Institute for Pharmacology and Toxicology (U.G., M.L.B., C.F., M.M., A.C., R.S., J.N.) and Cardiac Surgery (B.H.), Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; Institute of Pharmacy, University of Regensburg, Regensburg, Germany (M.B., C.H., S.P.); Institute for Pharmacology and Toxicology, University Hospital, Westfälische Wilhelms-Universität, Münster, Germany (U.K.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia (M.M., A.C.)
Institute for Pharmacology and Toxicology (U.G., M.L.B., C.F., M.M., A.C., R.S., J.N.) and Cardiac Surgery (B.H.), Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; Institute of Pharmacy, University of Regensburg, Regensburg, Germany (M.B., C.H., S.P.); Institute for Pharmacology and Toxicology, University Hospital, Westfälische Wilhelms-Universität, Münster, Germany (U.K.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia (M.M., A.C.).
J Pharmacol Exp Ther. 2021 Nov;379(3):223-234. doi: 10.1124/jpet.121.000822. Epub 2021 Sep 17.
In an integrative approach, we studied cardiac effects of recently published novel H receptor agonists in the heart of mice that overexpress the human H receptor (H-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 H receptor agonists UR-Po563, UR-MB-158, and UR-MB-159 increased force of contraction in left atrium from H-TG mice with pEC 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 H-TG mice with pEC values of 9.01, 9.24, and 7.91, respectively, but not from WT mice. These effects could be antagonized by famotidine, a H receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff-perfused hearts from H-TG but not WT mice. Similarly, UR-Po563, UR-MB-158, or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H-TG mice. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H-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 H 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 H receptor (HR) agonists has been developed as possible treatment option for Alzheimer's disease. Here, possible cardiac (side) effects of these novel HR agonists have been evaluated.
在综合方法中，我们研究了最近发表的新型 H 受体激动剂在心脏过表达人 H 受体（H-TG 小鼠）和同窝野生型（WT）对照小鼠中的心脏效应，以及接受心脏手术的患者的离体电驱动肌肉标本。在我们的实验条件下，H 受体激动剂 UR-Po563、UR-MB-158 和 UR-MB-159 分别使 H-TG 小鼠左心房的收缩力增加，pEC 值分别为 8.27、9.38 和 8.28，但在 WT 小鼠中没有增加。同样，UR-Po563、UR-MB-158 和 UR-MB-159 使 H-TG 小鼠右心房的搏动率增加，pEC 值分别为 9.01、9.24 和 7.91，但在 WT 小鼠中没有增加。这些作用可以被 H 受体拮抗剂法莫替丁拮抗。UR-Po563（1µM）增加了 H-TG 但不增加 WT 小鼠 Langendorff 灌注心脏的收缩力。同样，UR-Po563、UR-MB-158 或 UR-MB-159 增加了超声心动图中 H-TG 小鼠的左心室射血分数。最后，UR-Po563 增加了离体人右心房肌条的收缩力。UR-Po563 在 H-TG 小鼠中的收缩作用伴随着磷蛋白磷酸化状态的增加。总之，我们在这里报告了三种最近开发的激动剂，它们在体外和体内功能性刺激人心脏 H 受体。我们推测，如果这些化合物的心脏作用被同时应用的不能通过血脑屏障的受体拮抗剂阻断，或者可能对充血性心力衰竭患者有用，那么它们可能对治疗神经紊乱有一定的价值。意义声明：最近，新一代组胺 H 受体（HR）激动剂已被开发为治疗阿尔茨海默病的可能选择。在这里，评估了这些新型 HR 激动剂的可能心脏（副作用）。
