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http://dx.doi.org/10.25673/81349
Titel: | Cardiovascular effects of metoclopramide and domperidone on human 5-HT4-serotonin-receptors in transgenic mice and in human atrial preparations |
Autor(en): | Neumann, Joachim Seidler, Tom Fehse, Charlotte Marušáková, Margaréta Hofmann, Britt Gergs, Ulrich |
Erscheinungsdatum: | 2021 |
Art: | Artikel |
Sprache: | Englisch |
Zusammenfassung: | It is unclear whether metoclopramide and domperidone act on human cardiac serotonin 5-HT4-receptors. Therefore, we studied transgenic mice that only express the human 5-HT4 receptor in cardiomyocytes in the atrium and in the ventricle (5-HT4-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 (pEC50 = 6.0 ± 0.1; n = 7) from 5-HT4-TG, isolated spontaneously beating right atrial preparations (pEC50 = 6.1 ± 0.1; n = 7) from 5-HT4-TG, Langendorff perfused hearts from 5-HT4-TG, living 5-HT4-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-HT4-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-HT4-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-HT4-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-HT4-TG dextrally, resp., to higher concentrations: the pEC50 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-HT4 receptors. In summary, we showed that metoclopramide, but not domperidone, was a partial agonist at human cardiac 5-HT4-receptors. |
URI: | https://opendata.uni-halle.de//handle/1981185920/83304 http://dx.doi.org/10.25673/81349 |
Open-Access: | ![]() |
Nutzungslizenz: | ![]() |
Sponsor/Geldgeber: | Publikationsfonds MLU |
Journal Titel: | European journal of pharmacology |
Verlag: | Elsevier |
Verlagsort: | New York, NY [u.a.] |
Band: | 901 |
Originalveröffentlichung: | 10.1016/j.ejphar.2021.174074 |
Enthalten in den Sammlungen: | Open Access Publikationen der MLU |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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1-s2.0-S0014299921002272-main.pdf | 5.91 MB | Adobe PDF | ![]() Öffnen/Anzeigen |