β₁- and β₂-adrenergic receptor mediated spontaneous contractions and ryanodine receptor channel opening in human failing heart.

Authors

Weilan Mo, Nicole A Beard, Katherine T Gillette-Browne, Karen Hay, Elizabeth Cheesman, Alexander Dashwood, Melanie Spratt, Annalese B Semmler, Yee Weng Wong, Haris Haqqani, Derek R Laver, Torsten Christ, Kafa Walweel, Peter Molenaar

Published in

Naunyn-Schmiedeberg's archives of pharmacology. Aug 01, 2026. Epub Aug 01, 2026.

Abstract

In heart failure, β-adrenergic receptor (β-AR)-Gsα-cAMP-protein kinase A (PKA) signalling predisposes to delayed-afterdepolarisation-mediated arrhythmias. Phosphodiesterases (PDEs) hydrolyse cAMP, and PDE3 restrains β₁-AR, β₂-AR-mediated inotropic responses in failing hearts from β-blocker-treated patients. Whether these receptors provoke arrhythmias through ryanodine receptor (RyR2) dysregulation, and how PDE activity and prior β-blockade treatment modify this, is undefined. We sought to define how β₁-AR and β₂-AR activation provokes arrhythmias through RyR2 mechanisms in explanted human failing hearts, and how PDE activity and prior β-blocker therapy modulate this response. A diastolic model of ventricular arrhythmia using human right ventricular trabeculae with pacing stopped was used. Trabeculae were exposed to (-)-noradrenaline/(-)-adrenaline to activate β₁-AR/β₂-AR respectively with or without PDE inhibitors and monitored for spontaneous contractions. In parallel, sarcoplasmic reticulum vesicles from trabeculae were used to assess RyR2 channel function, phosphorylation and oxidation. Activation of β₁-AR or β₂-AR increased the frequency of spontaneous contractions, concomitant increases in diastolic RyR2 channel opening, phosphorylation and oxidation. Trabeculae from carvedilol-treated patients showed fewer β₂-AR-mediated spontaneous contractions than those treated with β₁-AR blockers. The PDE3 inhibitor cilostamide augmented β₂-AR-mediated spontaneous contractions, RyR2 channel opening and Ser2808 phosphorylation. In human failing heart, β₁-AR or β₂-AR activation increased arrhythmic contractions associated with greater diastolic RyR2 channel opening, phosphorylation and oxidation. PDE3 attenuated β₂-AR-mediated arrhythmic contractions, RyR2 channel opening and Ser2808 hyperphosphorylation. These findings suggest that combining β₁- and β₂-AR blockade with strategies that reduce RyR2 Ca²⁺ leak and preserve RyR2-associated PDE3 activity may improve arrhythmia control in heart failure.

PMID:
42538423
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.

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