Initial Characterization of a Transgenic Mouse with Overexpression of the Human H 1 -Histamine Receptor on the Heart.

There is a debate on whether H 1 -histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H 1 -histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H 1 -histamine receptors (H 1 -TG) and compared these findings with those in littermate wild-type mice (WT). In H 1 -TG mice, we studied the presence of H 1 -histamine receptors by autoradiography of the atrium and ventricle using [ 3 H]mepyramine. The messenger RNA for human H 1 -histamine receptors was present in the heart from H 1 -TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H 1 -histamine receptor in cardiac cells from H 1 -TG. We noted that histamine (1 nM-10 µ M) in paced (1 Hz) left atrial preparations from H 1 -TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H 1 -TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H 1 -TG were attenuated by the H 1 -histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H 1 -histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H 1 -histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H 1 -histamine receptor to contribute to the clarification of the controversy on 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 raise contractile force in the mammalian heart but exert solely negative chronotropic effects.