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These NIE in mammalian atrium are often accentuated in the presence of cAMP-increasing agonists acting through GTP-binding stimulatory proteins in the sarcolemma such as isoprenaline (via \u03b2-adrenoceptors), histamine (via H\n                    <jats:sub>2<\/jats:sub>\n                    -histamine receptors) or serotonin (via 5-HT\n                    <jats:sub>4<\/jats:sub>\n                    -serotonin receptors) so-called \u201cindirect\u201d effects. Cantharidin inhibits protein phosphatases 1 and 2A (PP1, PP2A). We hypothesized that cantharidin would attenuate this NIE of R-PIA because R-PIA activated the PPs, whereas isoprenaline, serotonin, and histamine most likely inhibit PPs. Thence, during open-heart surgery in patients suffering from severe coronary heart disease, trabeculae carneae from human right atrium (HAP) were studied. These HAPs were put into organ baths and electrically stimulated (1\u00a0Hz). For comparison, we investigated isolated electrically paced (1\u00a0Hz) left atrial preparations (LA) from wild type mice (WT) or from mice with cardiac overexpression of H\n                    <jats:sub>2<\/jats:sub>\n                    -histamine receptors (H\n                    <jats:sub>2<\/jats:sub>\n                    -TG) or mice with cardiac overexpression of the human 5-HT\n                    <jats:sub>4<\/jats:sub>\n                    -serotonin receptors (5-HT\n                    <jats:sub>4<\/jats:sub>\n                    -TG). R-PIA led to negative inotropic effects (NIE) in HAP and LA from WT in the presence of isoprenaline, which were lessened by cantharidin. Likewise, R-PIA diminished force of contraction (FOC) in HAP and in LA from H\n                    <jats:sub>2<\/jats:sub>\n                    -TG excited by histamine, and also these NIE were made smaller by cantharidin. Similarly, R-PIA dampened FOC in HAP and in LA from 5-HT\n                    <jats:sub>4<\/jats:sub>\n                    -TG aroused by serotonin, and these NIE were weakened by cantharidin. We hypothesize that A\n                    <jats:sub>1<\/jats:sub>\n                    -adenosine receptors shrink the positive inotropic effects of \u03b2-adrenoceptors, H\n                    <jats:sub>2<\/jats:sub>\n                    -histamine receptors, or 5-HT\n                    <jats:sub>4<\/jats:sub>\n                    -serotonin receptors, in part, by activating PP1 and\/or PP2A in the human atrium.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04333-2","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T07:07:44Z","timestamp":1749452864000},"page":"17325-17338","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cantharidin attenuates the anti-\u03b2-adrenergic or anti-histaminergic or anti-serotoninergic effect of A1-adenosine receptor stimulation in the isolated human atrium"],"prefix":"10.1007","volume":"398","author":[{"given":"Rebecca","family":"Schwarz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britt","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"Kirchhefer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Gergs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"4333_CR1","doi-asserted-by":"crossref","unstructured":"Ahmad Z, Green FJ, Subuhi HS, Watanabe AM (1989) Autonomic regulation of type 1 protein phosphatase in cardiac muscle. 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J Cell Physiol 216(1):83\u201390. https:\/\/doi.org\/10.1002\/jcp.21375","DOI":"10.1002\/jcp.21375"}],"container-title":["Naunyn-Schmiedeberg's Archives of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-025-04333-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00210-025-04333-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-025-04333-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T04:31:01Z","timestamp":1764822661000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00210-025-04333-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,9]]},"references-count":47,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["4333"],"URL":"https:\/\/doi.org\/10.1007\/s00210-025-04333-2","relation":{},"ISSN":["0028-1298","1432-1912"],"issn-type":[{"type":"print","value":"0028-1298"},{"type":"electronic","value":"1432-1912"}],"subject":[],"published":{"date-parts":[[2025,6,9]]},"assertion":[{"value":"29 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animals\n                      : The investigation conformed to the Guide for the Care and Use of Laboratory Animals as published by the National Research Council (2011). The animals were handled and maintained according to the approved protocols of the Animal Welfare Committee of the University of Halle-Wittenberg, Halle, Germany (permission number TM1).\n                      Humans:\n                      This study in patients complies with the Declaration of Helsinki and has been approved by the local ethics committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed written consent was obtained from all patients included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors declare that they have seen and approved the submitted version of this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}