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We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by \u03b2-blockers in animal hearts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Wild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure \u03b2-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes \u03b21 adrenergic receptor (\u03b21AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote \u03b21AR coupling to a Gi-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust \u03b21AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced \u03b21AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These observations present a novel \u03b21AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa266","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T23:39:16Z","timestamp":1599608356000},"page":"2237-2251","source":"Crossref","is-referenced-by-count":38,"title":["Carvedilol induces biased \u03b21 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility"],"prefix":"10.1093","volume":"117","author":[{"given":"Qingtong","family":"Wang","sequence":"first","affiliation":[{"name":"The Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education , Hefei 230032,","place":["China"]},{"name":"Collaborative Innovation Center of Anti-inflammatory and Immune Medicine , Hefei 230032,","place":["China"]},{"name":"Department of Pharmacology, University of California at Davis , Davis, 95616 CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California at Davis , Davis, 95616 CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7665-1860","authenticated-orcid":false,"given":"Toni 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