Cardiovascular effects of metoclopramide and domperidone on human 5-HT 4 -serotonin-receptors in transgenic mice and in human atrial preparations

It is unclear whether metoclopramide and domperidone act on human cardiac serotonin 5-HT -receptors. Therefore, we studied transgenic mice that only express the human 5-HT receptor in cardiomyocytes in the atrium and in the ventricle (5-HT -TG), their wild type-littermates (WT) and isolated human atrial preparations. We found that only metoclopramide but not domperidone enhanced the force of contraction in left atrial preparations (pEC = 6.0 ± 0.1; n = 7) from 5-HT -TG, isolated spontaneously beating right atrial preparations (pEC = 6.1 ± 0.1; n = 7) from 5-HT -TG, Langendorff perfused hearts from 5-HT -TG, living 5-HT -TG and human right atrial muscle preparations obtained during bypass surgery of patients suffering from coronary heart disease. The maximum inotropic effect of metoclopramide was smaller (81 ± 2%) than that of 5-HT on the left atria from 5-HT -TG. The maximum increase in the beating rate due to metoclopramide was 93 ± 2% of effect of 5-HT on right atrial preparations from 5-HT -TG. Metoclopramide and domperidone were inactive in WT. We found that metoclopramide but not domperidone increased the phosphorylation state of phospholamban in the isolated perfused hearts or muscle strips of 5-HT -TG, but not in WT. Metoclopramide, but not domperidone, shifted the positive inotropic or chronotropic effects of 5-HT in isolated left atrial and right atrial preparations from 5-HT -TG dextrally, resp., to higher concentrations: the pEC of 5-HT for increase in force was in the absence of metoclopramide 8.6 ± 0.1 (n = 5) versus 8.0 ± 0.3 in the presence of 1 μM metoclopramide (n = 5; P