TY - JOUR T1 - <strong>Cardiac effects of novel histamine H<sub>2</sub> receptor agonists</strong> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000822 SP - JPET-AR-2021-000822 AU - Ulrich Gergs AU - Maren L. Büxel AU - Merlin Bresinsky AU - Uwe Kirchhefer AU - Charlotte Fehse AU - Carina Höring AU - Britt Hofmann AU - Margareta Marusakova AU - Aneta Čináková AU - Rebecca Schwarz AU - Steffen Pockes AU - Joachim Neumann Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/09/17/jpet.121.000822.abstract N2 - In an integrative approach, we studied cardiac effects of recently published novel H2 receptor agonists in the heart of mice that overexpress the human H2 receptor (H2-TG), littermate wild type control mice (WT) and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H2 receptor agonists UR-Po563, UR-MB-158 and UR-MB-159 increased force of contraction in left atrium from H2-TG with pEC50 values of 8.27, 9.38, and 8.28, respectively, but not in WT. Likewise, UR-Po563, UR-MB-158 and UR-MB-159increased the beating rate in right atrium from H2-TG with pEC50 values of 9.01, 9.24, and 7.91, respectively, but not in WT. These effects could be antagonized by famotidine, a H2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff perfused hearts from H2-TG but not WT. Similarly, UR-Po563, UR-MB-158 or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H2-TG. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H2-TG were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H2 receptors in vitro and in vivo. We speculate that these compounds might be of some merit to treat neurological disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients. Significance Statement Recently, a new generation of H2R agonists has been developed as possible treatment option for Alzheimer's disease. Here, possible cardiac (side) effects of these novel H2R agonists have been evaluated. ER -