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Phosphodiesterases (PDEs) hydrolyse cAMP, and PDE3 restrains \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR, \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR-mediated inotropic responses in failing hearts from \u03b2-blocker-treated patients. Whether these receptors provoke arrhythmias through ryanodine receptor (RyR2) dysregulation, and how PDE activity and prior \u03b2-blockade treatment modify this, is undefined.\u00a0We sought to define how \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR activation provokes arrhythmias through RyR2 mechanisms in explanted human failing hearts, and how PDE activity and prior \u03b2-blocker therapy modulate this response.\u00a0A diastolic model of ventricular arrhythmia using human right ventricular trabeculae with pacing stopped was used. Trabeculae were exposed to (-)-noradrenaline\/(-)-adrenaline to activate \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR\/\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -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.\u00a0Activation of \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR or \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR increased the frequency of spontaneous contractions, concomitant increases in diastolic RyR2 channel opening, phosphorylation and oxidation. Trabeculae from carvedilol-treated patients showed fewer \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR-mediated spontaneous contractions than those treated with \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR blockers. The PDE3 inhibitor cilostamide augmented \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR-mediated spontaneous contractions, RyR2 channel opening and Ser2808 phosphorylation.\u00a0In human failing heart, \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR or \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR activation increased arrhythmic contractions associated with greater diastolic RyR2 channel opening, phosphorylation and oxidation. PDE3 attenuated \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR-mediated arrhythmic contractions, RyR2 channel opening and Ser2808 hyperphosphorylation. These findings suggest that combining \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    - and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR blockade with strategies that reduce RyR2 Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak and preserve RyR2-associated PDE3 activity may improve arrhythmia control in heart failure.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    The arrhythmogenic human failing heart. Figure shows \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR, \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR mediated arrhythmia mechanisms in human HF. Activated \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    -AR or \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR couple to the Gs\u03b1-protein-adenylyl cyclase signalling pathway to increase cyclic AMP, activation of PKA with consequent phosphorylation of RyR2. Other changes to RyR2 include oxidation and dissociation of FKBP12.6 (Walweel et al. 2017;\u00a0Denniss et al. 2020). The changes contribute to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak from the sarcoplasmic reticulum through RyR2 during diastole to cause outward transport of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/inward transport of Na\n                    <jats:sup>+<\/jats:sup>\n                    through the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/Ca\n                    <jats:sup>2+<\/jats:sup>\n                    exchanger resulting in DAD induced action potentials, depolarization of the myocyte and arrhythmic contractions (Walweel et al. 2017;\u00a0Denniss et al. 2020). The \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -AR pathway that mediates arrhythmia generation is under the control of PDE3 (this paper).\u00a0\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05768-x","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:47:05Z","timestamp":1785548825000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b21- and \u03b22-adrenergic receptor mediated spontaneous contractions and ryanodine receptor channel opening in human failing heart"],"prefix":"10.1007","author":[{"given":"Weilan","family":"Mo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A.","family":"Beard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine T.","family":"Gillette-Browne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Hay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Cheesman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Dashwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Spratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalese B.","family":"Semmler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee Weng","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haris","family":"Haqqani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek R.","family":"Laver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Christ","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-5767","authenticated-orcid":false,"given":"Kafa","family":"Walweel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Molenaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"5768_CR1","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1161\/CIRCRESAHA.109.197947","volume":"105","author":"A Abi-Gerges","year":"2009","unstructured":"Abi-Gerges A, Richter W, Lefebvre F et al (2009) Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on beta-adrenergic cAMP signals. 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