Cardiac Effects of Novel Histamine H₂ Receptor Agonists

Abstract

In an integrative approach, we studied cardiac effects of recently published novel H 2 receptor agonists in the heart of mice that overexpress the human H 2 receptor (H 2 -TG), littermate wild type control mice (WT) and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H 2 receptor agonists UR-Po563, UR-MB-158 and UR-MB-159 increased force of contraction in left atrium from H 2 -TG with pEC 50 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 H 2 -TG with pEC 50 values of 9.01, 9.24, and 7.91, respectively, but not in WT. These effects could be antagonized by famotidine, a H 2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff perfused hearts from H 2 -TG but not WT. Similarly, UR-Po563, UR-MB-158 or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H 2 -TG. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H 2 -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 H 2 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.

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

“…When generated, cAMP then activates a cAMP-dependent protein kinase (PKA), which then phosphorylates typical targets in the heart ( Figure 1A ). Some of these targets are still hypothetical substrates, such as the ryanodine receptor, whereas others have been shown in transgenic mice (phospholamban, phosphatase inhibitor 1) ( Gergs et al, 2019 , 2020 , 2021b ; Neumann et al, 2021d ). Moreover, H 2 R stimulation can increase the phosphorylation state of the inhibitory subunit of troponin (TnI) and the myocardial C-protein.…”

Cardiac effects of ephedrine, norephedrine, mescaline, and 3,4-methylenedioxymethamphetamine (MDMA) in mouse and human atrial preparations

“…In brief, the right or left atrial preparations from 4- to 6-month-old CD-1 mice were isolated and mounted in organ baths as previously described (Boknik et al 2019 ; Gergs et al 2021 ; Neumann et al 2021b ). The bathing solution of the organ baths contained 119.8 mM NaCI, 5.4 mM KCI, 1.8 mM CaCl 2 , 1.05 mM MgCl 2 , 0.42 mM NaH 2 PO 4 , 22.6 mM NaHCO 3 , 0.05 mM Na 2 EDTA, 0.28 mM ascorbic acid, and 5.05 mM glucose.…”

“…The contractile studies on human preparations were done as described before (Boknik et al 2019;Gergs et al 2009Gergs et al , 2021. Human right atrial preparations were used with the same setup and buffer as described for mouse preparations (see above).…”

Non-Invasive Assessment of Locally Overexpressed Human Adenosine 2A Receptors in the Heart of Transgenic Mice

“…Right atrium samples were obtained from patients undergoing open-heart surgery with coronary artery bypass grafts and electrically stimulated in organ baths, as described previously [31,32]. This study complied with the Declaration of Helsinki and was approved by the local ethics committee (hm-bü04.08.2005).…”

“…The contractile function of mouse left atrial preparations were performed as previously described [21,31]. Control conditions were obtained by 1 µg/mL adenosine deaminase (ADA; Roche Diagnostics Deutschland GmbH, Mannheim, Germany), 1 µM of A 1 -AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; TOCRIS, Bio-Techne GmbH, Wiesbaden-Nordenstadt, Germany), and for the CGS 21680 (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) antagonisation, 1 µM FLUDA instead of 1 µM ZM 241385 (TOCRIS, Bio-Techne GmbH, Wiesbaden-Nordenstadt, Germany) was used.…”