Ergometrine stimulates histamine H2 receptors in the isolated human atrium

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 beta-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 H-2 receptors (hH(2)R) 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 hH(2)R (H-2-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 mu M and reaching a plateau at 10 mu M in H-2-TGs (n = 7). This was accompanied by an increase in PLB phosphorylation at serine 16. Ergometrine up 10 mu M 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 H-2-TG but not 5-HT4-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 mu M), ergometrine at 10 mu M exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, and these effects were eliminated by 10 mu M of the H2R antagonist cimetidine but not by 10 mu M of the 5-HT4R antagonist tropisetron. Furthermore, ergometrine showed binding to human histamine H-2 receptors (at 100 mu M 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 H(2)Rs.