Imipramine Can Block Human Cardiac H1-Histamine Receptors

Imipramine was one of the first antidepressant drugs that entered the clinic and is still used to this day. The antidepressant action of imipramine is, at least in part, due to an inhibition of noradrenaline and serotonin transport in the brain. Binding studies indicated that imipramine binds to H ₁ -histamine receptors with high affinity. We have recently generated mice that overexpress the human H ₁ -histamine receptor in the heart (H ₁ -TG). Upon stimulation of these hearts with H ₁ -histamine receptor agonists, a positive inotropic effect was observed that was reversed by mepyramine, a selective H ₁ -histamine receptor antagonist. Moreover, we have recently described that stimulation of H ₁ -histamine receptors in the human atrium also increases force of contraction which was likewise reversed by mepyramine. Consequently, we investigated whether these H ₁ -histamine receptor-mediated increases of force in atria from H ₁ -TG and human atrium could be reversed by imipramine. We stimulated H ₁ -histamine receptors in atria from H ₁ -TG and noted that imipramine, starting at 100 nM, reduced force of contraction. To study imipramine in the human heart, we obtained human right atrial muscle preparations from adult patients succumbing to cardiac bypass surgery. Like in H ₁ -TG, imipramine, starting at 300 nM, antagonized the positive inotropic effects of H ₁ -histamine receptor stimulation in human atrial preparations. We conclude that imipramine can antagonize H ₁ -histamine receptor mediated positive inotropic effects in the mammalian atrium in general and, of note, in the human atrium. This may explain cardiac side effects of imipramine.