Human histamine H2 receptors can initiate cardiac arrhythmias in a transgenic mouse

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2021-09, Vol.394 (9), p.1963-1973
• Main Authors: Gergs, U., Weisgut, J., Griethe, K., Mißlinger, N., Kirchhefer, U., Neumann, Joachim
• Format: Article
• Language: English
• Subjects: Animal models; Arrhythmia; Biomedical and Life Sciences; Biomedicine; Calcium channels; Cardiac arrhythmia; Cimetidine; Fentanyl; Heart; Histamine; Histamine H2 receptors; Histamine receptors; Ketamine; Morphine; Muscle contraction; Neurosciences; Original; Original Article; Pharmacology/Toxicology; Signal transduction; Sodium channels; Transgenic animals; Transgenic mice; Ventricle
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-021-02098-y

Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H 2 -histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H 2 -histamine receptors in a cardiac-specific way (H 2 -TG) in comparison with their wild-type (WT) littermate controls. We had shown before that histamine exerted concentration and time-dependent positive inotropic and positive chronotropic effects only in cardiac preparations from H 2 -TG and not from WT. We noted under basal conditions (no drug addition) that right atrial preparations from H 2 -TG exhibited more spontaneous arrhythmias than right atrial preparations from WT. These arrhythmias in H 2 -TG could be blocked by the H 2 -histamine receptor antagonist cimetidine. In a similar fashion, histamine and dimaprit (an agonist at H 2 and not H 1 -histamine receptors) more often induced arrhythmias in right atrial preparations from H 2 -TG than from WT. To understand better the signal transduction mechanism(s) involved in these arrhythmias, we studied partially depolarized left atrial preparations. In these preparations, a positive inotropic effect of histamine was still present in the additional presence of 44 mM potassium ions (used to block sodium channels) in H 2 -TG but not WT and this positive inotropic effect could be blocked by cimetidine and this is consistent with the involvement of calcium ion channels in the contractile and thus might mediate also the arrhythmogenic effects of histamine in H 2 -TG. However, compounds reported to release histamine from cells and thereby leading to arrhythmias in humans, namely morphine, ketamine, and fentanyl, failed to induce a more pronounced positive inotropic effect in atrial preparations from H 2 -TG compared to WT, arguing against an involvement of histamine release in their proarrhythmic side effects in patients. Measuring left ventricular contractility in isolated retrogradely perfused hearts (Langendorff mode), we detected under basal conditions (no drug application) more spontaneous arrhythmias in hearts from H 2 -TG than from WT. In summary, we noted that overexpression of human H 2 -histamine receptors in