Phosphodiesterases 2, 3 and 4 can decrease cardiac effects of H 2-histamine-receptor activation in isolated atria of transgenic mice

Abstract

Histamine exerts cAMP-dependent positive inotropic effects (PIE) and positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic mice which overexpress the human H2-receptor in the heart (=H2-TG). To determine whether these effects are antagonized by phosphodiesterases (PDEs), contractile studies were done in isolated left and right atrial preparations of H2-TG. The contractile effects of histamine were tested in the additional presence of the PDE-inhibitorserythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 1 μM, PDE2-inhibitor) or cilostamide (1 μM, PDE3-inhibitor), rolipram (10 μM, a PDE4-inhibitor), and their combinations. Cilostamide (1 μM) and EHNA (1 μM), rolipram (1 μM), and EHNA (1 μM) and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of histamine to elevate the force of contraction (FOC) in H2-TG. Cilostamide (1 μM) and rolipram (10 μM) alone increased and EHNA (1 μM) decreased alone, and their combination increased the potency of histamine to increase the FOC in H2-TG indicating that PDE3 and PDE4 regulate the inotropic effects of histamine in H2-TG. The PDE inhibitors (EHNA, cilostamide, rolipram) alone did not alter the potency of histamine to increase the heart beat in H2-TG whereas a combination of rolipram, cilostamide, and EHNA, or of rolipram and EHNA increased the potency of histamine to act on the beating rate. In summary, the data suggest that the PCE of histamine in H2-TG atrium involves PDE 2 and 4 activities, whereas the PIE of histamine are diminished by activity of PDE 3 and 4.