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Which phosphodiesterase can decrease cardiac effects of 5-HT₄ receptor activation in transgenic mice?

Joachim Neumann¹, Benedikt Käufler¹, Ulrich Gergs²

¹Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097, Halle, Germany.

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|April 25, 2019

Summary

This summary is machine-generated.

Serotonin (5-HT) increases heart contraction and rate in specific mice via cAMP. Phosphodiesterase 4 (PDE4) activity diminishes this inotropic effect, while PDE2 and PDE4 influence contraction but not heart rate.

Keywords:

5-HT4 receptor Chronotropy Inotropy Phosphodiesterase Serotonin Transgenic mice

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Area of Science:

Cardiology
Pharmacology
Molecular Biology

Background:

Serotonin (5-hydroxy-tryptamine, 5-HT) elicits concentration-dependent positive inotropic and chronotropic effects in transgenic (TG) mice overexpressing the human 5-HT4a receptor.
These effects are primarily mediated by cyclic adenosine 3',5'-monophosphate (cAMP) within TG cardiomyocytes.

Purpose of the Study:

To investigate the role of endogenous phosphodiesterases (PDEs) in antagonizing the cardiac effects of serotonin (5-HT).
To determine the specific PDE subtypes (PDE2, PDE3, PDE4) involved in modulating 5-HT-induced inotropic and chronotropic responses in TG mice.

Main Methods:

Administered selective PDE inhibitors (EHNA for PDE2, cilostamide for PDE3, rolipram for PDE4) and an unspecific inhibitor (IBMX) to TG mice.
Assessed the inotropic (force of contraction) and chronotropic (beating rate) effects of 5-HT in the presence of various PDE inhibitors and their combinations.
Compared responses in TG mice with their wild-type (WT) littermates.

Main Results:

PDE4 and PDE2 inhibitors (rolipram, EHNA) in combination with PDE3 inhibitors (cilostamide) or alone potentiated 5-HT's inotropic effects, indicating PDE4 and PDE2 regulate contraction.
Specific PDE inhibitors did not alter the potency of 5-HT to increase heart rate, suggesting chronotropic effects are independent of PDE activity.
Endogenous PDE4 activity was found to diminish the positive inotropic effect of 5-HT and basal cardiac force in TG mice.

Conclusions:

The positive chronotropic effect of 5-HT in TG mice does not involve PDE activities.
The positive inotropic effect of 5-HT and basal cardiac force in TG mice are attenuated by endogenous PDE4 activity.
Phosphorylation of PDE4 may enhance its activity when PDE2 or PDE3 are inhibited, further impacting cardiac contractility.