Initial Characterization of a Transgenic Mouse with Overexpression of the Human H₁-Histamine Receptor on the Heart

There is controversy whether H₁-histamine receptors increase or decrease contractility in the mammalian heart. Therefore, we have generated mice that overexpress the human H₁-histamine receptor in the heart (H₁-TG). We hypothesized that histamine would either increase or decrease force of contraction and beating rate compared to littermate wild type mice (WT). In H₁-TG mice, we ascertained the presence of H₁-histamine receptors by autoradiography of atrium and ventricle using [³H]mepyramine. The messenger RNA for human H₁-histamine-receptors was present in cardiac samples from H₁-TG and absent from WT. Using in-situ-hybridization, we noted mRNA for the human H₁-histamine receptor in cardiomyocytes from H₁-TG. We noted that histamine (1 nM - 10 µM cumulatively applied) in electrically stimulated (1 Hz) left atrial preparations from H₁-TG, exerted at each concentration studied a transient negative inotropic effect followed by a positive inotropic effect. Likewise, in spontaneously beating left atrial preparations from H₁-TG, we noted a transient negative chronotropic effect, followed by a positive chronotropic effect of histamine. The negative inotropic and chronotropic and the positive inotropic effects in atrial preparations from H₁-TG were attenuated by the H₁-histamine receptor antagonist mepyramine. Neither a positive inotropic effect nor a negative chronotropic effect to histamine was discernable in atrial preparations from WT. We conclude that stimulation of H₁-histamine-receptors can decrease and then increase force of contraction in the mammalian heart and stimulation of H₁-histamine-receptors exerts a negative chronotropic effect. Significance Statement We have generated transgenic mice with cardiomyocyte-specific overexpression of the human H₁-histamine receptor to contribute to the clarification of the controversy whether H₁-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H₁-histamine-receptors first decrease and then increase force of contraction in the mammalian heart, but exert only a negative chronotropic effect. .