Contractile Effects of Histamine in Mice Overexpressing H1-Histamine and H2-Histamine Receptors in the Atrium.

Abstract

To identify the functional roles of human H1-histamine and H2-histamine receptors when they coexist in the heart, we crossbred mice that overexpressed human H1-histamine receptors only in the heart (H1-TG) with mice that overexpressed human H2-histamine receptors only in the heart (H2-TG) to obtain double transgenic mice (H1xH2-TG) and compared them with wild type (WT) mice. We measured the force of contraction (FOC) in isolated, electrically stimulated left atrial (LA) preparations and spontaneously beating right atrial (RA) preparations. We noted that when cumulatively applied (1 nM - 30 µM), histamine did not affect the force of contraction in the LA of WT mice. In H1xH2-TG mice, low concentrations (30 nM - 1 µM) of histamine increased the FOC in the LA, whereas higher concentrations (3 µM, 10 µM, 30 µM) of histamine reduced the FOC in the LA. Likewise, histamine in low concentrations (10 nM and higher) increased the beating rate in the RA, while higher concentrations of histamine (3 µM, 10 µM) reduced the beating rate in the RA. Dimaprit, an H2-histamine receptor agonist increased the force of contraction in the LA of H1xH2-TG mice but not in the LA of WT mice. 2-2-thiazol-ethan-amine (ThEA) an H1-histamine receptor agonist, increased the FOC in the LA of H1xH2-TG mice but not in the LA of WT mice. These data indicate that histamine, at least under our experimental conditions, at lower concentrations activates cardiac H2-histamine receptors, and at higher concentrations activated H1-histamine receptors.