Ergometrine (6aR,9R)-N-((S)-1-hydroxypropan-2-yl)-7-methyl-4,6,6a,7,8,9-hexa-hydro-indolo-[4,3-fg]chinolin-9-carboxamide or lysergide acid β-ethanolamide or ergonovine) activates several types of serotonin and histamine receptors in the animal heart. We thus examined whether ergometrine can activate human serotonin 5-HT₄ receptors (h5-HT₄R) and/or human histamine H₂ receptors (hH₂R) in the heart of transgenic mice and/or in the human isolated atrium. Force of contraction or beating rates were studied in electrically stimulated left atrial or spontaneously beating right atrial preparations or spontaneously beating isolated retrogradely perfused hearts (Langendorff setup) of mice with cardiac specific overexpression of the h5-HT₄R (5-HT₄-TG) or of mice with cardiac specific overexpression of the hH₂R (H₂-TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery. Western blots to assess phospholamban (PLB) phosphorylation on serine 16 were performed. Ergometrine exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in atrial preparations starting at 0.3 µM and reaching a plateau at 10 µM in H₂-TGs (n = 7). This was accompanied by an increase in PLB phosphorylation at serine 16. Ergometrine up 10 µM failed to increase force of contraction in left atrial preparations from 5-HT₄-TGs (n = 5). Ten micrometer ergometrine increased the force of contraction in isolated retrogradely perfused spontaneously beating heart preparations (Langendorff setup) from H₂-TG but not 5-HT₄-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergometrine at 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, and these effects were eliminated by 10 µM of the H₂R antagonist cimetidine but not by 10 µM of the 5-HT₄R antagonist tropisetron. Furthermore, ergometrine showed binding to human histamine H₂ receptors (at 100 µM and 1 mM) using HEK cells in a recombinant expression system (pK_i < 4.5, n = 3). In conclusion, we suggest that ergometrine is an agonist at cardiac human H₂Rs.

麦角新碱 (6a R ,9 R ) -N -(( S )-1-羟基丙-2-基)-7-甲基-4,6,6a,7,8,9-六氢吲哚-[4, 3- fg ]chinolin-9-carboxamide 或 lysergide Acid β-ethanolamide 或 ergonovine）可激活动物心脏中几种类型的血清素和组胺受体。因此，我们检查了麦角新碱是否可以激活转基因小鼠心脏和/或人离体心房中的人血清素5-HT ₄受体（h5-HT ₄ R）和/或人组胺H ₂受体（hH ₂ R）。在电刺激的左心房或自发跳动的右心房准备物或自发跳动的离体逆行灌注心脏（Langendorff 设置）中研究收缩力或跳动率，这些小鼠心脏特异性过度表达 h5-HT ₄ R (5-HT ₄ -TG) ) 或心脏特异性过度表达 hH ₂ R (H ₂ -TG) 的小鼠或在心脏手术期间获得的电刺激的人右心房制剂中。进行蛋白质印迹以评估丝氨酸 16 上的受磷蛋白 (PLB) 磷酸化。在心房制剂中，麦角新碱在 H ₂ -TG 中从 0.3 µM 开始并在 10 µM 时达到稳定水平（ n = 7），从而发挥浓度和时间依赖性的正性肌力作用和正性变时作用。这伴随着 PLB 丝氨酸 16 磷酸化的增加。10 µM 麦角新碱未能增加 5-HT ₄ -TG 左心房制剂的收缩力（ n = 5）。 10 微米的麦角新碱增加了来自 H ₂ -TG 而非 5-HT ₄ -TG 的分离逆行灌注自发跳动心脏制剂（Langendorff 设置）的收缩力。在磷酸二酯酶抑制剂西洛酰胺 (1 µM) 存在下，10 µM 麦角新碱在心脏手术过程中获得的隔离电刺激人右心房制剂中发挥正性肌力作用，而这些作用可被 10 µM H ₂ R 拮抗剂西咪替丁消除但不能受到 10 µM 5-HT ₄ R 拮抗剂托烷司琼的影响。此外，在重组表达系统中使用 HEK 细胞时，麦角新碱显示出与人组胺 H ₂受体（100 µM 和 1 mM）的结合（p K _i < 4.5， n = 3）。总之，我们认为麦角新碱是人类心脏 H ₂ Rs 的激动剂。