Phosphodiesterases 2, 3 and 4 can decrease cardiac effects of H2-histamine-receptor activation in isolated atria of transgenic mice

Joachim Neumann,Ulrich Laufs,Christian Werner,Ulrich Gergs,Rafaela Voss

doi:10.1007/s00210-021-02052-y

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.

Highlights

The effects of histamine are mediated by receptors known as H1, H2, H3, and H4-histamine receptors (Jutel et al, 2009)
T2 (=time of relaxation) amounted to 33.6 ± 0.74 ms and (n = 65) in WT and 32.3 ± 0.81 ms (n = 67) in H2-TG under basal conditions, and by 1 μM histamine remained unaltered at 33.39 ± 0.74 ms in WT and shortened to 27.71 ± 0.37 ms (n = 67) in H2-TG
DF/dTmax (=maximum rate of tension development) amounted to 302.6 ± 14.31 milli Newton (mN)/ms (n = 67) in WT and 271.9 ± 11.80 mN/ms (n = 68) in H2-TG under basal conditions, and were augmented in H2-TG but not WT by 1 μM histamine namely amounted to 267.6 ± 12.82 mN/ms (n = 67) in WT and 647.9 ± 18.96 mN/ms (n = 68) in H2-TG(compare Table 2 top)

Summary

Introduction

The effects of histamine are mediated by receptors known as H1, H2, H3, and H4-histamine receptors (Jutel et al, 2009). The cardiac H2-histamine-receptors mediate the PIE of histamine in isolated human cardiac preparations (Levi et al, 1981). These PIE in the human heart were accompanied by and probably mediated by an increase in cAMP (atrial preparations: Sanders et al, 1996). We failed to notice a PIE or PCE of histamine in WT atrium of mice (Gergs et al, 2019b, 2020) and we generated mice overexpressing human H2 receptors and in those mice detected an increase in force of contraction and the beating rate by histamine (Gergs et al, 2019b, 2020, this manuscript). In the human failing ventricle, treatment of trabeculae carneae with 3-isobutyl-1-methylxanthine (IBMX), an unspecific phosphodiesterase (PDE) inhibitor, uncovered a hidden effect: under these conditions, 5-HT elicited a PIE via 5-HT4-receptor

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Conclusion