Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model.
Action Potentials
/ drug effects
Adrenergic beta-Agonists
/ pharmacology
Animals
Calcium Signaling
/ drug effects
Cyclic AMP
/ metabolism
Cyclic Nucleotide Phosphodiesterases, Type 3
/ genetics
Cyclic Nucleotide Phosphodiesterases, Type 4
/ genetics
Excitation Contraction Coupling
/ genetics
Heart Ventricles
/ cytology
Multigene Family
Myocytes, Cardiac
/ drug effects
Phosphodiesterase 3 Inhibitors
/ pharmacology
Phosphodiesterase 4 Inhibitors
/ pharmacology
Receptors, Adrenergic, beta
/ metabolism
Swine
Journal
Journal of molecular and cellular cardiology
ISSN: 1095-8584
Titre abrégé: J Mol Cell Cardiol
Pays: England
ID NLM: 0262322
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
07
01
2019
revised:
05
05
2019
accepted:
30
05
2019
pubmed:
4
6
2019
medline:
26
6
2020
entrez:
4
6
2019
Statut:
ppublish
Résumé
Cyclic AMP phosphodiesterases (PDEs) are important modulators of the cardiac response to β-adrenergic receptor (β-AR) stimulation. PDE3 is classically considered as the major cardiac PDE in large mammals and human, while PDE4 is preponderant in rodents. However, it remains unclear whether PDE4 also plays a functional role in large mammals. Our purpose was to understand the role of PDE4 in cAMP hydrolysis and excitation-contraction coupling (ECC) in the pig heart, a relevant pre-clinical model. Real-time cAMP variations were measured in isolated adult pig right ventricular myocytes (APVMs) using a Förster resonance energy transfer (FRET) biosensor. ECC was investigated in APVMs loaded with Fura-2 and paced at 1 Hz allowing simultaneous measurement of intracellular Ca Our results show that PDE4 controls ECC in APVMs and suggest that PDE4 inhibitors exert inotropic and pro-arrhythmic effects upon PDE3 inhibition or β-AR stimulation in our pre-clinical model. Thus, PDE4 inhibitors should be used with caution in clinics as they may lead to arrhythmogenic events upon stress.
Identifiants
pubmed: 31158360
pii: S0022-2828(19)30112-9
doi: 10.1016/j.yjmcc.2019.05.025
pii:
doi:
Substances chimiques
Adrenergic beta-Agonists
0
Phosphodiesterase 3 Inhibitors
0
Phosphodiesterase 4 Inhibitors
0
Receptors, Adrenergic, beta
0
Cyclic AMP
E0399OZS9N
Cyclic Nucleotide Phosphodiesterases, Type 3
EC 3.1.4.17
Cyclic Nucleotide Phosphodiesterases, Type 4
EC 3.1.4.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
57-66Informations de copyright
Copyright © 2019. Published by Elsevier Ltd.