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

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.