Initial characterization of a transgenic mouse with overexpression of the human H 1 -histamine receptor on the heart.

There is controversy whether H 1 -histamine receptors increase or decrease contractility in the mammalian heart. Therefore, we have generated mice that overexpress the human H 1 -histamine receptor in the heart (H 1 -TG). We hypothesized that histamine would either increase or decrease force of contraction and beating rate compared to littermate wild type mice (WT). In H 1 -TG mice, we ascertained the presence of H 1 -histamine receptors by autoradiography of atrium and ventricle using [ 3 H]mepyramine. The messenger RNA for human H 1 -histamine-receptors was present in cardiac samples from H 1 -TG and absent from WT. Using in-situ-hybridization, we noted mRNA for the human H 1 -histamine receptor in cardiomyocytes from H 1 -TG. We noted that histamine (1 nM - 10 µM cumulatively applied) in electrically stimulated (1 Hz) left atrial preparations from H 1 -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 H 1 -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 H 1 -TG were attenuated by the H 1 -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 H 1 -histamine-receptors can decrease and then increase force of contraction in the mammalian heart and stimulation of H 1 -histamine-receptors exerts a negative chronotropic effect. Significance Statement We have generated transgenic mice with cardiomyocyte-specific overexpression of the human H 1 -histamine receptor to contribute to the clarification of the controversy whether H 1 -histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H 1 -histamine-receptors first decrease and then increase force of contraction in the mammalian heart, but exert only a negative chronotropic effect. .