Cardiovascular effects of metoclopramide and domperidone on human 5-HT4-serotonin-receptors in transgenic mice and in human atrial preparations
Joachim Neumann, Tom Seidler, Charlotte Fehse, Margaréta Marušáková, Britt Hofmann, Ulrich Gergs
Abstract
It is unclear whether metoclopramide and domperidone act on human cardiac serotonin 5-HT 4 -receptors. Therefore, we studied transgenic mice that only express the human 5-HT 4 receptor in cardiomyocytes in the atrium and in the ventricle (5-HT 4 -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 50 = 6.0 ± 0.1; n = 7) from 5-HT 4 -TG, isolated spontaneously beating right atrial preparations (pEC 50 = 6.1 ± 0.1; n = 7) from 5-HT 4 -TG, Langendorff perfused hearts from 5-HT 4 -TG, living 5-HT 4 -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 4 -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 4 -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 4 -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 4 -TG dextrally, resp., to higher concentrations: the pEC 50 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 < 0.05); and the beating rate was 7.8 ± 0.2 (n = 7) in the absence of metoclopramide versus 7.2 ± 0.1 in the presence of 1 μM metoclopramide (n = 6; P < 0.05). These results suggested that metoclopramide had an antagonistic effect on human cardiac 5-HT 4 receptors. In summary, we showed that metoclopramide, but not domperidone, was a partial agonist at human cardiac 5-HT 4 -receptors.