病的药物。我们检验了这样一个假设，即吗替麦考酚酯也会刺激心脏中的 5-HT 受体。吗替麦考酚酯增加了心脏过表达人 5-HT-血清素受体（5-HT-TG）的小鼠离体心房标本的收缩力和心率。然而，它在野生型小鼠心脏（WT）中不起作用。吗替麦考酚酯在升高收缩力或心率方面的效力和效力均低于血清素在 5-HT-TG 中的作用。只有在存在磷酸二酯酶 III 抑制剂西洛司特（1 μM）的情况下，吗替麦考酚酯及其主要代谢物才能在分离的起搏的人类右心房标本（HAP 中）在等长条件下有时间依赖性地升高收缩力（在心脏直视手术期间获得）。在 HAP 中，吗替麦考酚酯（10 μM）减少了血清素引起的收缩力增加。吗替麦考酚酯（10 µM）使 HAP 中血清素的浓度-反应曲线向右移动。这些数据表明，吗替麦考酚酯在 HAP 中的 5-HT-血清素受体中是部分激动剂。
