Cardiac Effects of Novel Histamine H₂ Receptor Agonists

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 mice) and littermate wild type (WT) control mice 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 mice with pEC₅₀ values of 8.27, 9.38, and 8.28, respectively, but not in WT mice. Likewise, UR-Po563, UR-MB-158, and UR-MB-159 increased the beating rate in right atrium from H₂-TG mice with pEC₅₀ values of 9.01, 9.24, and 7.91, respectively, but not from WT mice. 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 mice. Similarly, UR-Po563, UR-MB-158, or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H₂-TG mice. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H₂-TG mice 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 neurologic 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 histamine H₂ receptor (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.