Hypercaloric Diet Induces Cardiovascular Dysfunction Through Altered Purinergic Signaling on Atrial and Vascular Contractility

Hypercaloric diet and obesity are strongly associated with cardiovascular dysfunction, diabetes and hypertension development mediated by sympathetic nervous system hyperactivity. 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.