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In addition to the adrenergic system, purinergic signaling has emerged as a relevant modulator of cardiovascular physiopathology. However, its role in hypercaloric diet-induced cardiovascular dysfunction remains incompletely understood. In this study, we investigated the effects of a hypercaloric diet on metabolic parameters, atrial purinergic modulation and vascular reactivity. Rats fed the hypercaloric diet consumed a diet with ~31% greater caloric density than control animals that received a standard (3.5 kcal\/g) pellet diet for 8 weeks. Metabolic and cardiovascular parameters were measured, and isolated right atria (RA), left atria (LA) and thoracic aortic vessels were used to evaluate function, contractility and vascular responsiveness. A hypercaloric diet significantly increased body weight and visceral adiposity, with elevated systolic blood pressure (SBP) and cardiac hypertrophy, associated with alterations in glucose levels and insulin sensitivity. In isolated atria, a hypercaloric diet increased basal contractile force in the LA. Also, ATP induced a biphasic response characterized by an initial negative inotropic effect (NIE) followed by a positive inotropic effect (PIE). A hypercaloric diet reduced ATP-mediated NIE and enhanced PIE in both atria, suggesting an altered balance between inhibitory-P1 and excitatory-P2 purinergic signaling. At the vascular level, a hypercaloric diet impaired adenosine-mediated relaxation and increased contraction, indicating vascular hyperreactivity. Collectively, these findings suggest that a hypercaloric diet induces cardiometabolic dysfunction associated with alterations in cardiovascular function linked to impaired P1\/P2 purinergic regulation, contributing to obesity-associated cardiovascular remodeling and hypertension.<\/jats:p>","DOI":"10.3390\/biology15141166","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:23:14Z","timestamp":1784193794000},"page":"1166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypercaloric Diet Induces Cardiovascular Dysfunction Through Altered Purinergic Signaling on Atrial and Vascular Contractility"],"prefix":"10.3390","volume":"15","author":[{"given":"Diego Castro","family":"Musial","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"},{"name":"Department of Medicine, Federal University of Sergipe (UFS), Aracaju 49060-108, SE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron","family":"Jurkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neide Hyppolito","family":"Jurkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-7266","authenticated-orcid":false,"given":"Guilherme H.","family":"Souza Bomfim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM\/UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"},{"name":"Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S\u00e3o Paulo (ICB\/USP), S\u00e3o Paulo 05508-000, SP, Brazil"},{"name":"Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-48382-5_1","article-title":"The Definition and Prevalence of Obesity and Metabolic Syndrome","volume":"Volume 960","author":"Engin","year":"2017","journal-title":"Obesity and Lipotoxicity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1056\/NEJMoa1014296","article-title":"Changes in diet and lifestyle and long-term weight gain in women and men","volume":"364","author":"Mozaffarian","year":"2011","journal-title":"N. 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