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Clozapine binds to H<jats:sub>2<\/jats:sub>-histamine receptors in vitro. We wanted to test the hypothesis that clozapine might be a functional antagonist at human cardiac H<jats:sub>2<\/jats:sub>-histamine receptors. To that end, we studied isolated electrically stimulated left atrial preparations and spontaneously beating right atrial preparations from transgenic mice with cardiomyocyte-specific overexpression of the human H<jats:sub>2<\/jats:sub>-histamine receptor (H<jats:sub>2<\/jats:sub>-TG). For comparison, we used wild-type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium (HAP) obtained from patients during bypass surgery. After pre-stimulation with histamine, clozapine (up to 10 \u00b5M) concentration and time dependently decreased beating rate in right atrial preparations from H<jats:sub>2<\/jats:sub>-TG. Clozapine concentration dependently 1, 3, and 10 \u00b5M decreased histamine-stimulated force of contraction in HAP. Clozapine (10 \u00b5M) decreased also the isoprenaline-stimulated force of contraction in HAP. In summary, clozapine can antagonize the function of H<jats:sub>2<\/jats:sub>-histamine and \u03b2-receptors in the human heart.<\/jats:p>","DOI":"10.1007\/s00210-024-03683-7","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T16:07:46Z","timestamp":1733933266000},"page":"6691-6706","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clozapine is a functional antagonist at cardiac human H2-histamine receptors"],"prefix":"10.1007","volume":"398","author":[{"given":"Jonas M. 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