Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE₁ in mice.

Abstract

Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 μM). Bay 60-7550 (1 μM), but not EHNA (10 μM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 μM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 μM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.

• Authors: Alejandro Galindo-Tovar, María Luisa Vargas, Alberto J Kaumann
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 389 Issue 2 Pg. 177-86 (Feb 2016) ISSN: 1432-1912 [Electronic] Germany
• PMID: 26531832 (Publication Type: Journal Article)

Chemical References

• Adrb1 protein, mouse
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase 4 Inhibitors
• Receptors, Adrenergic, beta-1
• Receptors, Prostaglandin E
• Cyclic AMP
• Cyclic Nucleotide Phosphodiesterases, Type 2
• Alprostadil
• Norepinephrine

Topics

• Alprostadil
• Animals
• Arrhythmia, Sinus (chemically induced, enzymology, physiopathology)
• Cyclic AMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Heart Rate (drug effects)
• Hydrolysis
• Isolated Heart Preparation
• Male
• Mice
• Norepinephrine
• Phosphodiesterase 3 Inhibitors (pharmacology, toxicity)
• Phosphodiesterase 4 Inhibitors (pharmacology, toxicity)
• Receptors, Adrenergic, beta-1 (metabolism)
• Receptors, Prostaglandin E (metabolism)
• Second Messenger Systems (drug effects)
• Tachycardia, Supraventricular (chemically induced, enzymology, physiopathology)
• Time Factors